Spiro compound

Abstract

The present invention provides compounds that bind to the universally expressed E3 ligase protein cereblon (CRBN), and their use 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 April 16, 2019, application number 201980040368.1, and invention name “Spirocyclic Compounds”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of European Patent Application No. EP18167561 filed on April 16, 2018 and European Patent Application No. EP18168269 filed on April 19, 2018. The entire contents of these applications 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 nevertheless 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] Other compound publications include: US2012 / 071459; WO 2003 / 020721; WO 2011 / 025690; WO2012 / 176123; WO 2013 / 020557; WO 2013 / 063560; WO 2013 / 106643; WO 2013 / 124026; WO2015 / 031036; WO 2015 / 160845; WO 2016 / 011906; WO 2016 / 022644; WO 2016 / 105518; WO2017 / 007612; WO 2017 / 024318; WO 2017 / 117473;WO 2017 / 189386;WO 2018 / 005591; U.S. Patent No. 9,206,142.

[0014] 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

[0015] 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).

[0016] 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.

[0017] The present invention includes novel compounds of Formula Ia, Formula Ib, Formula II, Formula IIIa, Formula IIIb, Formula IV, Formula V, Formula VI, Formula VIII, Formula IX, Formula X, Formula XI, and Formula XII. In addition, the present invention includes the use of compounds generally in Formula VII and Formula XIII for treating conditions that can be treated by modulating the function or activity of a cereblon-containing E3 ubiquitin ligase protein complex. The present invention also includes the use of compounds generally in Formula XIV and Formula XV in the preparation of bifunctional compounds that degrade target proteins through the ubiquitin proteasome pathway (UPP). The present invention also includes formula XIV-a, formula XIV-b, formula XIV-c, formula XIV-d, formula XIV-e, formula XIV-f, formula XIV-g, formula XIV-h, formula XIV-i, formula XIV-j, formula XIV-k, formula XIV-l, formula XIV-m, formula XIV-n, formula XIV-o, formula XIV-p, formula XIV-q, formula XIV-r, formula XIV-s, formula XIV-t, Compounds of formula XIV-u, formula XIV-v, formula XIV-w, formula XIV-x, formula XV-a, formula XV-b, formula XV-c, formula XV-d, formula XV-e, formula XV-f, formula XV-g, formula XV-h, formula XV-i, formula XV-j, formula XV-k, formula XV-m, formula XV-n, formula XV-o, formula XV-p, formula XV-q, formula XV-r, formula XV-s, and formula XV-t.

[0018] In one aspect, provided are compounds of Formula Ia or Formula Ib:

[0019]

[0020]

[0021] or a pharmaceutically acceptable salt thereof;

[0022] in:

[0023] X 1a is selected from aryl and R 2a substituted aryl;

[0024] X 1b is selected from aryl and R 2b substituted aryl;

[0025] R 1 Does not exist or is =O;

[0026] R 2a Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; -OH; and -NO2; and

[0027] R 2b Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; and -NO2.

[0028] In another aspect, provided is a compound of Formula II:

[0029]

[0030] or a pharmaceutically acceptable salt thereof;

[0031] in:

[0032] X 2a is selected from heterocyclic groups, R 3 Substituted heterocyclic group, heteroaryl group, R 4 substituted heteroaryl, and C 1-6 -alkyl;

[0033] R 3 Selected from -C(=O)-C 1-6 -alkyl and =O;

[0034] R 4 Selected from -C(=O)-OC 1-6 -alkyl; C 1-6 Alkyl; -NH2; -NH-C(=O)-C 1-6 -alkyl; and –NO2;

[0035] and all other variables are as defined herein.

[0036] In another aspect, a compound of Formula IIIa or Formula IIIb is provided:

[0037]

[0038]

[0039] or a pharmaceutically acceptable salt thereof;

[0040] in:

[0041] X 1c is selected from aryl and R 2c substituted aryl;

[0042] X 1d is selected from aryl and R 2d substituted aryl;

[0043] R 2c Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; and –NO2;

[0044] R 2d Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; and –NO2;

[0045] and all other variables are as defined herein.

[0046] In another aspect, a compound of formula IV is provided:

[0047]

[0048] or a pharmaceutically acceptable salt thereof;

[0049] in:

[0050] X 3a is selected from hydrogen, heterocyclic, R 3 Substituted heterocyclic group, heteroaryl group, R 4 substituted heteroaryl, and C 1-6 -alkyl;

[0051] and all other variables are as defined herein.

[0052] In another aspect, provided are compounds of Formula V or VI:

[0053]

[0054]

[0055] or a pharmaceutically acceptable salt thereof;

[0056] in:

[0057] X 4a is selected from hydrogen, aryl, R 2 Substituted aryl, heterocyclic, R 3 Substituted heterocyclic group, heteroaryl group, R 4 substituted heteroaryl, and C 1-6 -alkyl;

[0058] R 2 Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; -OH; and –NO2;

[0059] R 5 C 1-6 -alkyl;

[0060] and all other variables are as defined herein.

[0061] In another aspect, there is provided the use of a compound of formula VII for treating a therapeutic condition treatable by modulating the function or activity of a cereblon containing E3 ubiquitin ligase protein complex:

[0062]

[0063] or a pharmaceutically acceptable salt thereof;

[0064] in:

[0065] Y A Not present or selected from: -C(=O)-; -C(=O)-C(H,C 1-6 -alkyl)-; and -C(=O)-CH2-;

[0066] X A Selected from: hydrogen; aryl; 2 Substituted aryl, heterocyclic, R 3 Substituted heterocyclic group, heteroaryl group, R 4 substituted heteroaryl, and C 1-6 -alkyl;

[0067] If Y A If it does not exist, then X A It cannot be hydrogen;

[0068] and all other variables are as defined herein.

[0069] In another aspect, provided is a compound of formula VIII:

[0070]

[0071] or a pharmaceutically acceptable salt thereof;

[0072] in:

[0073] A is selected from CH2 and NH;

[0074] X 5a For R 6a substituted aryl; and

[0075] R 6a Selected from: -C(=O)-OH; -NH-C(=O)-C 1-6 -alkyl; and –NO 。

[0076] In another aspect, provided is a compound of Formula IX:

[0077]

[0078] or a pharmaceutically acceptable salt thereof;

[0079] Where X 6a is an aryl group substituted with -C(=O)-OH.

[0080] In another aspect, a compound of formula X is provided:

[0081]

[0082] or a pharmaceutically acceptable salt thereof;

[0083] in:

[0084] X B Selected from: aryl; 6 substituted aryl; heteroaryl; and 7 substituted heteroaryl;

[0085] R 6 Selected from: -C(=O)-OH; -NH-C(=O)-C 1-6 -alkyl; -NH2; and -NO2; and

[0086] R 7 Selected from: -C(=O)-OH; -C(=O)-OC 1-6 -alkyl; -NH2; and -NO2.

[0087] In another aspect, a compound of Formula XI is provided:

[0088]

[0089] or a pharmaceutically acceptable salt thereof;

[0090] Where X 7a is selected from heteroaryl and R 7 Substituted heteroaryl.

[0091] In another aspect, provided is a compound of Formula XII:

[0092]

[0093] or a pharmaceutically acceptable salt thereof;

[0094] in:

[0095] Y B Absent or –C(=O)-;

[0096] X 8a For R 7a substituted heteroaryl; and

[0097] R 7a Selected from -C(=O)-OH and -C(=O)-OC 1-6 -alkyl.

[0098] In another aspect, there is provided the use of a compound of formula XIII for treating a therapeutic condition treatable by modulating the function or activity of a cereblon containing E3 ubiquitin ligase protein complex:

[0099]

[0100] or a pharmaceutically acceptable salt thereof;

[0101] wherein all variables are as defined herein.

[0102] The compounds of Formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VIII, IX, X, XI, and XII 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.

[0103] In certain embodiments, the invention provides for administering an effective amount of a compound of Formula Ia, Ib, II, IIIa, IIIb, IV, V, VI, VIII, IX, X, XI and XII 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.

[0104] 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.

[0105] Thus, provided are compounds of Formula XIV or XV, or pharmaceutically acceptable salts thereof, which can be used to prepare compounds that can cause selected protein degradation via UPP:

[0106]

[0107] in:

[0108] X A1 is selected from arylene, heterocyclylene, heteroarylene, and C 1-6 - alkylene;

[0109] X B1 is selected from arylene and heteroarylene;

[0110] 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

[0111] 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;

[0112] In one embodiment, the "tail" is "T",

[0113] Where "T" is

[0114] X 1 Selected from key, NR 34 , CH2, CHR 34 , C(R 34 )2, O, and S;

[0115] 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, -NR 34 C(O)alkyne, cyano, -SC(O)alkyl, OC(O)alkyl, heterocycle, -C(O)OH, hydrogen, alkyl, aryl, heteroaryl, aliphatic, heteroaliphatic, and carbocycle;

[0116] 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 ;

[0117] 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;

[0118] 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)(OR26 )-,-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.

[0119] 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;

[0120] 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;

[0121] R 26 is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic;

[0122] 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;

[0123] 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

[0124] All other variables are as defined herein.

[0125] In one aspect, a compound of one of the following formulae is provided:

[0126]

[0127]

[0128]

[0129] or a pharmaceutically acceptable salt thereof;

[0130] Where T is and all other variables are as defined herein.

[0131] In another aspect, a compound of one of the following formulae is provided:

[0132]

[0133]

[0134] or a pharmaceutically acceptable salt thereof;

[0135] wherein all variables are as defined herein.

[0136] In a first aspect, the present invention provides 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, and XV-a to XV-t as defined herein for use as therapeutically active substances.

[0137] In a further aspect, the present invention provides a pharmaceutical composition comprising 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, and XV-a to XV-t as defined herein and a therapeutically inert carrier.

[0138] In certain embodiments, 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, and XV-a to XV-t 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 Ia, Ib, II, IIIa, IIIb, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XIV-a to XIV-x, and XV-a to XV-t include one deuterium or more deuterium atoms.

[0139] The compounds of the present invention are useful for the therapeutic and / or prophylactic treatment of cancer.

[0140] 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 said protein.

[0141] Other features and advantages of the application will be apparent from the following detailed description, and from the claims.

[0142] Therefore, the present invention includes at least the following features:

[0143] a) a compound of Formula Ia, Formula Ib, Formula II, Formula IIIa, Formula IIIb, Formula IV, Formula V, Formula VI, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-t, or a pharmaceutically acceptable salt thereof;

[0144] b) use of an 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, 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;

[0145] c) 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, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a medical condition as further described herein;

[0146] 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 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 is used in the preparation;

[0147] e) 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, 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;

[0148] f) Use of a compound 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, and Formula XV-a to XV-t, 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);

[0149] 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 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 is used in the preparation;

[0150] h) a compound 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, or a pharmaceutically acceptable salt thereof, which can be used to treat a tumor in a host, including any tumor described herein;

[0151] i) Use of a compound 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, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a tumor in a host (including any tumor described herein);

[0152] 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 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 is used in the preparation;

[0153] k) a compound 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, or a pharmaceutically acceptable salt thereof, which can be used to treat an immune, autoimmune or inflammatory disorder in a host;

[0154] l) Use of a compound 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, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating an immune, autoimmune or inflammatory disorder in a host;

[0155] 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 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 is used in the preparation;

[0156] n) a pharmaceutical preparation comprising an effective amount of a compound 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, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent;

[0157] o) 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 in an enantiomerically or diastereomerically (as relevant) enriched form, including as an isolated enantiomer or diastereomer (i.e., greater than 85, 90, 95, 97 or 99% pure);

[0158] p) a method for preparing a therapeutic product containing an 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, or a pharmaceutically acceptable salt thereof; and

[0159] q) A method for preparing a bifunctional compound that degrades a selected protein via the ubiquitin proteasome pathway, characterized in that a compound of formula XIV, formula XV, formula XIV-a to XIV-x, or formula XV-a to XV-t is used in the preparation of the bifunctional compound.

[0160] The present invention also relates to the following items:

[0161] 1. A compound selected from the group consisting of:

[0162]

[0163] or a pharmaceutically acceptable salt thereof;

[0164] in:

[0165] A is selected from CH2 and NH;

[0166] X 1a is selected from aryl and R 2a substituted aryl;

[0167] X 1b is selected from aryl and R 2b substituted aryl;

[0168] X 1c Selected from aryl and R 2c substituted aryl;

[0169] X 1d Selected from aryl and R 2d substituted aryl;

[0170] X 2a is selected from heterocyclic groups, R 3 Substituted heterocyclic group, heteroaryl group, R 4 substituted heteroaryl, and C 1-6 -alkyl;

[0171] X 3a is selected from hydrogen, heterocyclic, R 3 Substituted heterocyclic group, heteroaryl group, R 4 substituted heteroaryl, and C 1-6 -alkyl;

[0172] X4a is selected from hydrogen, aryl, R 2 Substituted aryl, heterocyclic, R 3 Substituted heterocyclic group, heteroaryl group, R 4 substituted heteroaryl, and C 1-6 -alkyl;

[0173] X 5a For R 6a substituted aryl;

[0174] X 6a is an aryl group substituted with -C(=O)-OH;

[0175] X 7a is selected from heteroaryl and R 7 substituted heteroaryl;

[0176] X 8a For R 7a substituted heteroaryl;

[0177] X B Selected from: aryl; 6 substituted aryl; heteroaryl; and 7 substituted heteroaryl;

[0178] Y B Absent or –C(=O)-;

[0179] R 1 Does not exist or is = O;

[0180] R 2 Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; -OH; and –NO2;

[0181] R 2a Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; -OH; and –NO2;

[0182] R 2b Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; and –NO2;

[0183] R 2c Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; and –NO2;

[0184] R 2d Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; and –NO2;

[0185] R 3 Selected from -C(=O)-C 1-6 -alkyl and =O;

[0186] R 4 Selected from -C(=O)-OC 1-6 -alkyl; C 1-6 Alkyl; -NH2; -NH-C(=O)-C 1-6 -alkyl; and –NO2;

[0187] R 5 C 1-6 -alkyl;

[0188] R 6 Selected from: -C(=O)-OH; -NH-C(=O)-C 1-6 -alkyl; -NH2; and –NO2;

[0189] R 6a Selected from: -C(=O)-OH; -NH-C(=O)-C 1-6 -alkyl; and –NO2;

[0190] R 7 Selected from: -C(=O)-OH; -C(=O)-OC 1-6 -alkyl; -NH2; and -NO2; and

[0191] R 7a Selected from -C(=O)-OH and -C(=O)-OC 1-6 -alkyl.

[0192] 2. The compound of item 1, wherein the compound is of the following formula:

[0193]

[0194] 3. The compound of item 1, wherein the compound is of the following formula:

[0195]

[0196] 4. The compound of item 1, wherein the compound is of the following formula:

[0197]

[0198] 5. The compound of item 1, wherein the compound is selected from:

[0199]

[0200] 6. The compound of item 1, wherein the compound is of the following formula:

[0201] 7. The compound of item 1, wherein the compound is of the following formula:

[0202] 8. The compound of item 1, wherein the compound is selected from:

[0203]

[0204] 9. The compound of item 1, wherein the compound is selected from:

[0205]

[0206] 10. The compound of item 1, wherein the compound is selected from:

[0207]

[0208] 11. The compound described in any one of item 1 or 2, wherein R 2a is –NO2.

[0209] 12. The compound described in any one of items 1, 5 or 8-10, wherein R 4 is –NH2.

[0210] 13. The compound described in any one of items 1, 5 or 8-10, wherein R 4 is –NO2.

[0211] 14. The compound described in any one of items 1, 5 or 8-10, wherein R 4 –C(=O)-OC 1-6 -alkyl.

[0212] 15. The compound of any one of items 1, 5 or 8-10, wherein R 4 C 1-6 -alkyl.

[0213] 16. The compound of any one of items 1, 5 or 8-10, wherein R 4 is –NH-C(=O)-C 1-6 -alkyl.

[0214] 17. The compound described in any one of item 1 or 8, wherein R 3 is –C(=O)-C 1-6-alkyl.

[0215] 18. The compound described in any one of item 1 or 8, wherein R 3 is =O.

[0216] 19. The compound of item 1, wherein the compound is selected from:

[0217]

[0218] 20. The compound of item 1, wherein the compound is selected from:

[0219]

[0220] 21. The compound of item 1, wherein the compound is selected from:

[0221]

[0222] 22. The compound of item 1, wherein the compound is selected from:

[0223]

[0224] 23. The compound according to item 1, wherein the compound is of the following formula:

[0225]

[0226] 24. The compound described in any one of items 1 or 19, wherein R 6a is –NO2.

[0227] 25. The compound described in any one of items 1 or 21, wherein R 6 is –NH-C(=O)-C 1-6 -alkyl.

[0228] 26. The compound described in any one of items 1 or 21, wherein R 6 is –NO2.

[0229] 27. The compound described in any one of items 1, 21 or 22, wherein R 7 –C(=O)-OC 1-6 -alkyl.

[0230] 28. The compound described in any one of items 1, 21 or 22, wherein R 7 is –NO2.

[0231] 29. The compound described in any one of items 1 or 22, wherein R 7a is –NO2.

[0232] 30. The compound according to item 1, which is selected from:

[0233]

[0234] or a pharmaceutically acceptable salt thereof.

[0235] 31. The compound according to item 1, which is selected from:

[0236]

[0237]

[0238] or a pharmaceutically acceptable salt thereof.

[0239] 32. The compound according to item 1, which is selected from:

[0240]

[0241] or a pharmaceutically acceptable salt thereof.

[0242] 33. The compound according to item 1, which is selected from:

[0243]

[0244]

[0245] or a pharmaceutically acceptable salt thereof.

[0246] 34. The compound according to item 1, which is selected from:

[0247]

[0248] or a pharmaceutically acceptable salt thereof.

[0249] 35. Compounds of formula XIV or XV:

[0250]

[0251]

[0252] or a pharmaceutically acceptable salt thereof;

[0253] in:

[0254] X A1 is selected from arylene, heterocyclylene, heteroarylene, and C 1-6 - alkylene;

[0255] X B1 is selected from arylene and heteroarylene;

[0256] Y ANot present or selected from: -C(=O)-; -C(=O)-C(H,C 1-6 -alkyl)-; and -C(=O)-CH2-;

[0257] Y B Absent or –C(=O)-;

[0258] The "tail" is "T";

[0259] "T" is

[0260] X 1 Selected from key, NR 34 , CH2, CHR 34 , C(R 34 )2, O, and S;

[0261] 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 carbocycle;

[0262] 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 ;

[0263] R 36is 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;

[0264] 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-;

[0265] The R 20 , R 21 , R 22 , R 23 and R 24 Each optionally selected from R 101 Substituents are substituted;

[0266] Where R 20 , R 21 , R 22 , R 23 and R 24 At least one of them is not a bond;

[0267] 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;

[0268] R 26 is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic;

[0269] 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

[0270] R 40at 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.

[0271] 36. The compound of item 35, wherein the compound is selected from:

[0272]

[0273]

[0274]

[0275] or a pharmaceutically acceptable salt thereof.

[0276] 37. The compound of item 35, wherein the compound is selected from:

[0277]

[0278]

[0279] or a pharmaceutically acceptable salt thereof.

[0280] 38. 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 1-37, or a pharmaceutically acceptable salt thereof.

[0281] 39. The method of claim 38, wherein the abnormal cell proliferation is cancer.

[0282] 40. The method of claim 38, wherein the abnormal cell proliferation is a tumor.

[0283] 41. The method of claim 38, wherein the abnormal cell proliferation is multiple myeloma.

[0284] 42. Use of a compound according to any one of items 1 to 37 or a pharmaceutically acceptable salt thereof for treating abnormal cell proliferation in a subject in need thereof.

[0285] 43. Use of a compound according to any one of items 1 to 37 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating abnormal cell proliferation in a subject in need thereof.

[0286] 44. The use of any one of items 42 or 43, wherein the abnormal cell proliferation is cancer.

[0287] 45. The use of any one of items 42 or 43, wherein the abnormal cell proliferation is a tumor.

[0288] 46. ​​The use of any one of items 42 or 43, wherein the abnormal cell proliferation is multiple myeloma.

[0289] 48. A compound according to any one of items 1 to 37 for use in treating abnormal cell proliferation in a subject in need thereof.

[0290] 49. The compound of claim 48, wherein the abnormal cell proliferation is cancer.

[0291] 50. The compound of claim 48, wherein the abnormal cell proliferation is a tumor.

[0292] 51. The compound of claim 48, wherein the abnormal cell proliferation is multiple myeloma.

[0293] 52. A method of treating abnormal cell proliferation in a subject in need thereof, comprising administering an effective amount of a compound of Formula VII or Formula XIII:

[0294]

[0295] or a pharmaceutically acceptable salt thereof;

[0296] in:

[0297] A is selected from CH2 and NH;

[0298] Y A Not present or selected from: -C(=O)-; -C(=O)-C(H,C 1-6 -alkyl)-; and -C(=O)-CH2-;

[0299] Y B Absent or –C(=O)-;

[0300] X A Selected from: hydrogen; aryl; 2 Substituted aryl; heterocyclic group; R 3 Substituted heterocyclic group; heteroaryl; R 4 substituted heteroaryl; and C 1-6 -alkyl;

[0301] X B Selected from: aryl; 6 substituted aryl; heteroaryl; and7 substituted heteroaryl;

[0302] If Y A If it does not exist, then X A It cannot be hydrogen;

[0303] R 1 Does not exist or is = O;

[0304] R 2 Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; -OH; and –NO2;

[0305] R 3 Selected from -C(=O)-C 1-6 -alkyl and =O;

[0306] R 4 Selected from -C(=O)-OC 1-6 -alkyl; C 1-6 Alkyl; -NH2; -NH-C(=O)-C 1-6 -alkyl; and –NO2;

[0307] R 6 Selected from: -C(=O)-OH; -NH-C(=O)-C 1-6 -alkyl; -NH2; and -NO2; and

[0308] R 7 Selected from: -C(=O)-OH; -C(=O)-OC 1-6 -alkyl; -NH2; and -NO2.

[0309] 53. The method of claim 52, wherein the abnormal cell proliferation is cancer.

[0310] 54. The method of claim 52, wherein the abnormal cell proliferation is a tumor.

[0311] 55. The method of claim 52, wherein the abnormal cell proliferation is multiple myeloma.

[0312] 56. A pharmaceutical composition comprising an effective amount of a compound according to any one of items 1 to 37, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. DETAILED DESCRIPTION

[0313] I. Definitions

[0314] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those of ordinary skill in the art to which the application belongs. In the specification, unless the context clearly specifies otherwise, the singular also includes the plural. Although methods and materials similar or equivalent to those described herein can be used for the practice or testing of the present application, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not considered to be the prior art of the application claimed. In the event of a conflict, this specification (including definitions) will prevail. In addition, materials, methods and embodiments are illustrative only and are not intended to be limiting.

[0315] The following definitions of general terms used in this specification apply regardless of whether the term in question appears alone or in combination with other groups.

[0316] 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.

[0317] The compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0318] The compounds of any formula described herein may be in the form of racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, isomers such as rotamers, as if each is explicitly described, unless clearly excluded by the context.

[0319] The compounds of the present invention can form solvates with solvents (including water). Therefore, in a non-limiting embodiment, the present invention includes solvated forms of compounds. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salt) and one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be isotopically substituted (e.g., D2O, d6-acetone, d6-DMSO). Solvates can be in liquid or solid form.

[0320] 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.

[0321] 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 yl, isoxazolyl, benzofuranyl, isothiazolyl, benzothiophenyl, indolinyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydropyrrolidinepyridinyl, dihydronaphthypyridinyl, chromanyl, tetrahydroquinolinyl, dihydrocyclopentadienylpyridinylquinazoline or quinoxalinyl. Particular examples are pyridinyl, benzimidazolyl, pyrimidinyl, benzothiazolyl, thiazolylthiazolo[4,5-b]pyridinyl, benzothiazolyl, quinolyl, oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazolo[4,5-c]pyridinyl, indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl.

[0322] In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0323] 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.

[0324] Additional non-limiting examples of 5-membered "heteroaryl" groups include:

[0325]

[0326] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0327] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include:

[0328]

[0329] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0330] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole and benzothiazole.

[0331] Additional non-limiting examples of bicyclic "heteroaryl" groups include:

[0332]

[0333] Additional non-limiting examples of bicyclic "heteroaryl" groups include:

[0334]

[0335] Additional non-limiting examples of bicyclic "heteroaryl" groups include:

[0336]

[0337] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0338] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline and naphthyridine.

[0339] Additional non-limiting examples of bicyclic "heteroaryl" groups include:

[0340]

[0341] In another embodiment, the "heteroaryl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0342] The term "heterocycloalkyl" or "heterocyclyl" means a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having 4 to 9 ring atoms, containing 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of monocyclic saturated heterocycloalkyl are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxepanyl. Examples of bicyclic saturated heterocycloalkyl are 8-azabicyclo[3.2.1]octyl, quinucl, 8-oxa-3-azabicyclo[3.2.1]octyl, 9-azabicyclo[3.3.1]nonyl, 3-oxa-9-azabicyclo[3.3.1]nonyl, or 3-thia-9-azabicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyl are dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl or dihydropyranyl. A particular example is indolinyl.

[0343] In one embodiment, "heterocyclyl" refers to a ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0344] In one embodiment, "heterocyclyl" refers to a ring having one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0345] In one embodiment, "heterocyclyl" refers to a ring having two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0346] In one embodiment, "heterocyclyl" refers to a ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0347] In one embodiment, "heterocyclyl" refers to a ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0348] Non-limiting examples of "heterocyclyl" include aziridine, oxirane, thietidine, azetidine, 1,3-diazetidine, oxetane and thietane.

[0349] Other non-limiting examples of "heterocyclyl" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine and imidazolidine.

[0350] Other non-limiting examples of "heterocyclyl" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane and 1,3-oxathiolane.

[0351] Additional non-limiting examples of "heterocyclyl" include: piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine and thiomorpholine.

[0352] Non-limiting examples of "heterocyclyl" also include:

[0353]

[0354] Additional non-limiting examples of "heterocyclyl" include:

[0355]

[0356] Additional non-limiting examples of "heterocyclyl" include:

[0357]

[0358] Non-limiting examples of "heterocyclyl" also include:

[0359]

[0360] Non-limiting examples of "heterocyclyl" also include:

[0361]

[0362] Additional non-limiting examples of "heterocyclyl" include:

[0363]

[0364] Additional non-limiting examples of "heterocyclyl" include:

[0365]

[0366] In another embodiment, the "heterocyclyl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0367] 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, indanyl and 1,2,3,4-tetrahydronaphthyl.

[0368] In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0369] In one embodiment, "aryl" is a 10 carbon aromatic group (naphthyl).

[0370] In another embodiment, the "aryl" group is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0371] 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.

[0372] 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.

[0373] In one embodiment, a group described herein as substituted with 1, 2, 3, or 4 substituents is substituted with one substituent.

[0374] In one embodiment, a group described herein as substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.

[0375] In one embodiment, a group described herein as substituted with 1, 2, 3, or 4 substituents is substituted with three substituents.

[0376] In one embodiment, a group described herein as substituted with 1, 2, 3, or 4 substituents is substituted with four substituents.

[0377] 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.

[0378] 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.

[0379] 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).

[0380] 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.

[0381] 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.

[0382] "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.

[0383] 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.

[0384] 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.

[0385] 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).

[0386] 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.

[0387] 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.

[0388] Furthermore, the present invention includes all optical isomers, ie diastereomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers, and their solvates of the compounds described herein.

[0389] The compound 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 encompass 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 so that each enantiomer is isolated. 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.

[0390] 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.

[0391] All individual embodiments can be combined.

[0392] As used herein, the term "treating" includes: (1) inhibiting a state, disorder or condition (e.g., inhibiting, reducing or delaying the development of a disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof); and / or (2) alleviating a condition (i.e., causing regression of a state, disorder or condition or at least one clinical or subclinical symptom thereof). However, it will be understood that when a drug is administered to a patient to treat a disease, the result may not always be an effective treatment.

[0393] As used herein, the term "preventing" includes preventing or delaying the appearance of clinical symptoms of a state, disorder or condition that develops in a mammal, and particularly a human, who may be suffering from or susceptible to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

[0394] Isotope substitution

[0395] The present invention includes 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, and XV-a to XV-t 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.

[0396] 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, 18F-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.

[0397] 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.

[0398] In a non-limiting embodiment, the substitution of hydrogen atoms can be provided as deuterium atoms in any 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, and XV-a to XV-t. 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.

[0399] II. Compounds of the Invention

[0400] The present invention provides compounds of formula Ia, formula Ib, formula II, formula IIIa, formula IIIb, formula IV, formula V, formula VI, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIV, formula XV, formula XIV-a to XIV-x, and formula XV-a to XV-t, and pharmaceutically acceptable salts thereof. The present invention also provides the use of compounds of formula VII and formula XIII, as further described herein.

[0401] Compounds of Formula Ia to Formula VI

[0402] In one aspect, provided are compounds of Formula Ia or Formula Ib:

[0403]

[0404] or a pharmaceutically acceptable salt thereof;

[0405] wherein all variables are as defined herein.

[0406] In one embodiment of Formula Ia, a compound of the formula:

[0407]

[0408] In one embodiment of Formula Ia, a compound selected from the group consisting of:

[0409]

[0410] In one embodiment of Formula Ib, a compound selected from the group consisting of:

[0411]

[0412] In one embodiment of Formula Ib, a compound selected from the group consisting of:

[0413]

[0414] In another aspect, a compound of Formula II is provided:

[0415]

[0416] or a pharmaceutically acceptable salt thereof;

[0417] wherein all variables are as defined herein.

[0418] In one embodiment of Formula II, a compound selected from the group consisting of:

[0419]

[0420] In one embodiment of Formula II, a compound selected from the group consisting of:

[0421]

[0422] In one embodiment of Formula II, a compound selected from the group consisting of:

[0423]

[0424] In one embodiment of Formula II, a compound selected from the group consisting of:

[0425]

[0426] In one embodiment of Formula II, a compound selected from the group consisting of:

[0427]

[0428] In one embodiment of Formula II, a compound selected from the group consisting of:

[0429]

[0430] In one embodiment of Formula II, a compound selected from the group consisting of:

[0431]

[0432] In one embodiment of Formula II, a compound selected from the group consisting of:

[0433]

[0434]

[0435] In one embodiment of Formula II, a compound selected from the group consisting of:

[0436]

[0437] In one embodiment of Formula II, a compound selected from the group consisting of:

[0438]

[0439] In one embodiment of Formula II, a compound selected from the group consisting of:

[0440]

[0441]

[0442] In another aspect, a compound of Formula IIIa or Formula IIIb is provided:

[0443]

[0444] or a pharmaceutically acceptable salt thereof;

[0445] wherein all variables are as defined herein.

[0446] In one embodiment of Formula IIIa, a compound of the formula:

[0447]

[0448] In one embodiment of Formula IIIa, a compound selected from the group consisting of:

[0449]

[0450] In one embodiment of Formula IIIb, a compound of the formula:

[0451]

[0452] In one embodiment of Formula IIIb, a compound selected from the group consisting of:

[0453]

[0454] In another embodiment, a compound of formula IV is provided;

[0455]

[0456] or a pharmaceutically acceptable salt thereof;

[0457] wherein all variables are as defined herein.

[0458] In one embodiment of Formula IV, a compound selected from the group consisting of:

[0459]

[0460] In one embodiment of Formula IV, a compound selected from the group consisting of:

[0461]

[0462] In one embodiment of Formula IV, a compound selected from the group consisting of:

[0463]

[0464] In one embodiment of Formula IV, a compound selected from the group consisting of:

[0465]

[0466] In one embodiment of Formula IV, a compound selected from the group consisting of:

[0467]

[0468] In one embodiment of Formula IV, a compound selected from the group consisting of:

[0469]

[0470]

[0471] In one embodiment of Formula IV, a compound selected from the group consisting of:

[0472]

[0473]

[0474] In one embodiment of Formula IV, a compound selected from the group consisting of:

[0475]

[0476] In one embodiment of Formula IV, a compound selected from the group consisting of:

[0477]

[0478]

[0479] In one embodiment of Formula IV, a compound selected from the group consisting of:

[0480]

[0481] In one embodiment of Formula IV, a compound selected from the group consisting of:

[0482]

[0483] In one embodiment of Formula IV, a compound selected from the group consisting of:

[0484]

[0485]

[0486] In another embodiment, a compound of Formula V or VI is provided:

[0487]

[0488] or a pharmaceutically acceptable salt thereof;

[0489] wherein all variables are as defined herein.

[0490] In one embodiment of Formula V, a compound selected from the group consisting of:

[0491]

[0492] In one embodiment of Formula V, a compound selected from the group consisting of:

[0493]

[0494] In one embodiment of Formula V, a compound selected from the group consisting of:

[0495]

[0496] In one embodiment of Formula VI, a compound selected from the group consisting of:

[0497]

[0498] In one embodiment of Formula VI, a compound selected from the group consisting of:

[0499]

[0500] In one embodiment of Formula VI, a compound selected from the group consisting of:

[0501]

[0502]

[0503] In one embodiment, a compound selected from the group consisting of:

[0504]

[0505] In one embodiment, a compound selected from the group consisting of:

[0506]

[0507]

[0508] In one embodiment, a compound selected from the group consisting of:

[0509]

[0510]

[0511] Compound of formula VII

[0512] In another aspect, there is provided a use of a compound of formula VII 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:

[0513]

[0514] wherein all variables are as defined herein.

[0515] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0516]

[0517] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0518]

[0519] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0520]

[0521]

[0522] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0523]

[0524] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0525]

[0526] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0527]

[0528] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0529]

[0530] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0531]

[0532] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0533]

[0534] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0535]

[0536] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0537]

[0538] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0539]

[0540] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0541]

[0542] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0543]

[0544] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0545]

[0546]

[0547] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0548]

[0549] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0550]

[0551]

[0552] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0553]

[0554] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0555]

[0556]

[0557] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0558]

[0559]

[0560] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0561]

[0562] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0563]

[0564]

[0565] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0566]

[0567] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0568]

[0569] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0570]

[0571]

[0572] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0573]

[0574] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0575]

[0576] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0577]

[0578] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0579]

[0580] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0581]

[0582]

[0583] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0584]

[0585] In one embodiment, the compound of Formula VII used in the methods described herein is selected from:

[0586]

[0587] Compounds of Formula VII for use in the methods described herein are also provided in the following enumerated embodiments, all of which can be combined individually.

[0588] E1: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0589] X A Selected from

[0590] i) heteroaryl, in particular pyridyl, benzimidazolyl, pyrimidinyl, benzothiazolyl or thiazolyl, each of which is replaced by R 4 replace;

[0591] ii) heteroaryl, in particular thiazolo[4,5-b]pyridinyl, benzothiazolyl, quinolyl, oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazolo[4,5-c]pyridinyl, indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl,

[0592] iii) heterocyclic groups, especially indolinyl groups,

[0593] iv) a heterocyclic group, in particular an indolinyl group, which is 3 replace,

[0594] v) phenyl, indanyl or 1,2,3,4-tetrahydronaphthyl, and

[0595] vi) phenyl, which is substituted by NO2, -COOCH3 or -NH-C(=O)-CH3;

[0596] Y A Does not exist or is selected

[0597] i) -C(=O)-;

[0598] ii) -C(=O)-C(H,C 1-6 -alkyl)-, and

[0599] iii) -C(=O)-CH2-;

[0600] R 1 Does not exist or is = O;

[0601] R 2 Selected from

[0602] i) -C(=O)-OC 1-6 -alkyl, especially -C(=O)-O-CH3,

[0603] ii) -NH-C(=O)-C 1-6 -alkyl, in particular -NH-C(=O)-CH3, and

[0604] iii) -NO2;

[0605] R 3 Selected from

[0606] i) -C(=O)-C 1-6 -alkyl, in particular -C(=O)-CH3; and

[0607] ii) = O;

[0608] R 4 Selected from

[0609] i)-C 1-6 -alkyl groups, especially CH 3,

[0610] ii)-COOC 1-6 -alkyl, especially -COOCH3 or -COOC(CH3)3,

[0611] iii) -NH2,

[0612] iv) -NH-C(=O)-C 1-6 -alkyl, in particular -NH-C(=O)-CH3, and

[0613] v)-NO2.

[0614] E2: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0615] a)X A is unsubstituted phenyl or is replaced by R 2 substituted phenyl, and

[0616] R 2 Selected from

[0617] i) -C(=O)-O-CH3,

[0618] ii) -NH-C(=O)-CH3, and

[0619] iii) -NO2,

[0620] b)X A is indanyl or 1,2,3,4-tetrahydronaphthyl,

[0621] c)X A is thiazo[4,5-b]pyridinyl, benzothiazolyl, quinolyl, oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazo[4,5-c]pyridinyl, indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl,

[0622] d)X A is pyridyl, benzimidazolyl, pyrimidinyl, benzothiazolyl or thiazolyl, each of which is independently replaced by R 4 Replace, and

[0623] R 4 Selected from

[0624] i) -CH3,

[0625] ii) –COOCH3 or –COOC(CH3)3,

[0626] iii) -NH2,

[0627] iv) -NH-C(=O)-CH3, and

[0628] v) -NO2; or

[0629] e)X A is an unsubstituted indolinyl or R 3 substituted indolinyl, and

[0630] R 3 Selected from

[0631] i)-C(=O)-CH3; and

[0632] ii)=O.

[0633] E3: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, selected from the following

[0634] 2-((R)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0635] 2-((S)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0636] 2-Methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione,

[0637] 2-(2,3-dihydro-1H-indene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0638] 6-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)nicotinate,

[0639] 2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0640] 2-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)-1H-benzo[d]imidazole-7-carboxylic acid methyl ester,

[0641] 2-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)pyrimidine-4-carboxylic acid methyl ester,

[0642] 2-(1-methyl-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0643] 2-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)benzo[d]thiazole-6-carboxylic acid methyl ester,

[0644] 2-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)thiazole-4-carboxylic acid methyl ester,

[0645] 2-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)thiazole-5-carboxylic acid methyl ester,

[0646] 6-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)nicotinate tert-butyl ester,

[0647] 4-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzoic acid methyl ester,

[0648] 6-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)picolinic acid methyl ester,

[0649] 2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0650] N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)acetamide,

[0651] N-(6-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)pyridin-3-yl)acetamide,

[0652] 2-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0653] 2,7-diazaspiro[4.5]decane-6,8-dione,

[0654] 2-(2-phenylacetyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0655] 2-(3-nitrobenzoyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0656] 2-(Thiazolo[4,5-b]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0657] 2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0658] 2-(Benzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0659] 2-(Quinolin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0660] 2-(6-aminobenzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0661] 2-(Oxazolo[4,5-b]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0662] 2-(Benzo[d]oxazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0663] 2-(Thiazolo[4,5-c]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0664] 2-(Benzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0665] 2-(4-nitropyridinecarbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0666] 2-(2-oxoindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0667] 2-(Benzo[d]thiazole-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0668] 2-(5-nitropyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0669] 2-(2-(Pyridin-3-yl)propanoyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0670] 2-(1-acetylindole-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0671] 2-Benzoyl-2,7-diazaspiro[4.5]decane-6,8-dione,

[0672] 2-(1H-indazole-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0673] 2-(5-aminopyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0674] 2-(Indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0675] 2-(Indoline-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0676] 2-(1-acetylindole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0677] 2-(Benzofuran-3-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0678] 2-(Benzo[d]oxazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione, and

[0679] 2-(Indoline-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione.

[0680] E4: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, selected from the following

[0681] 2-((R)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0682] 2-((S)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0683] 2-(2,3-dihydro-1H-indene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0684] 6-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)nicotinate,

[0685] 2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0686] 2-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)-1H-benzo[d]imidazole-7-carboxylic acid methyl ester,

[0687] 2-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)pyrimidine-4-carboxylic acid methyl ester,

[0688] 2-(1-methyl-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0689] 2-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)benzo[d]thiazole-6-carboxylic acid methyl ester,

[0690] 2-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)thiazole-4-carboxylic acid methyl ester,

[0691] 2-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)thiazole-5-carboxylic acid methyl ester,

[0692] 6-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)nicotinate tert-butyl ester,

[0693] 4-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzoic acid methyl ester,

[0694] 6-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)picolinic acid methyl ester,

[0695] 2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0696] N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)acetamide,

[0697] N-(6-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)pyridin-3-yl)acetamide,

[0698] 2-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0699] 2-(2-phenylacetyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0700] 2-(3-nitrobenzoyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0701] 2-(Thiazolo[4,5-b]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0702] 2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0703] 2-(Benzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0704] 2-(Quinolin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0705] 2-(6-aminobenzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0706] 2-(Oxazolo[4,5-b]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0707] 2-(Benzo[d]oxazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0708] 2-(Thiazolo[4,5-c]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0709] 2-(Benzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0710] 2-(4-nitropyridinecarbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0711] 2-(2-oxoindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0712] 2-(Benzo[d]thiazole-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0713] 2-(5-nitropyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0714] 2-(2-(Pyridin-3-yl)propanoyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0715] 2-(1-acetylindole-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0716] 2-Benzoyl-2,7-diazaspiro[4.5]decane-6,8-dione,

[0717] 2-(1H-indazole-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0718] 2-(5-aminopyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0719] 2-(Indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0720] 2-(Indoline-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0721] 2-(1-acetylindole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0722] 2-(Benzofuran-3-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,

[0723] 2-(Benzo[d]oxazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione, and

[0724] 2-(Indoline-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione.

[0725] E5: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein XA Selected from

[0726] i) H,

[0727] ii) aryl, in particular indanyl or 1,2,3,4-tetrahydronaphthyl,

[0728] iii) aryl, especially phenyl, which is replaced by R 2 replace,

[0729] iv) heterocyclic groups, especially indolinyl groups,

[0730] v) heterocyclic groups, especially indolinyl groups, which are 3 replace,

[0731] vi) heteroaryl, in particular thiazolo[4,5-b]pyridinyl, benzothiazolyl, quinolyl, oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazolo[4,5-c]pyridinyl, indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl,

[0732] vii) heteroaryl, in particular pyridyl, benzimidazolyl, pyrimidinyl, benzothiazolyl or thiazolyl, each of which is independently R 4 Replace, and

[0733] viii) C 1-6 - alkyl, especially methyl.

[0734] E6: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A Selected from

[0735] i) H,

[0736] ii) phenyl, indanyl or 1,2,3,4-tetrahydronaphthyl,

[0737] iii) phenyl, which is replaced by R 2 replace,

[0738] iv) indolinyl,

[0739] v) indolinyl, which is R 3 replace,

[0740] vi) thiazolo[4,5-b]pyridinyl, benzothiazolyl, quinolyl, oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazolo[4,5-c]pyridinyl, indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl,

[0741] vii) pyridyl, benzimidazolyl, pyrimidinyl, benzothiazolyl or thiazolyl, each of which is independently replaced by R 4 Replace, and

[0742] viii) methyl.

[0743] E7: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A Selected from

[0744] i) aryl, in particular phenyl, indanyl or 1,2,3,4-tetrahydronaphthyl,

[0745] ii) an aryl group, in particular a phenyl group, which is replaced by R 2 replace,

[0746] iii) heterocyclic group, especially indolinyl group,

[0747] iv) a heterocyclic group, in particular an indolinyl group, which is 3 replace,

[0748] v) heteroaryl, in particular thiazolo[4,5-b]pyridinyl, benzothiazolyl, quinolyl, oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazolo[4,5-c]pyridinyl, indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl, and

[0749] vi) heteroaryl, in particular pyridyl, benzimidazolyl, pyrimidinyl, benzothiazolyl or thiazolyl, each of which is independently R 4 replace.

[0750] E8: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A Selected from

[0751] i) phenyl, indanyl or 1,2,3,4-tetrahydronaphthyl,

[0752] ii) phenyl, which is replaced by R 2 replace,

[0753] iii) indolinyl,

[0754] iv) indolinyl, which is R 3 replace,

[0755] v) thiazolo[4,5-b]pyridinyl, benzothiazolyl, quinolyl, oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazolo[4,5-c]pyridinyl, indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl, and

[0756] vi) pyridyl, benzimidazolyl, pyrimidinyl, benzothiazolyl or thiazolyl, each of which is independently R 4 replace.

[0757] E9: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A It's H.

[0758] E10: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A It is an aromatic group.

[0759] E11: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A It is phenyl, indanyl or 1,2,3,4-tetrahydronaphthyl.

[0760] E12: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A It is phenyl.

[0761] E13: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A It is indanyl.

[0762] E14: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A It is 1,2,3,4-tetrahydronaphthyl.

[0763] E15: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A Is R 2 Substituted aryl.

[0764] E16: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A Is R 2 Substituted phenyl.

[0765] E17: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A It is a heterocyclic group.

[0766] E18: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A It is indolinyl.

[0767] E19: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A Is R 3 Substituted heterocyclic group.

[0768] E20: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A Is R 3 Substituted indolinyl.

[0769] E21: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A It is a heteroaryl group.

[0770] E21: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A is thiazo[4,5-b]pyridinyl, benzothiazolyl, quinolyl, oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazo[4,5-c]pyridinyl, indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl.

[0771] E23: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A Is R 4 Substituted heteroaryl.

[0772] E24: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A is pyridyl, benzimidazolyl, pyrimidinyl, benzothiazolyl or thiazolyl, each of which is independently replaced by R 4 replace.

[0773] E25: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A It is C 1-6 -alkyl.

[0774] E26: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein X A It's methyl.

[0775] E27: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein Y A Selected from

[0776] i) -C(=O)-;

[0777] ii) -C(=O)-C(H,C 1-6 -alkyl)-, in particular -C(=O)-C(H,CH3)-, and

[0778] iii) -C(=O)-CH2-.

[0779] E28: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein Y A Selected from

[0780] i) -C(=O)-;

[0781] ii) -C(=O)-C(H,CH3)-, and

[0782] iii) -C(=O)-CH2-.

[0783] E29: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein Y A It is -C(=O)-.

[0784] E30: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein Y A is -C(=O)-C(H,C 1-6 -alkyl)-.

[0785] E31: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein Y A It is -C(=O)-C(H,CH3)-.

[0786] E32: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein Y A It is -C(=O)-CH2-.

[0787] E33: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 Does not exist.

[0788] E34: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is =O.

[0789] E35: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from

[0790] i) -C(=O)-OC 1-6 -alkyl, especially -C(=O)-O-CH3,

[0791] ii) -NH-C(=O)-C 1-6 -alkyl, especially -NH-C(=O)-CH3,

[0792] iii) – NH2,

[0793] iv)–OH, and

[0794] v)-NO2.

[0795] E36: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from

[0796] i) -C(=O)-OC 1-6-alkyl, especially -C(=O)-O-CH3,

[0797] ii) -NH-C(=O)-C 1-6 -alkyl, in particular -NH-C(=O)-CH3, and

[0798] iii)-NO2.

[0799] E37: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from

[0800] i) -C(=O)-O-CH3,

[0801] ii) -NH-C(=O)-CH3, and

[0802] iii)-NO2.

[0803] E38: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 Yes -C(=O)-OC 1-6 -alkyl.

[0804] E39: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 It is -C(=O)-O-CH3.

[0805] E40: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is -NH-C(=O)-C 1-6 -alkyl.

[0806] E41: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 It is -NH-C(=O)-CH3.

[0807] E42: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 It is -NO2.

[0808] E43: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from

[0809] i) -C(=O)-C 1-6 -alkyl, in particular -C(=O)-CH3, and

[0810] ii)=O.

[0811] E44: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from

[0812] i)-C(=O)-CH3, and

[0813] ii)=O.

[0814] E45: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 Yes -C(=O)-C 1-6 -alkyl.

[0815] E46: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 It is -C(=O)-CH3.

[0816] E47: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 Yes = O.

[0817] E48: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from

[0818] i) -C(=O)-OC 1-6 -alkyl, in particular -C(=O)-O-CH3 or -C(=O)-OC(CH3)3,

[0819] ii) C 1-6 - alkyl groups, especially methyl groups,

[0820] iii) -NH2,

[0821] iv) -NH-C(=O)-C 1-6 -alkyl, in particular -NH-C(=O)-CH3, and

[0822] v)-NO2.

[0823] E49: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from

[0824] i)-C(=O)-O-CH3 or –C(=O)-OC(CH3)3,

[0825] ii) methyl,

[0826] iii) -NH2,

[0827] iv) -NH-C(=O)-CH3, and

[0828] v)-NO2.

[0829] E50: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 Yes -C(=O)-OC 1-6 -alkyl.

[0830] E51: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 It is -C(=O)-O-CH3.

[0831] E52: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 It is –C(=O)-OC(CH3)3.

[0832] E53: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 -alkyl.

[0833] E54: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 It's methyl.

[0834] E55: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is -NH-C(=O)-C 1-6 -alkyl.

[0835] E56: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 It is -NH-C(=O)-CH3.

[0836] E57: A compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 It is -NO2.

[0837] E58: A certain embodiment of the present invention relates to a compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.

[0838] E59: A certain embodiment of the present invention relates to a compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of cancer.

[0839] E60: A certain embodiment of the present invention relates to a compound of formula VII 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.

[0840] E61: A certain embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula VII as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance.

[0841] E62: 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 formula VII as described herein or a pharmaceutically acceptable salt thereof.

[0842] Compounds of Formula VIII to Formula XII

[0843] In another aspect, provided is a compound of formula VIII:

[0844]

[0845] or a pharmaceutically acceptable salt thereof;

[0846] wherein all variables are as defined herein.

[0847] In one embodiment, a compound of formula VIII selected from the group consisting of:

[0848]

[0849] In one embodiment, a compound of formula VIII selected from the group consisting of:

[0850]

[0851] In one embodiment, a compound of formula VIII selected from the group consisting of:

[0852]

[0853] In another aspect, provided is a compound of Formula IX:

[0854]

[0855] or a pharmaceutically acceptable salt thereof;

[0856] wherein all variables are as defined herein.

[0857] In one embodiment, a compound of Formula IX is provided that is selected from the group consisting of:

[0858]

[0859] In another aspect, a compound of formula X is provided:

[0860]

[0861] or a pharmaceutically acceptable salt thereof;

[0862] wherein all variables are as defined herein.

[0863] In one embodiment, a compound of formula X selected from the following is provided:

[0864]

[0865] In one embodiment, a compound of formula X selected from the following is provided:

[0866]

[0867] In one embodiment, a compound of formula X selected from the following is provided:

[0868]

[0869] In one embodiment, a compound of formula X selected from the following is provided:

[0870]

[0871] In one embodiment, a compound of formula X selected from the following is provided:

[0872]

[0873] In another aspect, provided is a compound of formula XI:

[0874]

[0875] or a pharmaceutically acceptable salt thereof;

[0876] wherein all variables are as defined herein.

[0877] In one embodiment, a compound of formula XI is provided which is selected from:

[0878]

[0879] In one embodiment, a compound of formula XI is provided which is selected from:

[0880]

[0881]

[0882] In one embodiment, a compound of formula XI is provided which is selected from:

[0883]

[0884] In one embodiment, a compound of formula XI is provided which is selected from:

[0885]

[0886] In another aspect, provided is a compound of Formula XII:

[0887]

[0888] or a pharmaceutically acceptable salt thereof;

[0889] wherein all variables are as defined herein.

[0890] In one embodiment, the compound of Formula XII is as follows:

[0891]

[0892] In one embodiment, a compound of Formula XII selected from the group consisting of:

[0893]

[0894] In one embodiment, there is provided a formula In one embodiment, a compound selected from the following is provided:

[0895]

[0896] In one embodiment, a compound selected from the group consisting of:

[0897]

[0898] In one embodiment, a compound selected from the group consisting of:

[0899]

[0900] In one embodiment, a compound selected from the group consisting of:

[0901]

[0902] In one embodiment, a compound selected from the group consisting of:

[0903]

[0904] In one embodiment, a compound selected from the group consisting of:

[0905]

[0906] In one embodiment, a compound selected from the group consisting of:

[0907] Compound of formula XIII

[0908] In another aspect, there is provided the use of a compound of formula XIII for treating a therapeutic condition treatable by modulating the function or activity of a cereblon containing E3 ubiquitin ligase protein complex:

[0909]

[0910] or a pharmaceutically acceptable salt thereof;

[0911] wherein all variables are as defined herein.

[0912] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0913]

[0914] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0915]

[0916] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0917]

[0918] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0919]

[0920] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0921]

[0922] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0923]

[0924] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0925]

[0926] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0927]

[0928]

[0929] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0930]

[0931] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0932]

[0933] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0934]

[0935] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0936]

[0937] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0938]

[0939] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0940]

[0941]

[0942] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0943]

[0944] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0945]

[0946]

[0947] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0948]

[0949] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0950]

[0951] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0952]

[0953] In one embodiment, the compound of Formula XIII used in the methods provided herein is selected from:

[0954]

[0955] Compounds of Formula XIII for use in the methods described herein are also provided in the following enumerated embodiments, all of which can be combined individually.

[0956] E1: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0957] X B Selected from

[0958] i) aryl, in particular 1,2,3,4-tetrahydronaphthyl or phenyl,

[0959] ii) By R 6 Substituted phenyl;

[0960] iii) heteroaryl, in particular benzo[d]thiazolyl, thiazolo[4,5-b]pyridinyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl,

[0961] iv) R 7 substituted pyridyl;

[0962] R 6 Selected from

[0963] i) -NH-C(=O)-C 1-6 -alkyl, in particular -NH-C(=O)-CH3, and

[0964] ii) -NO2;

[0965] R 7 Selected from

[0966] i) -C(=O)-OC1-6 -alkyl, in particular -C(=O)-O-CH3, and

[0967] ii)-NO2.

[0968] E2: A compound of Formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein A is NH.

[0969] E3: A compound of Formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein A is CH2.

[0970] E4: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein Y B Does not exist.

[0971] E5: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein Y B It is -C(=O)-.

[0972] E6: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, selected from

[0973] (S)-8-(1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione,

[0974] (R)-8-(1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione,

[0975] (S)-8-(1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,

[0976] (R)-8-(1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,

[0977] 8-Benzoyl-1,3,8-triazaspiro[4.5]decane-2,4-dione,

[0978] 8-(Benzo[d]thiazol-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,

[0979] 8-(Thiazolo[4,5-b]pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,

[0980] 6-(2,4-dioxo-1,3,8-triazaspiro[4.5]dec-8-yl)nicotinate,

[0981] N-(4-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)phenyl)acetamide, N-(3-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)phenyl)acetamide, 8-(benzofuran-3-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,

[0982] 8-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,

[0983] 8-(5-nitropyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,

[0984] 8-(4-nitrophenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,

[0985] 8-(Benzo[d]thiazole-5-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,

[0986] 8-(Thiazolo[4,5-b]pyridin-2-yl)-2,8-diazaspiro[4.5]decane-1,3-dione,

[0987] 8-(5-nitropyridin-2-yl)-2,8-diazaspiro[4.5]decane-1,3-dione,

[0988] 8-(Benzo[d]thiazol-2-yl)-2,8-diazaspiro[4.5]decane-1,3-dione,

[0989] 8-(4-nitrophenyl)-2,8-diazaspiro[4.5]decane-1,3-dione,

[0990] 8-Benzoyl-2,8-diazaspiro[4.5]decane-1,3-dione,

[0991] 8-(Benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione,

[0992] 8-(Benzofuran-3-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione,

[0993] 6-(1,3-dioxo-2,8-diazaspiro[4.5]dec-8-yl)nicotinate, and

[0994] 8-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione.

[0995] E7: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B Selected from

[0996] ix) 1,2,3,4-tetrahydronaphthyl or phenyl,

[0997] x) is R 6 Substituted phenyl, wherein R 6 is -NH-C(=O)-CH3 or -NO2,

[0998] xi) benzo[d]thiazolyl, thiazolo[4,5-b]pyridinyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl,

[0999] xii) By R 7 Substituted pyridyl, wherein R 7 It is -C(=O)-O-CH3 or -NO2.

[1000] E8: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is an aromatic group.

[1001] E9: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is phenyl.

[1002] E10: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is 1,2,3,4-tetrahydronaphthyl.

[1003] E11: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B Is R 6 Substituted aryl.

[1004] E12: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is a phenyl group substituted by -NH-C(=O)-CH3 or -NO2.

[1005] E13: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is a phenyl group substituted by -NH-C(=O)-CH3.

[1006] E14: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is a phenyl group substituted by -NO2.

[1007] E15: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is a heteroaryl group.

[1008] E16: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B is benzo[d]thiazolyl, thiazolo[4,5-b]pyridinyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl.

[1009] E17: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is benzo[d]thiazolyl.

[1010] E18: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is thiazolo[4,5-b]pyridinyl.

[1011] E19: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is benzofuranyl.

[1012] E20: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is pyrazolo[1,5-a]pyridinyl.

[1013] E21: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B Is R 7 Substituted heteroaryl.

[1014] E22: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is a pyridyl group substituted by -C(=O)-O-CH3 or -NO2.

[1015] E23: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is a pyridyl group substituted by -C(=O)-O-CH3.

[1016] E25: A compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, wherein X B It is a pyridyl group substituted by -NO2.

[1017] E26: A certain embodiment of the present invention relates to a compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.

[1018] E27: A certain embodiment of the present invention relates to a compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of cancer.

[1019] E28: A certain embodiment of the present invention relates to a compound of formula XIII 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.

[1020] E29: A certain embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula XIII as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance.

[1021] E30: 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 formula XIII as described herein or a pharmaceutically acceptable salt thereof.

[1022] Compounds of formula XIV or XV

[1023] In one aspect, provided is a compound of Formula XIV or XV, or a pharmaceutically acceptable salt thereof:

[1024]

[1025] In one embodiment, a compound of Formula XIV selected from the group consisting of:

[1026]

[1027]

[1028]

[1029]

[1030] In one embodiment, a compound of formula XV is provided that is selected from the group consisting of:

[1031]

[1032]

[1033]

[1034]

[1035] In one embodiment, a compound of formula XIV-a is provided:

[1036]

[1037] wherein all variables are as defined herein.

[1038] In one embodiment, a compound of formula XV-a is provided:

[1039]

[1040] wherein all variables are as defined herein.

[1041] In some embodiments of Formula XIV-a or XV-a, Selected from:

[1042]

[1043] In one embodiment, a compound of Formula XIV-b is provided:

[1044]

[1045] wherein all variables are as defined herein.

[1046] In one embodiment, a compound of formula XV-b is provided:

[1047]

[1048] wherein all variables are as defined herein.

[1049] In some embodiments of Formula XIV-b or XV-b, Selected from:

[1050]

[1051] In one embodiment, a compound of formula XIV-c is provided:

[1052]

[1053] wherein all variables are as defined herein.

[1054] In one embodiment, a compound of formula XV-c is provided:

[1055]

[1056] wherein all variables are as defined herein.

[1057] In some embodiments of Formula XIV-c or XV-c, Selected from:

[1058]

[1059] In one embodiment, a compound of formula XIV-d is provided:

[1060]

[1061] wherein all variables are as defined herein.

[1062] In one embodiment, a compound of formula XV-d is provided:

[1063]

[1064] wherein all variables are as defined herein.

[1065] In some embodiments of Formula XIV-d or XV-d, Selected from:

[1066]

[1067] In one embodiment, a compound of formula XIV-e is provided:

[1068]

[1069] wherein all variables are as defined herein.

[1070] In one embodiment, a compound of formula XV-e is provided:

[1071]

[1072] wherein all variables are as defined herein.

[1073] In some embodiments of Formula XIV-e or XV-e, Selected from:

[1074]

[1075] In one embodiment, a compound of Formula XIV-f is provided:

[1076]

[1077] wherein all variables are as defined herein.

[1078] In one embodiment, a compound of formula XV-f is provided:

[1079]

[1080] wherein all variables are as defined herein.

[1081] In some embodiments of XIV-f or XV-f, Selected from:

[1082]

[1083] In one embodiment, a compound of formula XIV-g is provided:

[1084]

[1085] wherein all variables are as defined herein.

[1086] In one embodiment, a compound of formula XV-g is provided:

[1087]

[1088] wherein all variables are as defined herein.

[1089] In some embodiments of Formula XIV-g or XV-g, Selected from:

[1090]

[1091] In one embodiment, a compound of Formula XIV-h is provided:

[1092]

[1093] wherein all variables are as defined herein.

[1094] In one embodiment, a compound of Formula XV-h is provided:

[1095]

[1096] wherein all variables are as defined herein.

[1097] In some embodiments of Formula XIV-h or XV-h, Selected from:

[1098]

[1099] In one embodiment, a compound of Formula XIV-i is provided:

[1100]

[1101] wherein all variables are as defined herein.

[1102] In one embodiment, a compound of formula XV-i is provided:

[1103]

[1104] wherein all variables are as defined herein.

[1105] In some embodiments of Formula XIV-i or XV-i, Selected from:

[1106]

[1107] In one embodiment, a compound of formula XIV-j is provided:

[1108]

[1109] wherein all variables are as defined herein.

[1110] In one embodiment, a compound of formula XV-j is provided:

[1111]

[1112] wherein all variables are as defined herein.

[1113] In some embodiments of Formula XIV-j or XVj, Selected from:

[1114]

[1115] In one embodiment, a compound of Formula XIV-k is provided:

[1116]

[1117] wherein all variables are as defined herein.

[1118] In one embodiment, a compound of formula XV-k is provided:

[1119]

[1120] wherein all variables are as defined herein.

[1121] In some embodiments of Formula XIV-k or XV-k, Selected from:

[1122]

[1123] In one embodiment, a compound of formula XIV-1 is provided:

[1124]

[1125] wherein all variables are as defined herein.

[1126] In one embodiment, a compound of formula XV-1 is provided:

[1127]

[1128] wherein all variables are as defined herein.

[1129] In some embodiments of Formula XIV-1 or XV-1, Selected from:

[1130]

[1131] In one embodiment, a compound of formula XIV-m is provided:

[1132]

[1133] wherein all variables are as defined herein.

[1134] In one embodiment, a compound of formula XV-m is provided:

[1135]

[1136] wherein all variables are as defined herein.

[1137] In some embodiments of Formula XIV-m or XV-m, Selected from:

[1138]

[1139] In one embodiment, a compound of formula XIV-n is provided:

[1140]

[1141] wherein all variables are as defined herein.

[1142] In one embodiment, a compound of formula XV-n is provided:

[1143]

[1144] wherein all variables are as defined herein.

[1145] In some embodiments of Formula XIV-n or XV-n, Selected from:

[1146]

[1147] In one embodiment, a compound of formula XIV-o is provided:

[1148]

[1149] wherein all variables are as defined herein.

[1150] In one embodiment, a compound of formula XV-o is provided:

[1151]

[1152] wherein all variables are as defined herein.

[1153] In some embodiments of XIV-o or XV-o, Selected from:

[1154]

[1155] In one embodiment, a compound of Formula XIV-p is provided:

[1156]

[1157] wherein all variables are as defined herein.

[1158] In one embodiment, a compound of formula XV-p is provided:

[1159]

[1160] wherein all variables are as defined herein.

[1161] In some embodiments of Formula XIV-p or XV-p, Selected from:

[1162]

[1163] In one embodiment, a compound of formula XIV-q is provided:

[1164]

[1165] wherein all variables are as defined herein.

[1166] In one embodiment, a compound of formula XV-q is provided:

[1167]

[1168] wherein all variables are as defined herein.

[1169] In some embodiments of Formula XIV-q or XV-q, Selected from:

[1170]

[1171] In one embodiment, a compound of formula XIV-r is provided:

[1172]

[1173] wherein all variables are as defined herein.

[1174] In one embodiment, a compound of formula XV-r is provided:

[1175]

[1176] wherein all variables are as defined herein.

[1177] In some embodiments of Formula XIV-r or XV-r, Selected from:

[1178]

[1179] In one embodiment, a compound of formula XIV-s is provided:

[1180]

[1181] wherein all variables are as defined herein.

[1182] In one embodiment, a compound of formula XV-s is provided:

[1183]

[1184] wherein all variables are as defined herein.

[1185] In some embodiments of Formula XIV-s or XV-s, Selected from:

[1186]

[1187] In one embodiment, a compound of formula XIV-t is provided:

[1188]

[1189] wherein all variables are as defined herein.

[1190] In one embodiment, a compound of formula XV-t is provided:

[1191]

[1192] wherein all variables are as defined herein.

[1193] In some embodiments of Formula XIV-t or XV-t, Selected from:

[1194]

[1195] In one embodiment, a compound of formula XIV-u is provided:

[1196]

[1197] wherein all variables are as defined herein.

[1198] In some embodiments of Formula XIV-u, Selected from:

[1199]

[1200] In one embodiment, a compound of formula XIV-v is provided:

[1201]

[1202] wherein all variables are as defined herein.

[1203] In some embodiments of Formula XIV-v, Selected from:

[1204]

[1205] In one embodiment, a compound of formula XIV-w is provided:

[1206]

[1207] wherein all variables are as defined herein.

[1208] In some embodiments of Formula XIV-w, Selected from:

[1209] In one embodiment, a compound of formula XIV-x is provided:

[1210]

[1211] wherein all variables are as defined herein.

[1212] In some embodiments of Formula XIV-x, Selected from:

[1213] III. Tail Implementation Method

[1214] 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:

[1215]

[1216] where all variables are defined as above.

[1217] In another embodiment, the "tail" is a moiety selected from the group consisting of formulas T-VIII, T-IX and TX:

[1218]

[1219] 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.

[1220] 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.

[1221] 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:

[1222]

[1223]

[1224] In other embodiments, the "tail" is selected from:

[1225]

[1226] In other embodiments, the "tail" is selected from:

[1227]

[1228]

[1229] R 20 , R 21 , R 22 , R 23 and R 24 Non-limiting examples of parts include:

[1230]

[1231] R 20 , R 21 , R 22 , R 23 and R 24 Additional non-limiting examples of portions include:

[1232]

[1233] R 20 , R21 , R 22 , R 23 and R 24 Additional non-limiting examples of portions include:

[1234]

[1235]

[1236] 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.

[1237] In other embodiments, the "tail" is selected from:

[1238] -NR 61 (CH2) n1 -(lower alkyl)-X 22 , -NR 61 (CH2) n1 -(lower alkoxy)-X 22 ,

[1239] -NR 61 (CH2) n1 -(lower alkoxy)-OCH2-X 22 , -NR 61 (CH2) n1 -(lower alkoxy)-(lower alkyl)-OCH2-X 22 ,

[1240] -NR 61 (CH2) n1 -(Cycloalkyl)-(lower alkyl)-OCH2-X 22 , -NR 61 (CH2) n1 -(Heterocycloalkyl)-X 22 ,

[1241] -NR 61 (CH2CH2O) n1 -(lower alkyl)-O-CH2-X 22 ,

[1242] -NR 61 (CH2CH2O) n1 -(Heterocycloalkyl)-O-CH2-X 22 ,

[1243] -NR 61 (CH2CH2O) n1 -Aryl-O-CH2-X 22 , -NR 61 (CH2CH2O) n1 -(Heteroaryl)-O-CH2-X 22 ,

[1244] -NR 61 (CH2CH2O) n1 -(cycloalkyl)-O-(heteroaryl)-O-CH2-X 22 ,

[1245] -NR 61 (CH2CH2O) n1 -(Cycloalkyl)-O-aryl-O-CH2-X 22 ,

[1246] -NR 61 (CH2CH2O) n1 -(lower alkyl)-NH-aryl-O-CH2-X 22 ,

[1247] -NR 61 (CH2CH2O) n1 -(lower alkyl)-O-aryl-CH2-X 22 ,

[1248] -NR 61 (CH2CH2O) n1 -cycloalkyl-O-aryl-X 22 , -NR 61 (CH2CH2O) n1 -cycloalkyl-O-heteroaryl-X 22 ,

[1249] -NR 61 (CH2CH2) n1 -(Cycloalkyl)-O-(Heterocyclic)-CH2-X 22 ,

[1250] -NR61 (CH2CH2) n1 -(Heterocyclic)-(Heterocyclic)-CH2-X 22 , and -NR 61 -(Heterocyclic)-CH2-X 22 ;

[1251] wherein n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and R 61 is H, methyl or ethyl.

[1252] In other embodiments, the "tail" is selected from:

[1253] -N(R 61 )-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-X 22 ,

[1254] -O-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-X 22 ,

[1255] -O-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OH;

[1256] -N(R 61 )-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OH;

[1257] -(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1-O(CH2) q1 -O(CH2) r1 -OH;

[1258] -(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-X 22 ;

[1259] -O(CH2) m1 O(CH2) n2 O(CH2) p1 O(CH2) q1 OCH2-X 22 ;

[1260] -O(CH2) m1 O(CH2) n2 O(CH2) p1 O(CH2) q1 OCH2-X 22 ;in

[1261] m1, n2, o1, p1, q1 and r1 are independently 1, 2, 3, 4 or 5; and R 61 is H, methyl or ethyl.

[1262] In other embodiments, the "tail" is selected from:

[1263]

[1264]

[1265] m1, n2, o1, p1, q2, and r1 are independently 1, 2, 3, 4 or 5. In another embodiment, the "tail" is selected from:

[1266]

[1267]

[1268] In other embodiments, the "tail" is selected from:

[1269]

[1270] In other embodiments, the "tail" is selected from:

[1271]

[1272]

[1273]

[1274]

[1275]

[1276]

[1277] Where R 71 is -O-, -NH, N-alkyl, heteroaliphatic, aliphatic or -NMe. In another embodiment, the "tail" is selected from:

[1278]

[1279]

[1280]

[1281]

[1282]

[1283] In other embodiments, the "tail" is selected from:

[1284]

[1285] In other embodiments, the "tail" is selected from:

[1286]

[1287] In other embodiments, the "tail" is selected from:

[1288]

[1289]

[1290] In other embodiments, the "tail" is selected from:

[1291]

[1292] In the above implementation, select X 22 Make the compound sufficiently stable or achieve its intended use.

[1293] In other embodiments, the "tail" is selected from:

[1294]

[1295] In certain embodiments, the "tail" is selected from:

[1296]

[1297]

[1298] In certain embodiments, the "tail" is selected from:

[1299]

[1300]

[1301] In the above structure, represent and

[1302] 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:

[1303]

[1304]

[1305] In certain embodiments, the "tail" may be a non-linear chain, and may be or include an aliphatic or aromatic or heteroaromatic cyclic moiety.

[1306] 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.

[1307] 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:

[1308]

[1309] X 22 Representative examples include:

[1310]

[1311] In certain embodiments, the length may be adjusted as desired and may also be adjusted as required for the desired application.

[1312] IV. Treatment Methods

[1313] 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.

[1314] 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.

[1315] 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.

[1316] 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.

[1317] 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.

[1318] 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.

[1319] Other hyperproliferative cell disorders include vascular proliferative disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancer.

[1320] 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.

[1321] 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.

[1322] 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.

[1323] 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.

[1324] 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.

[1325] 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.

[1326] 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.

[1327] 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.

[1328] 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.

[1329] 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.

[1330] 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.

[1331] 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.

[1332] 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.

[1333] In one embodiment, the cancer is NUT midline carcinoma.

[1334] In one embodiment, the cancer is adenoid cystic carcinoma.

[1335] 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.

[1336] 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.

[1337] 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.

[1338] 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.

[1339] 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.

[1340] 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.

[1341] 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.

[1342] 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.

[1343] 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.

[1344] 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.

[1345] 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.

[1346] 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.

[1347] 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).

[1348] 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.

[1349] 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)).

[1350] 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.

[1351] 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.

[1352] 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.

[1353] In one embodiment, the multiple myeloma is a plasma cell leukemia.

[1354] In one embodiment, the multiple myeloma is high-risk multiple myeloma.

[1355] 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 a genetic abnormality, 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.

[1356] 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.

[1357] 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.

[1358] 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.

[1359] 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).

[1360] 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).

[1361] 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.

[1362] 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.

[1363] 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 thereof, an isotopic analog or a prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. 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 thereof, an isotopic analog or a 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.

[1364] 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.

[1365] 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.

[1366] 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.

[1367] 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.

[1368] 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).

[1369] 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.

[1370] V. Combination Therapy

[1371] 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.

[1372] 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 (e.g., a human) suffering from a condition described herein.

[1373] 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.

[1374] 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.

[1375] VI. Pharmaceutical Compositions

[1376] 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.

[1377] 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.

[1378] 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.

[1379] 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.

[1380] 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.

[1381] 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.

[1382] 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.

[1383] 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.

[1384] 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.

[1385] 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.

[1386] 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).

[1387] 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.

[1388] 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.

[1389] 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.

[1390] 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.

[1391] 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:

[1392] Example A

[1393] Tablets of the following composition are manufactured in the usual manner:

[1394]

[1395]

[1396] Table 1: Possible tablet compositions

[1397] Manufacturing Process

[1398] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

[1399] 2. Dry the granules at 50°C.

[1400] 3. Pass the granules through suitable grinding equipment.

[1401] 4. Add ingredient 5 and mix for three minutes; compress on a suitable press.

[1402] Example B-1

[1403] Capsules of the following composition are manufactured:

[1404]

[1405] Table 2: Possible capsule composition

[1406] Manufacturing Process

[1407] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[1408] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[1409] 3. Fill into suitable capsules.

[1410] First, the compound of formula VII or XIII, lactose and corn starch are 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.

[1411] Example B-2

[1412] Soft gelatin capsules of the following composition are manufactured:

[1413] 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

[1414] Table 3: Possible composition of soft capsules

[1415] Element mg / capsule gelatin 75 Glycerin 85% 32 Karion 83 8 (Dry matter) Titanium Dioxide 0.4 Iron oxide yellow 1.1 total 116.5

[1416] Table 4: Possible soft gelatin capsule compositions

[1417] Manufacturing Process

[1418] 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.

[1419] Example C

[1420] Prepare suppositories of the following composition:

[1421] Element mg / suppository Compounds of formula VII or XIII 15 Suppository base 1285 total 1300

[1422] Table 5: Possible suppository compositions

[1423] Manufacturing Process

[1424] 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.

[1425] Example D

[1426] Prepare an injection solution of the following composition:

[1427] Element mg / injection solution Compounds of formula VII or XIII 3 Polyethylene glycol 400 150 Acetic acid pH 5.0 Water for injection solution ad 1.0 ml

[1428] Table 6: Possible compositions of injection solutions

[1429] Manufacturing Process

[1430] 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.

[1431] Example E

[1432] Make a sachet of the following composition:

[1433] 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

[1434] Table 7: Possible sachet compositions

[1435] Manufacturing Process

[1436] 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.

[1437] VII. Uses of the Compounds

[1438] 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.

[1439] 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.

[1440] 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.

[1441] 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.

[1442] 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.

[1443] 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.

[1444] 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.

[1445] General synthesis example

[1446] The preparation of the compounds of the present invention can be carried out in a sequential or convergent synthetic route. In the description of the specific examples, the synthesis of the compounds of the present invention is shown in the following scheme. 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 above herein.

[1447] 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.

[1448] General solution 1

[1449]

[1450] Step A: Formation of the glutarimide ring of 3 is accomplished by reaction between (2-amino-2-oxo-ethyl)-phosphonium salt 1 (CAS 25361-54-0) and ethyl acrylate 2 in a protic organic solvent such as methanol or ethanol in the presence of an aqueous base such as lithium hydroxide, sodium hydroxide or potassium hydroxide. The preferred conditions are NaOH in methanol at room temperature for 16 hours.

[1451] Step B: Conjugated olefin 4 can be prepared by Wittig-Horner-Emmons reaction of phosphine subunit 3 with paraformaldehyde. The reaction is carried out at elevated temperature in a halogenated solvent such as dichloromethane or 1,2-dichloroethane. The preferred conditions are dichloroethane at 80°C for 30 minutes.

[1452] Step C: The formation of pyrrolidine ring 6 can be accomplished by a 1,3-cycloaddition reaction between a dipolephile 4 and an imine ylide, which is formed in situ from the precursor N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methylamine 5 (CAS 93102-05-7), which is treated with an acid catalyst such as trifluoroacetic acid or trifluoromethanesulfonic acid according to the method of Terao et al., Chem. Pharm. Bull. 1985, 33, 2762. The reaction is carried out in a halogenated solvent such as dichloromethane or 1,2-dichloroethane. Preferred conditions are trifluoroacetic acid in dichloromethane for 16 hours at room temperature.

[1453] Step D: Removal of the benzyl protecting group of 6 to give the secondary amine 7 can be achieved by a two-step procedure according to the method of Olofson et al., J. Org. Chem. 1984, 49, 2081. The first step involves treating the tertiary amine 6 with 1-chloroethyl chloroformate (CAS 50893-53-3). The reaction is carried out at elevated temperatures in a halogenated solvent such as dichloromethane or 1,2-dichloroethane. In the second step, the carbamate compound obtained in the first step is thermally decomposed by heating in an alcoholic solvent such as methanol or ethanol at elevated temperatures. Preferred conditions are: the first step is carried out at 80°C for 12 hours with dichloromethane and the second step is carried out at 65°C for 2 hours with methanol.

[1454] General Solution 2

[1455]

[1456] Step A: Nitrile ester 10 can be prepared by conjugate addition of the enolate of nitrile ester 8 (CAS 6283-71-2) to α,β-unsaturated ester 9 (CAS 1663-39-4). The enolate of 8 can be preformed in situ by treating 8 with a tertiary amine base such as triethylamine or N,N-diisopropylethylamine before adding the α,β-unsaturated ester 9 to the reaction mixture. Preferred conditions for the enolate are triethylamine in a mixture of methanol and water at 0-5°C for 30 minutes. Preferred conditions for the conjugate addition are 0-5°C for 90 minutes followed by warming to room temperature for 2 hours.

[1457] Step B: The preparation of lactam 11 can be carried out by selectively reducing the nitrile group of nitrile ester 10 to obtain the corresponding primary amine, which can then be cyclized in situ to obtain lactam 11. The selective reduction of the nitrile group in the presence of the ester group can be accomplished by catalytic hydrogenation. Preferred conditions are to use Raney nickel as a hydrogenation catalyst, in a hydrogen atmosphere and elevated pressure (preferably at a pressure of 40 atm) in methanol at room temperature for 16 hours.

[1458] Step C: The transesterification of the mixed methyl / tert-butyl ester 11 to all methyl esters 12 can be accomplished by reaction with methanol in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid. The reaction is preferably carried out using pure methanol as solvent. The preferred conditions are hydrochloric acid in methanol at 60°C for 2 hours.

[1459] Step D: The conversion of diester 12 to diamide 13 can be achieved by reaction with 4-methoxybenzylamine at elevated temperature and pressure. The reaction is preferably carried out using pure methoxybenzylamine as solvent. The preferred conditions are to stir the reaction mixture in a sealed container at 200°C for 2 hours under microwave irradiation.

[1460] Step E: Formation of the glutarimide ring of 14 can be accomplished by cyclizing the diamide 13 in an aromatic solvent such as benzene, toluene or xylene in the presence of an acid such as p-toluenesulfonic acid at elevated temperature. Preferred conditions are p-toluenesulfonic acid in xylene at 145°C for 2 hours.

[1461] Step F: N-alkylation of lactam 14 can be accomplished by treatment with an alkyl halide such as alkyl bromide or alkyl iodide in an aprotic organic solvent such as tetrahydrofuran, dioxane, toluene or N,N-dimethylformamide in the presence of a base such as sodium hydride or potassium hydride at elevated temperature. In the case where the alkyl halide reagent is methyl iodide, the preferred conditions are sodium hydride in toluene at 60°C for 1 hour.

[1462] Step G: The 4-methoxybenzyl protecting group of 15 can be removed by treatment with an oxidizing agent such as cerium ammonium (IV) nitrate in a mixture of water and a miscible polar organic solvent such as acetonitrile and dioxane to afford the glutarimide 16. Preferred conditions are cerium ammonium (IV) nitrate in aqueous acetonitrile for 1 hour at room temperature.

[1463] General solution 3

[1464]

[1465] The substituents are as described herein and in the claims.

[1466] Step A: Amide bond formation can be accomplished by coupling reaction between carboxylic acid 17 and pyrrolidine-glutarimide 7 in the presence of coupling agents such as DCC, EDC, TBTU or HATU and organic bases such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ether solvents such as diethyl ether, dioxane, THF, DME or TBME or polar aprotic organic solvents such as N,N-dimethylformamide at room temperature or at elevated temperature for 2-18 hours. Preferred conditions are HATU with N,N-diisopropylethylamine in N,N-dimethylformamide for 3 hours at room temperature.

[1467] General solution 4

[1468]

[1469] The substituents are as described in the claims, EWG is an electron withdrawing group such as -CN, -CO2R, -SO2R or -NO2, and hal is F or Cl.

[1470] Step A: Nucleophilic Aromatic Substitution (S NThe reaction can be accomplished by reaction of pyrrolidine-glutarimide 7 with an electron-deficient mono- or fused bicyclic heteroaromatic compound 19 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.

[1471] Examples of suitable electron-deficient heteroaromatic compounds 19 with suitable leaving groups include, but are not limited to, methyl 6-chloronicotinate (CAS 73781-91-6), 2-chlorothiazolo[4,5-b]pyridine (CAS 152170-30-4), 1-fluoro-4-nitrobenzene (CAS 350-46-9), 2-chloro-5-nitro-1H-benzo[d]imidazole (CAS 5955-72-6), 2-chlorobenzo[d]thiazole (CAS 615-20-3), methyl 2-chloro-1H-benzo[d]imidazole-7-carboxylate (CAS 1171129-05-7), methyl 2-chloropyrimidine-4-carboxylate (CAS 149849-94-5), 2-chloroquinoline (CAS 612-62-4), 2-chlorobenzo[d]thiazol-6-amine (CAS2406-90-8), 2-chlorooxazolo[4,5-b]pyridine (CAS 325976-45-2), 2-chloro-1-methyl-1H-benzo[d]imidazole (CAS1849-02-1), 2-chlorothiazolo[4,5-c]pyridine (CAS 884860-63-3), 2-chlorobenzo[d]thiazole-6-carboxylic acid methyl ester (CAS90792-69-1), 2-chlorothiazole-4-carboxylic acid methyl ester (CAS 850429-61-7), 2-chlorothiazole-5-carboxylic acid methyl ester (CAS72605-86-8), 6-chloronicotinic acid tert-butyl ester (CAS 115309-57-4), 2-chloro-5-nitropyridine (CAS 4548-45-2) or methyl 6-chloro-2-picolinate (CAS 6636-55-1). Preferred conditions are N,N-diisopropylethylamine in N,N-dimethylformamide at 110°C for 24 hours.

[1472] General solution 5

[1473]

[1474]

[1475] As an illustrative example, a degrader compound targeting BET bromodomain BRD4 can be prepared based on the known BRD4 ligand JQ1 (Filippakopoulos, P. et al., Nature 2010, 468, 1067-1073, CAS 1268524-70-4). The synthesis uses the corresponding carboxylic acid derivative 25 (CAS 202592-23-2).

[1476] Step A: The formation of the amide bond can be accomplished by a coupling reaction between amine 7 and a linker-containing compound 21 with a terminal carboxyl functional group and a terminal BOC-protected amine functional group. The reaction is carried out at room temperature or elevated temperature in the presence of a coupling agent such as DCC, EDC, TBTU or HATU, in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine or 4-(N,N-dimethylamino)pyridine, 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. The preferred conditions are HATU with N,N-diisopropylethylamine in N,N-dimethylformamide for 18 hours at room temperature.

[1477] Alternatively, the formation of the amide bond can be accomplished by a coupling reaction between the amine 7 and the acid chloride compound 22, which is formed in situ from the linker-containing compound 21 with a terminal carboxyl function and a terminal BOC-protected amine function. The acid chloride compound 22 can be prepared in situ from the corresponding carboxylic acid 21 by treatment with 1-chloro-N,N,2-trimethylpropyleneamine (CAS 26189-59-3) in a halogenated solvent such as dichloromethane or 1,2-dichloroethane at a temperature between 0°C and room temperature according to the method of Ghosez and co-workers (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 compound 22 with the amine 7 in a halogenated solvent such as dichloromethane or 1,2-dichloroethane. The preferred conditions are dichloromethane at room temperature for 2 hours.

[1478] Step B: Removal of the Boc N protecting group of 23 can be achieved with inorganic acids such as HCl, HSO or HPO or organic acids such as CFCOOH, CHClCOOH, HOAc or p-toluenesulfonic acid in solvents such as CHCl, CHCl, THF, EtOAc, dioxane, MeOH, EtOH or HO at temperatures between 0°C and reflux. Preferred conditions are 4 M aqueous HCl in dioxane and ethyl acetate at room temperature for 1 hour.

[1479] Step C: Amide bond formation can be accomplished by coupling reaction between carboxylic acid 25 and amine 24 in the presence of coupling agent such as DCC, EDC, TBTU or HATU and organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine in halogenated solvents such as dichloromethane or 1,2-dichloroethane or ether solvents such as diethyl ether, dioxane, THF, DME or TBME or polar aprotic organic solvents such as N,N-dimethylformamide at room temperature or elevated temperature for 2-18 hours. Preferred conditions are HATU with N,N-diisopropylethylamine in N,N-dimethylformamide at room temperature for 3 hours.

[1480] General Solution 6

[1481]

[1482] The substituent X is as described in the claims, and A is NH or CH2

[1483] Step A: Amide bond formation can be accomplished by coupling reaction between spiro-piperidine 28 and carboxylic acid 29 in the presence of coupling agents 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 at room temperature or elevated temperature for 2-18 hours.

[1484] Preferred conditions are HATU and N,N-diisopropylethylamine in N,N-dimethylformamide at room temperature for 15 hours.

[1485] Examples of suitable spiro-piperidine compounds 28 include, but are not limited to, 1,3,8-triazaspiro[4.5]decane-2,4-dione (CAS 13625-39-3) or 2,8-diazaspiro[4.5]decane-1,3-dione (CAS 2079-25-6), or their corresponding salts 1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (CAS 13625-48-4) or 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (CAS 2696-03-9).

[1486] Alternatively, the formation of the amide bond can be accomplished by a coupling reaction between the spiro-piperidine 28 and the acid chloride 29a, which is formed in situ from the carboxylic acid 29. The acid chloride 29a can be prepared in situ from the corresponding carboxylic acid 29 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 reaction of the acid chloride 29a with the spiro-piperidine 28 in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine 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. Preferred conditions are N,N-diisopropylethylamine in THF for 2 hours at room temperature.

[1487] General Solution 7

[1488]

[1489] The substituents are as described in the claims, A is NH or CH2, EWG is an electron withdrawing group such as -CN, -CO2R, -SO2R or -NO2, and hal is F or Cl.

[1490] Step A: Nucleophilic Aromatic Substitution (S N Ar) reaction can be accomplished by reaction of spiro-piperidine 28 with an electron-deficient mono- or fused bicyclic heteroaromatic compound 31 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.

[1491] Examples of suitable spiro-piperidine compounds 28 include, but are not limited to, 1,3,8-triazaspiro[4.5]decane-2,4-dione (CAS 13625-39-3) or 2,8-diazaspiro[4.5]decane-1,3-dione (CAS 2079-25-6), or their corresponding salts 1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (CAS 13625-48-4) or 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (CAS 2696-03-9).

[1492] Examples of suitable electron-deficient heteroaromatic compounds 21 with a suitable leaving group include, but are not limited to, 2-chlorobenzo[d]thiazole (CAS 615-20-3), 2-chlorothiazolo[4,5-b]pyridine (CAS 152170-30-4), methyl 6-chloronicotinate (CAS 73781-91-6), 2-chloro-5-nitropyridine (CAS 4548-45-2) or 1-fluoro-4-nitrobenzene (CAS 350-46-9).

[1493] Preferred conditions are N,N-diisopropylethylamine in N,N-dimethylformamide at 120°C for 2 hours.

[1494] Representative Embodiments of the Invention

[1495] 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.

[1496] 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 compound of formula I can be separated using chiral HPLC. The racemic mixture of chiral synthetic intermediates can also be separated using chiral HPLC.

[1497] Example 1

[1498] 2,7-Diazaspiro[4.5]decane-6,8-dione

[1499]

[1500] a) 3-(triphenyl-λ 5 -phosphinylidene)piperidine-2,6-dione

[1501] To a solution of (2-amino-2-oxo-ethyl)-triphenylphosphonium chloride (CAS25361-54-0, 70.0 g, 219 mmol, 1.00 eq) and NaOH (8.04 g, 201 mmol, 0.92 eq) in methanol (300 mL) was added ethyl acrylate (20.7 g, 240 mmol, 21.6 mL, 1.10 eq). The reaction mixture was stirred at 25 ° C for 16 hours. The starting material was consumed, and the product was detected by LC / MS. The reaction mixture was filtered, washed with methanol (2x20 mL) and petroleum ether (100 mL) and dried to obtain 3-(triphenylphosphonium) as a white solid.5 -phosphanylidene)piperidine-2,6-dione (35.0 g, crude), which was used directly in the next step without further purification. MS (ISP): 374.1 ([M+H] + ).

[1502] b) 3-Methylenepiperidin-2,6-dione

[1503] 3-(triphenyl-λ 5 -phosphinyl)piperidine-2,6-dione (35.0 g, 93.7 mmol, 1.00 eq) and paraformaldehyde (10.1 g, 112 mmol, 1.20 eq) in dichloroethane (200 mL) were stirred at 80 ° C for 30 minutes. The starting material was consumed and the product was detected by LC / MS. The reaction was filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give 3-methylenepiperidine-2,6-dione (4.30 g, 34.4 mmol, 36.7% yield) as an off-white solid. MS (ISP): 126.0 ([M+H] + ).

[1504] c) 2-Benzyl-2,7-diazaspiro[4.5]decane-6,8-dione

[1505] To a solution of 3-methylenepiperidine-2,6-dione (4.30 g, 34.36 mmol, 1.00 eq) and N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methanamine (CAS 93102-05-7, 8.97 g, 37.8 mmol, 1.10 eq) in dichloromethane (200 mL) was added trifluoroacetic acid (2.55 g, 22.3 mmol, 1.65 mL, 0.65 eq). The reaction was stirred at 25 ° C for 16 hours. The starting material was consumed and the product was detected by LC / MS. The reaction was quenched with saturated NaHCO (200 mL), extracted with dichloromethane (50 mL), washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The obtained solid residue was triturated with a mixture of ethyl acetate and petroleum ether (1:10) and purified by preparative HPLC to give 2-benzyl-2,7-diazaspiro[4.5]decane-6,8-dione (3.00 g, 11.6 mmol, 33.8% yield) as a white solid. MS (ISP): 259.1 ([M+H] + ).

[1506] d) 2,7-diazaspiro[4.5]decane-6,8-dione

[1507] To a solution of 2-benzyl-2,7-diazaspiro[4.5]decane-6,8-dione (1.50 g, 5.81 mmol, 1.00 eq) in dichloroethane (50.0 mL) was added 1-chloroethyl chloroformate (CAS 50893-53-3, 1.66 g, 11.6 mmol, 2.00 eq). The reaction mixture was stirred at 80 °C for 12 hours. The solution was concentrated in vacuo and the residue was dissolved in methanol (50.0 mL) and stirred at 65 °C for 2 hours. After vacuum concentration, 1 H NMR showed the presence of starting material. The residue was dissolved in dichloroethane (100 ml) and treated again with 1-chloroethyl chloroformate (1.66 g, 11.6 mmol, 4.00 eq) at 80 ° C for 12 hours. After evaporation of the solvent, methanol was added and the solution was stirred at 65 ° C for 2 hours. The solvent was evaporated and the residue was dissolved in dichloromethane, stirred for 5 hours and filtered to obtain 2,7-diazaspiro [4.5] decane -6,8-dione (300 mg, 1.78 mmol, 30.7% yield) in the form of its hydrochloride as a gray solid. MS (ISP): 169.1 ([M+H] + ).

[1508] Example 2

[1509] 2-Methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione

[1510]

[1511] a) 4-O-tert-butyl 1-O,2-O-dimethyl 2-cyanobutane-1,2,4-tricarboxylate

[1512] To a solution of dimethyl 2-cyanosuccinate (CAS 6283-71-2, 10.0 g, 58.4 mmol, 1.00 eq) in methanol (60.0 mL) and water (60.0 mL) was added triethylamine (8.87 g, 87.6 mmol, 12.1 mL, 1.50 eq) at 0-5°C. After stirring for 30 minutes, tert-butyl prop-2-enoate (CAS 1663-39-4, 8.99 g, 70.1 mmol, 10.2 mL, 1.20 eq) was added to the reaction mixture. The mixture was stirred at 0-5°C for 1.5 hours, allowed to warm to 25°C and stirred for an additional 2 hours. TLC showed that the starting material was consumed and a new spot was detected. The reaction mixture was acidified to pH = 4 with 2N HCl aqueous solution and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2, petroleum ether: ethyl acetate = 20: 1 to 4: 1) to give 4-O-tert-butyl 1-O, 2-O-dimethyl 2-cyanobutane-1,2,4-tricarboxylate (10.0 g, 33.4 mmol, 57.2%) as a yellow gum. 1 HNMR: 400MHz, CDCl3: δ3.82-3.87 (m, 3H), 3.73 (s, 3H), 3.09 (d, J=17.07Hz, 1H), 2.83 (d, J=17 .32Hz, 1H), 2.47-2.61(m, 1H), 2.31-2.43(m, 1H), 2.10-2.25(m, 2H), 2.03(s, 1H), 1.43(s, 9H)

[1513] b) 3-(3-tert-Butoxy-3-oxo-propyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester

[1514] 4-O-tert-butyl 1-O, 2-O-dimethyl 2-cyanobutane-1,2,4-tricarboxylate (5.00 g, 16.7 mmol, 1.00 eq) was dissolved in methanol (200 mL) and Raney-Ni (143 mg, 1.67 mmol, 0.10 eq) was added to the mixture. The reaction mixture was hydrogenated with H2 (40 psi) for 16 hours. According to LC / MS, the starting material was consumed and the desired compound was detected. The solution was removed with a pipette and the catalyst was washed with methanol. The filtrate was concentrated under reduced pressure to obtain 3-(3-tert-butoxy-3-oxo-propyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (4.00 g, 14.7 mmol, 88.3%) as a yellow solid, which was directly used in the next reaction. MS (ISP): 543.2 ([2M+H] + ).

[1515] c) 3-(3-methoxy-3-oxo-propyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester

[1516] With stirring, concentrated HCl (0.8 ml) was added to a solution of 3-(3-tert-butoxy-3-oxo-propyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (2.00 g, 7.37 mmol, 1.00 eq) in methanol (25.0 mL). The mixture was heated at 60 ° C for 2 hours. LC / MS showed that the starting material was consumed and the desired compound was detected. The reaction mixture was quenched by adding saturated NaHCO (50 mL) and extracted with ethyl acetate (3 x 50 ml). The combined organic layer was washed with brine (50 mL), dried over Na SO, filtered and the filtrate was concentrated under reduced pressure to obtain a yellow colloid-like crude 3-(3-methoxy-3-oxo-propyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (1.60 g), which was directly used in the next reaction without further purification. MS (ISP): 459.2 ([2M+H] + ).

[1517] d) N-[(4-methoxyphenyl)methyl]-3-[3-[(4-methoxyphenyl)methylamino]-3-oxo-propyl]-5-oxo-pyrrolidine-3-carboxamide

[1518] The mixture of 3-(3-methoxy-3-oxo-propyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (800mg, 3.49mmol, 1.00eq) and 4-methoxybenzylamine (CAS2393-23-9, 15.0g, 109mmol, 14.2mL, 31.3eq.) was heated together at 200 ℃ and microwave irradiation for 2 hours. LC / MS shows that the starting material is consumed, and the desired compound is detected. The reaction mixture is diluted with water (100mL), acidified to pH=7 with 1N HCl aqueous solution, and extracted with dichloromethane (3x 200mL). The combined organic layer is washed with saline (100mL), through Na2SO4 drying, filtered and the filtrate is evaporated in vacuo. The residue was purified by preparative HPLC to give N-[(4-methoxyphenyl)methyl]-3-[3-[(4-methoxyphenyl)methylamino]-3-oxo-propyl]-5-oxo-pyrrolidine-3-carboxamide (1.00 g, 2.28 mmol, 32.7%) as a yellow gum. MS (ISP): 440.1 ([M+H] + ).

[1519] e) 7-[(4-methoxyphenyl)methyl]-2,7-diazaspiro[4.5]decane-3,6,8-trione

[1520] To a solution of N-[(4-methoxyphenyl)methyl]-3-[3-[(4-methoxyphenyl)methylamino]-3-oxo-propyl]-5-oxo-pyrrolidine-3-carboxamide (1.00 g, 2.28 mmol, 1.00 eq) in dimethylbenzene (20.0 mL), p-toluenesulfonic acid monohydrate (500 mg, 2.63 mmol, 1.15 eq) was added. The reaction mixture was degassed and purged with nitrogen three times, then stirred at 145 ° C and N2 atmosphere for 2 hours. LC / MS showed that the starting material was consumed and the desired compound was detected. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 7-[(4-methoxyphenyl)methyl]-2,7-diazaspiro[4.5]decane-3,6,8-trione (200 mg, 662 μmol, 29%) as a yellow gum. MS (ISP): 303.2 ([M+H] + ).

[1521] f) 7-[(4-methoxyphenyl)methyl]-2-methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione

[1522] To 7-[(4-methoxyphenyl)methyl]-2,7-diazaspiro[4.5]decane-3,6,8-trione (200mg, 662μmol, 1.00eq) in toluene (20.0mL) solution, sodium hydride (66.0mg, 1.65mmol, 60% purity, 2.49eq) was added, followed by iodomethane (235mg, 1.66mmol, 2.50eq). The reaction mixture was stirred at 60°C and N2 atmosphere for 1 hour. LC / MS showed that the starting material was consumed, and the desired compound was detected. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (50mL) and extracted with dichloromethane (3x 50mL). The combined organic layer was washed with brine (50mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, eluent: 0 to 5% methanol / dichloromethane) to give 7-[(4-methoxyphenyl)methyl]-2-methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione (100 mg, 316 μmol, 47.8%) as a yellow gum. MS (ISP): 317.1 ([M+H] + ).

[1523] g) 2-methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione

[1524] A solution of 7-[(4-methoxyphenyl)methyl]-2-methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione (300 mg, 948 μmol, 1.00 eq) in acetonitrile (10.0 mL) was treated with ammonium cerium (IV) nitrate (1.04 g, 1.90 mmol, 2.00 eq) in H2O (5.00 mL). The mixture was stirred at 25 °C for 1 hour. LC / MS showed that the starting material was consumed and the desired compound was detected. The reaction mixture was diluted with water (20 ml) and set to pH=7 by adding saturated NaHCO3 aqueous solution. The solid was filtered, concentrated under reduced pressure, dissolved in anhydrous methanol (20 ml) and filtered. The filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC to give 2-methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione (35.0 mg, 178 μmol, 18.8%) as a white solid. MS (ISP): 197.1 ([M+H] + ).

[1525] Example 3

[1526] (2-(2-phenylacetyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1527]

[1528] a) 2-(2-(4-bromophenyl)acetyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1529] To a suspension of 2-(4-bromophenyl)acetic acid (84.4 mg, 392 μmol, eq.1.1) and 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (60 mg, 357 μmol, eq.1) in N,N-dimethylformamide (1.5 ml) was added DIPEA (138 mg, 187 μl, 1.07 mmol, eq.3) and HATU (271 mg, 713 μmol, eq.2) at room temperature. The reaction mixture was stirred for 3 hours. The reaction mixture was distributed between ethyl acetate (40 ml) and 0.5 M aqueous sodium hydroxide solution (20 ml). The layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 25 ml). The combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by reverse phase HPLC and then freeze-dried to give 2-(2-(4-bromophenyl)acetyl)-2,7-diazaspiro[4.5]decane-6,8-dione (44 mg, 120 μmol, 34%) as an off-white solid. MS (ISP): 366.9 ([M+H] + ).

[1530] b) 2-(2-phenylacetyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1531] 10% palladium / carbon (11.4 mg, 10.7 μmol, Eq. 0.1) was added to a stirred suspension of 2-(2-(4-bromophenyl)acetyl)-2,7-diazaspiro[4.5]decane-6,8-dione (39 mg, 107 μmol, eq. 1) in methanol (5 ml). The reaction mixture was stirred for 4 hours at room temperature and a hydrogen atmosphere. The catalyst was collected by filtration and washed with methanol. The filtrate was then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluent: 0 to 10% methanol / dichloromethane) to obtain 2-(2-phenylacetyl)-2,7-diazaspiro[4.5]decane-6,8-dione (8.5 mg, 107 μmol, 28%) as an off-white solid. MS (ISP): 287 ([M+H] + ).

[1532] Example 4

[1533] 2-(2,3-Dihydro-1H-indene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1534]

[1535] Analogously to Example 3(a), using 2,3-dihydro-1H-indene-1-carboxylic acid (CAS 14381-42-1) instead of 2-(4-bromophenyl)acetic acid, the title compound was obtained as a white solid. MS (ISP): 374.1 ([M+H] + ).

[1536] Example 5

[1537] 2-(3-Nitrobenzoyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1538]

[1539] 3-Nitrobenzoic acid (238 mg, 1.43 mmol, eq. 1.2) was added to a mixture of 2,7-diazaspiro [4.5] decane-6,8-dione hydrochloride (200 mg, 1.19 mmol, eq. 1) and a solution of HATU in N,N-dimethylformamide 0.269 M (4.87 ml, 1.31 mmol, eq. 1.34), followed by DIPEA (615 mg, 831 μl, 4.76 mmol, eq. 4). The reaction mixture was stirred for 3 hours and kept overnight at room temperature. The reaction mixture was distributed between ethyl acetate and water. The layers were separated. The aqueous phase was extracted with ethyl acetate for the second time. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The product was purified by column chromatography (silica gel, eluent: 0 to 10% methanol / dichloromethane) to give 2-(3-nitrobenzoyl)-2,7-diazaspiro[4.5]decane-6,8-dione (50 mg, 158 μmol, 13.3%) as a pink powder. MS (ISP): 318.1 ([M+H] + ).

[1540] Example 6

[1541] 6-(6,8-Dioxo-2,7-diazaspiro[4.5]dec-2-yl)nicotinate

[1542]

[1543] 6-Chloronicotinoic acid methyl ester (CAS 73781-91-6, 41.9 mg, 244 μmol, eq. 1) and DIPEA (94.7 mg, 128 μl, 733 μmol, eq. 3) were added to a stirred solution of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (50 mg, 244 μmol, Eq. 1) in N,N-dimethylformamide (0.6 ml). The reaction mixture was shaken at 110 ° C for 24 hours and directly purified by preparative HPLC, then lyophilized to give 6-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)nicotinoic acid methyl ester (30.2 mg, 99.6 μmol, 40.8% yield) as a white solid. MS (ISP): 304.3 ([M+H] + ).

[1544] Example 7

[1545] 2-(Thiazolo[4,5-b]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1546]

[1547] Analogously to Example 6, 2-chlorothiazolo[4,5-b]pyridine (CAS 152170-30-4) was used instead of 6-chloronicotinate to obtain the title compound as a white solid. MS (ISP): 304.3 ([M+H] + ).

[1548] Example 8

[1549] 2-(4-Nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1550]

[1551] Analogously to Example 6, using 1-fluoro-4-nitrobenzene (CAS 350-46-9) instead of 6-chloronicotinate methyl ester, the title compound was obtained as a white solid. MS (ISP): 290.3 ([M+H] + ).

[1552] Example 9

[1553] 2-(5-Nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1554]

[1555] Analogously to Example 6, using 2-chloro-5-nitro-1H-benzo[d]imidazole (CAS 5955-72-6) instead of 6-chloronicotinate methyl ester, the title compound was obtained as a white solid. MS (ISP): 330.3 ([M+H] + ).

[1556] Example 10

[1557] (+)-2-(4-Nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione (Enantiomer 1)

[1558]

[1559] a) 2-(4-Nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1560] Analogously to Example 6, using 1-fluoro-4-nitrobenzene (CAS 350-46-9) instead of 6-chloronicotinate methyl ester, the title compound was obtained as a white solid. MS (ISP): 330.3 ([M+H] + ).

[1561] b) (+)-2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione (enantiomer 1)

[1562] The enantiomers of 2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione (415 mg) were separated using chiral HPLC (column: Chiralcel OD, eluent: heptane / ethanol+NH4OAc (60:40), pressure: 18 bar; flow rate: 35 ml / min) to give (+)-2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione (62 mg, yellow solid), retention time = 19.0 min. MS (ISP): 290.3 ([M+H] + ).

[1563] Embodiment 11

[1564] (-)-2-(4-Nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione (Enantiomer 2)

[1565]

[1566] The enantiomers of 2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione (415 mg) were separated using chiral HPLC (column: Reprosil Chiral-NR, eluent: heptane / ethanol+NH4OAc (60:40), pressure: 18 bar; flow rate: 35 ml / min) to give (-)-2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione (65 mg, yellow solid), retention time = 25.5 min. MS (ISP): 290.3 ([M+H] + ).

[1567] Example 12

[1568] 2-(Benzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1569]

[1570] To a suspension of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (23 mg, 112 μmol, Eq. 1) and DIPEA (43.6 mg, 58.9 μl, 337 μmol, Eq. 3) in DMF (0.5 ml) was added 2-chlorobenzo[d]thiazole (CAS 615-20-3, 21 mg, 16.1 μl, 124 μmol, eq. 1.1). The reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate / tetrahydrofuran (1:1). The organic layer was washed with water, then brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, eluent: 0 to 5% methanol / dichloromethane) to give 2-(benzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (10 mg, 33.2 μmol, 29.5%) as a white solid. MS (ISP): 302.1 ([M+H] + ).

[1571] Example 13

[1572] 2-(6,8-Dioxo-2,7-diazaspiro[4.5]dec-2-yl)-1H-benzo[d]imidazole-7-carboxylic acid methyl ester

[1573]

[1574] 2,7-diazaspiro [4.5] decane-6,8-dione hydrochloride (50 mg, 244 μmol, Eq. 1) was added to a stirred solution of N,N-dimethylformamide (600 μl) with 2-chloro-1H-benzo [d] imidazole-7-carboxylic acid methyl ester (CAS1171129-05-7, 51.5 mg, 244 μmol, eq. 1) and DIPEA (94.7 mg, 128 μl, 733 μmol, eq. 3). The reaction mixture was shaken at 110 ° C for 17 hours. The reaction mixture was distributed between water and a 1: 1 mixture of ethyl acetate and THF. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was added to CH2Cl2 and stirred at room temperature for 30 minutes. The product was collected by filtration, washed with CH2Cl2 and dried to give methyl 2-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)-1H-benzo[d]imidazole-7-carboxylate (19 mg, 55.5 μmol, 22.7% yield) as a light brown solid. MS (ISP): 343.3 ([M+H] + ).

[1575] Embodiment 14

[1576] 2-(6,8-Dioxo-2,7-diazaspiro[4.5]dec-2-yl)pyrimidine-4-carboxylic acid methyl ester

[1577]

[1578] Analogously to Example 13, using 2-chloropyrimidine-4-carboxylic acid methyl ester (CAS 149849-94-5) instead of 2-chloro-1H-benzo[d]imidazole-7-carboxylic acid methyl ester, the title compound was obtained as a light brown solid. MS (ISP): 305.3 ([M+H] + ).

[1579] Embodiment 15

[1580] 2-(Quinolin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1581]

[1582] Analogously to Example 13, using 2-chloroquinoline (CAS 612-62-4) instead of 2-chloro-1H-benzo[d]imidazole-7-carboxylic acid methyl ester, the title compound was obtained as a light brown solid. MS (ISP): 296.3 ([M+H] + ).

[1583] Example 16

[1584] 2-(6-Aminobenzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1585]

[1586] To a suspension of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (23 mg, 112 μmol, Eq. 1) and 2-chlorobenzo[d]thiazol-6-amine (CAS 2406-90-8, 20.8 mg, 112 μmol, eq. 1) in N,N-dimethylformamide (0.5 ml) was added DIPEA (43.6 mg, 58.9 μl, 337 μmol, eq. 3). The reaction mixture was stirred at 100° C. for 1 hour, then at 120° C. for 1 hour, and finally at 130° C. overnight. The reaction mixture was poured into a mixture of ethyl acetate / tetrahydrofuran (1:1), the organic layer was washed with water, then brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, eluent: 0 to 5% methanol / dichloromethane) to give 2-(6-aminobenzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (3 mg, 9.48 μmol, 8.44%) as a yellow solid. MS (ISP): 317.1 ([M+H] + ).

[1587] Embodiment 17

[1588] 2-(Oxazolo[4,5-b]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1589]

[1590] Analogously to Example 12, using 2-chlorooxazolo[4,5-b]pyridine (CAS 325976-45-2) instead of 2-chlorobenzo[d]thiazole, the title compound was obtained as a white solid. MS (ISP): 287.1 ([M+H] + ).

[1591] Embodiment 18

[1592] 2-(Benzo[d]oxazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1593]

[1594] Analogously to Example 12, using 2-chlorobenzo[d]oxazole (CAS 615-18-9) instead of 2-chlorobenzo[d]thiazole, the title compound was obtained as a white solid. MS (ISP): 286.1 ([M+H] + ).

[1595] Embodiment 19

[1596] 2-(1-Methyl-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1597]

[1598] Analogously to Example 12, using 2-chloro-1-methyl-1H-benzo[d]imidazole (CAS 1849-02-1) instead of 2-chlorobenzo[d]thiazole and heating at 135°C overnight instead of 100°C for 1 hour, the title compound was obtained as a brown solid. MS (ISP): 299.1 ([M+H] + ).

[1599] Embodiment 20

[1600] 2-(Thiazolo[4,5-c]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1601]

[1602] Analogously to Example 12, using 2-chlorothiazolo[4,5-c]pyridine (CAS 884860-63-3) instead of 2-chlorobenzo[d]thiazole, the title compound was obtained as a white solid. MS (ISP): 303.2 ([M+H] + ).

[1603] Embodiment 21

[1604] 2-(6,8-Dioxo-2,7-diazaspiro[4.5]dec-2-yl)benzo[d]thiazole-6-carboxylic acid methyl ester

[1605]

[1606] Analogously to Example 12, using methyl 2-chlorobenzo[d]thiazole-6-carboxylate (CAS 90792-69-1) instead of 2-chlorobenzo[d]thiazole and heating at 125°C overnight instead of 100°C for 1 hour, the title compound was obtained as a yellow solid. MS (ISP): 360.1 ([M+H] + ).

[1607] Embodiment 22

[1608] 2-(6,8-Dioxo-2,7-diazaspiro[4.5]dec-2-yl)thiazole-4-carboxylic acid methyl ester

[1609]

[1610] Analogously to Example 12, using methyl 2-chlorothiazole-4-carboxylate (CAS 850429-61-7) instead of 2-chlorobenzo[d]thiazole, the title compound was obtained as a white solid. MS (ISP): 310.1 ([M+H] + ).

[1611] Embodiment 23

[1612] 2-(6,8-Dioxo-2,7-diazaspiro[4.5]dec-2-yl)thiazole-5-carboxylic acid methyl ester

[1613]

[1614] Analogously to Example 12, using methyl 2-chlorothiazole-5-carboxylate (CAS 72605-86-8) instead of 2-chlorobenzo[d]thiazole, the title compound was obtained as a white solid. MS (ISP): 310.1 ([M+H] + ).

[1615] Embodiment 24

[1616] 6-(6,8-Dioxo-2,7-diazaspiro[4.5]dec-2-yl)nicotinate tert-butyl ester

[1617]

[1618] Analogously to Example 13, using tert-butyl 6-chloronicotinate (CAS 115309-57-4) instead of methyl 2-chloro-1H-benzo[d]imidazole-7-carboxylate, the title compound was obtained as a white solid. MS (ISP): 346.2 ([M+H] + ).

[1619] Embodiment 25

[1620] 2-(Benzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1621]

[1622] To a mixture of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (30 mg, 147 μmol, eq. 1) and benzo[d]thiazole-6-carboxylic acid (CAS 3622-35-3, 28.9 mg, 161 μmol, eq. 1.1) was added a solution of HATU in N,N-dimethylformamide 0.358 M (491 μl, 176 μmol, eq. 1.2) and N,N-diisopropylethylamine (75.8 mg, 100 μl, 586 μmol, eq. 4). The reaction mixture was shaken at 25 ° C for 4 hours. The reaction mixture was distributed between water and a 1: 1 mixture of ethyl acetate and tetrahydrofuran. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, eluent: 0 to 10% methanol / dichloromethane) to give 2-(benzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (17 mg, 51.6 μmol, 35.2%) as a white solid. MS (ISP): 330.1 ([M+H] + )

[1623] Embodiment 26

[1624] 2-(4-Nitropyridinecarbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1625]

[1626] Analogously to Example 25, 4-nitropyridinecarboxylic acid (CAS 13509-19-8) was used instead of benzo[d]thiazole-6-carboxylic acid to obtain the title compound as a white solid. MS (ISP): 319.1 ([M+H] + ).

[1627] Embodiment 27

[1628] 2-(2-Oxoindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1629]

[1630] Analogously to Example 25, using 2-oxoindoline-4-carboxylic acid (CAS 90322-37-5) instead of benzo[d]thiazole-6-carboxylic acid, the title compound was obtained as a light brown thick oil. MS (ISP): 328.2 ([M+H] + ).

[1631] Embodiment 28

[1632] Methyl 4-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzoate

[1633]

[1634] 4-(Methoxycarbonyl)benzoic acid (CAS 1679-64-7, 22 mg, 122 μmol, eq. 1), pyridine (93.4 μl) and 50% 1-propanephosphonic anhydride / ethyl acetate solution (155 mg, 145 μl, 244 μmol, eq. 2) were added to a mixture of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (30 mg, 147 μmol, eq. 1.2) and ethyl acetate (187 μl). The reaction mixture was shaken at 60 ° C for 17 hours. The reaction mixture was distributed between water and a 1: 1 mixture of ethyl acetate and tetrahydrofuran. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, eluent: 0 to 10% methanol / dichloromethane) to give methyl 4-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzoate (27 mg, 81.7 μmol, 66.9%) as a white solid. MS (ISP): 331.2 ([M+H] + )

[1635] Embodiment 29

[1636] 2-(Benzo[d]thiazole-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1637]

[1638] HATU (204 mg, 537 μmol, Eq. 2.2) and DIPEA (94.7 mg, 128 μl, 733 μmol, eq. 3.0) were added to a solution of 2,7-diazaspiro [4.5] decane-6,8-dione hydrochloride (50 mg, 244 μmol, eq. 1) and benzo [d] thiazole-5-carboxylic acid (CAS 68867-17-4, 48.2 mg, 269 μmol, eq. 1.1) in N, N-dimethylformamide (1.5 ml) at room temperature. The reaction mixture was stirred for 2 hours and then partitioned between ethyl acetate (30 ml) and water (15 ml). The layers were separated. The aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layers were washed with brine (25 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, eluent: 0 to 5% methanol / dichloromethane) to give 2-(benzo[d]thiazole-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (14 mg, 34 μmol, 13.9%) as a white solid. MS (ISP): 330.0 ([M+H] + ).

[1639] Embodiment 30

[1640] 2-(5-Nitropyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1641]

[1642] Analogously to Example 12, using 2-chloro-5-nitropyridine (CAS 4548-45-2) instead of 2-chlorobenzo[d]thiazole and heating at 100° C. for 5 hours instead of 1 hour, the title compound was obtained as a yellow solid. MS (ISP): 291.1 ([M+H] + ).

[1643] Embodiment 31

[1644] 2-(2-(Pyridin-3-yl)propionyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1645]

[1646] To a mixture of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (50 mg, 244 μmol, eq. 1) and 2-(pyridin-3-yl)propionic acid (CAS 90005-62-2, 44.3 mg, 293 μmol, eq. 1.2) in ethyl acetate (560 μl) was added 50% ethyl acetate solution of 1-propanephosphonic anhydride (311 mg, 291 μl, 489 μmol, eq. 2) and triethylamine (98.9 mg, 136 μl, 977 μmol, eq. 4). The reaction mixture was shaken at 60 ° C for 3 hours. According to LC / MS, the reaction was complete. The reaction mixture was filtered and the filtrate was directly purified by flash column chromatography (silica gel, 10 g, eluent: 0 to 20% methanol / dichloromethane) to give 2-(2-(pyridin-3-yl)propanoyl)-2,7-diazaspiro[4.5]decane-6,8-dione (57.2 mg, 190 μmol, 77.7%) as a white solid. MS (ISP): 302.15 ([M+H] + )

[1647] Embodiment 32

[1648] Methyl 6-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)picolinate

[1649]

[1650] Analogously to Example 6, using 6-chloro-2-pyridinecarboxylic acid methyl ester (CAS 6636-55-1) instead of 6-chloronicotinate methyl ester, the title compound was obtained as a brown solid. MS (ISP): 304.3 ([M+H] + ).

[1651] Embodiment 33

[1652] 2-(5-Nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (Enantiomer 1)

[1653]

[1654] The enantiomers of 2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (Example 9) were separated using chiral SFC (column: IC, 12 nm, 5 μm, 250 x 4.6 mm, 20% ethanol) to give 2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (Enantiomer 1) (24 mg, white solid), retention time = 4.07 min. MS (ISP): 330.3 ([M+H]+ ).

[1655] Embodiment 34

[1656] 2-(5-Nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (Enantiomer 2)

[1657]

[1658] The enantiomers of 2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (Example 9) were separated using chiral SFC (column: IC, 12 nm, 5 μm, 250 x 4.6 mm, 20% ethanol) to give 2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (Enantiomer 2) (24 mg, white solid), retention time = 4.55 min. MS (ISP): 330.3 ([M+H] + ).

[1659] Embodiment 35

[1660] 2-(1-Acetylindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1661] a) tert-Butyl 4-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)indoline-1-carboxylate

[1662] Analogously to Example 29, using 1-(tert-butyloxycarbonyl)indoline-4-carboxylic acid (CAS 208774-11-2) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as a light yellow solid. MS (ISP): 330.0 0 ([M+H] + ).

[1663] b) 2-(Indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1664] To a solution of tert-butyl 4-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)indoline-1-carboxylate (194 mg, 469 μmol, eq. 1) in 1,4-dioxane (2 ml) was added 4M hydrogen chloride solution in 1,4-dioxane (1.17 ml, 4.69 mmol, eq. 10) at room temperature. The reaction mixture was stirred for 3 days. The reaction mixture was then partitioned between ethyl acetate / tetrahydrofuran (1:1) (50 ml) and 2M aqueous sodium carbonate solution (30 ml). The layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluent: 0 to 10% methanol / dichloromethane) to give 2-(indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (102 mg, 326 μmol, 69.4%) as a yellow solid. MS (ISP): 314.0 ([M+H] + ).

[1665] c) 2-(1-acetylindole-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1666] Acetic anhydride (10.8 mg, 9.94 μl, 105 μmol, Eq.1.1) was added to a solution of 2-(indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (30 mg, 95.7 μmol, Eq.1) and triethylamine (19.4 mg, 26.7 μl, 191 μmol, Eq.2.0) in dichloromethane (0.5 ml) at room temperature. The reaction mixture was stirred for 15 hours. The crude material was directly purified by flash chromatography (loaded as impregnation, silica gel, eluent: 0 to 10% methanol / dichloromethane) to obtain 2-(1-acetylindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (34 mg, 95.7 μmol, 99.9% yield) as a white solid. MS(ISP):356.0([M+H] + ).

[1667] Embodiment 36

[1668] 2-Benzoyl-2,7-diazaspiro[4.5]decane-6,8-dione

[1669]

[1670] Analogously to Example 29, using benzoic acid (CAS 65-85-0) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as an orange solid. MS (ISP): 273.0 ([M+H] + ).

[1671] Embodiment 37

[1672] N-(3-(6,8-Dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)acetamide

[1673]

[1674] Analogously to Example 29, using 3-acetamidobenzoic acid (CAS 587-48-4) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as a white solid. MS (ISP): 330.0 ([M+H] + ).

[1675] Embodiment 38

[1676] 2-(1H-indazole-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1677]

[1678] Analogously to Example 29, using 1H-indazole-4-carboxylic acid (CAS 677306-38-6) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as a white solid. MS (ISP): 313.1 ([M+H] + ).

[1679] Embodiment 39

[1680] 2-(5-Aminopyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1681]

[1682] 10% palladium / carbon (34.6 mg, 32.6 μmol, eq. 0.05) was added to a solution of 2-(5-nitropyridine-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (189 mg, 651 μmol, eq. 1) in methanol (30 ml) and tetrahydrofuran (30 ml). The reaction mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The catalyst was collected by filtration and washed with methanol. The filtrate was then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluent: 0 to 10% methanol / dichloromethane) to obtain 2-(5-aminopyridine-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (101 mg, 388 μmol, 59.6%) as an off-white solid. MS (ISP): 287.0 ([M+H] + ).

[1683] Embodiment 40

[1684] 2-(Indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1685]

[1686] As described in Example 35(a) and (b), the title compound was obtained as a yellow solid. MS (ISP): 314.0 ([M+H] + ).

[1687] Embodiment 41

[1688] 2-(Indoline-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1689]

[1690] Analogously to Example 35a) and b), using 1-(tert-butyloxycarbonyl)indoline-6-carboxylic acid (CAS 208772-41-2) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as a white solid. MS (ISP): 314.0 ([M+H] + ).

[1691] Embodiment 42

[1692] 2-(1-Acetylindoline-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1693]

[1694] Analogously to Example 35(c), using 2-(indoline-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (from Example 41) instead of 2-(indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione, the title compound was obtained as a white solid. MS (ISP): 356.0 ([M+H] + ).

[1695] Embodiment 43

[1696] N-(6-(6,8-Dioxo-2,7-diazaspiro[4.5]dec-2-yl)pyridin-3-yl)acetamide

[1697]

[1698] To a suspension of 2-(5-aminopyridine-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (17 mg, 65.3 μmol, eq. 1) and Et3N (16.5 mg, 22.8 μl, 163 μmol, eq. 2.5) in dichloromethane (1 ml) was added acetic anhydride (10 mg, 9.24 μl, 98 μmol, eq. 1.5). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a mixture of ethyl acetate / tetrahydrofuran (1:2) and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluent: 0 to 10% methanol / dichloromethane) to give N-(6-(6,8-dioxo-2,7-diazaspiro[4.5]dec-2-yl)pyridin-3-yl)acetamide (11 mg, 36.4 μmol, 55.7%) as a light brown solid. MS (ISP): 303.1 ([M+H] + ).

[1699] Embodiment 44

[1700] 2-(Benzofuran-3-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1701]

[1702] Analogously to Example 29, using benzofuran-3-carboxylic acid (CAS 26537-68-8) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as an off-white solid. MS (ISP): 313.1 ([M+H] + ).

[1703] Embodiment 45

[1704] 2-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1705]

[1706] Analogously to Example 29, using pyrazolo[1,5-a]pyridine-3-carboxylic acid (CAS 16205-46-2) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as an off-white solid. MS (ISP): 313.1 ([M+H] + ).

[1707] Embodiment 46

[1708] 2-(Benzo[d]oxazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1709]

[1710] Analogously to Example 29, using 1,3-benzoxazole-6-carboxylic acid (CAS 154235-77-5) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as an off-white solid. MS (ISP): 314.1 ([M+H] + ).

[1711] Embodiment 47

[1712] 2-(Indoline-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1713]

[1714] Analogously to Example 29, using indoline-5-carboxylic acid (CAS 15861-30-0) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as an off-white solid. MS (ISP): 314.1 ([M+H] + ).

[1715] Embodiment 48

[1716] (+)-2-((R)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1717]

[1718] To a mixture of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (50 mg, 244 μmol, eq. 1) and (R)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (51.7 mg, 293 μmol, eq. 1.2) in ethyl acetate (560 μl) was added 50% 1-propanephosphonic anhydride in ethyl acetate (311 mg, 291 μl, 489 μmol, eq. 2), followed by triethylamine (98.9 mg, 136 μl, 977 μmol, eq. 4). The reaction mixture was shaken at 60 ° C for 3 hours. According to LC / MS, the reaction was complete. The reaction mixture was filtered and the filtrate was directly purified by flash column chromatography (silica gel, 10 g, eluent: 0 to 20% methanol / dichloromethane). According to chiral HPLC, the compound obtained was a racemic mixture of four diastereomers. The sample was purified by chiral HPLC (column: Reprosil Chiral-NR, eluent: heptane / ethanol+NH4OAc (70:30), pressure: 18 bar; flow rate: 35 ml / min) to give (+)-2-((R)-1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (25.6 mg, 78.4 μmol, 32.1% yield, mixture of epimers) as a white solid. Retention time = 46.8 min MS (ISP): 327.3 ([M+H] + ).

[1719] Embodiment 49

[1720] (-)-2-((S)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1721]

[1722] The mixture of diastereomers from Example 48 was purified by chiral HPLC (column: Reprosil Chiral-NR, eluent: heptane / ethanol+NH4OAc (70:30), pressure: 18 bar; flow rate: 35 ml / min) to give (-)-2-((S)-1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (27.9 mg, 85.5 μmol, 35% yield, mixture of epimers) as a white solid. Retention time = 68 min MS (ISP): 327.3 ([M+H] + ).

[1723] Embodiment 50

[1724] N-(5-(6,8-Dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzo[d]thiazol-2-yl)acetamide

[1725]

[1726] Analogously to Example 29, using 2-acetamidobenzo[d]thiazole-5-carboxylic acid (CAS 77850-40-9) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as an off-white solid. MS (ISP): 387.1 ([M+H] + ).

[1727] Embodiment 51

[1728] N-(6-(6,8-Dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzo[d]thiazol-2-yl)acetamide

[1729]

[1730] Analogously to Example 29, using 2-acetamidobenzo[d]thiazole-6-carboxylic acid (CAS 100817-94-5) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as an off-white solid. MS (ISP): 387.1 ([M+H]+).

[1731] Embodiment 52

[1732] 2-(1-Acetylindoline-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1733]

[1734] Analogously to Example 35(c), using 2-(indoline-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (from Example 47) instead of 2-(indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione, the title compound was obtained as a white solid. MS (ISP): 356.1 ([M+H] + ).

[1735] Embodiment 53

[1736] tert-Butyl (5-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzo[d]thiazol-2-yl)carbamate

[1737]

[1738] Analogously to Example 29, using 2-((tert-butoxycarbonyl)amino)benzo[d]thiazole-5-carboxylic acid (CAS 1824350-51-7) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as a white solid. MS (ISP): 445.1 ([M+H]+).

[1739] Embodiment 54

[1740] tert-Butyl (6-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzo[d]thiazol-2-yl)carbamate

[1741]

[1742] Analogously to Example 29, using 2-((tert-butoxycarbonyl)amino)benzo[d]thiazole-6-carboxylic acid (CAS 225525-50-8) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as an off-white solid. MS (ISP): 445.1 ([M+H]+).

[1743] Embodiment 55

[1744] 2-(2-Aminobenzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1745]

[1746] Trifluoroacetic acid (298 μl, 3.87 mmol, eq. 40) was added dropwise to a stirred solution of tert-butyl (6-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzo[d]thiazol-2-yl)carbamate (43 mg, 96.7 μmol, eq. 1) in dichloromethane (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was added to EtOAc / THF (1:3) and extracted with water and brine in sequence. 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% MeOH / DCM) to give 2-(2-aminobenzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (14 mg, 40.7 μmol, 42% yield) as a white solid. MS (ISP): 345.0 ([M+H] + ).

[1747] Embodiment 56

[1748] 2-(Benzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

[1749]

[1750] Analogously to Example 29, using benzo[d]thiazole-6-carboxylic acid (CAS 3622-35-3) instead of benzo[d]thiazole-5-carboxylic acid, the title compound was obtained as an off-white solid. MS (ISP): 330.1 ([M+H]+).

[1751] Embodiment 57

[1752] 8-(2-((R)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)octanamide

[1753]

[1754] a)(tert-Butyl 8-((3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)amino)-8-oxooctyl)carbamate

[1755] 2,7-diazaspiro[4.5]decane-6,8-dione (200 mg, 1.19 mmol, eq. 1) was dissolved in a solution of HATU in N,N-dimethylformamide (4.86 ml, 1.31 mmol, eq. 1.1, 0.269 mol / l), 3-(8-((tert-butyloxycarbonyl)amino)octanamido)benzoic acid (540 mg, 1.43 mmol, eq. 1.2) was added, followed by DIPEA (615 mg, 831 μl, 4.76 mmol, eq. 4). The reaction mixture was stirred at room temperature for 3 hours and then left overnight at room temperature. Water and ethyl acetate were added. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluent: 0 to 50% of ethyl acetate / heptane) to give tert-butyl (8-((3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)amino)-8-oxooctyl)carbamate (90 mg, 170 μmol, 14.3% yield) as an off-white powder. MS (ISP): 529.4 ([M+H] + ).

[1756] b) 8-Amino-N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)octanamide hydrochloride

[1757] To a solution of tert-butyl (8-((3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)amino)-8-oxooctyl)carbamate (90 mg, 170 μmol, eq.1) in ethyl acetate (1 ml) was added 4M HCl / dioxane solution (638 μl, 2.55 mmol, eq.15). The reaction was stirred at room temperature for 1 hour. According to LC-MS, the reaction was complete. The solvent was evaporated. The crude product was dissolved in a minimum amount of ethanol and diethyl ether was added. The obtained suspension was filtered to give 8-amino-N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)octanamide hydrochloride (40 mg, 86 μmol, 50.5% yield) and used directly in the next step.

[1758] c) 8-(2-((R)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)octanamide

[1759] (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (CAS 202592-23-2, 40 mg, 99.8 μmol, eq. 1) and 8-amino-N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)octanamide hydrochloride (51 mg, 110 μmol, eq. 1.1) were dissolved in a solution of HATU (445 μl, 120 μmol, eq. 1.2, 0.269 mol / l) in N,N-dimethylformamide and DIPEA (51.6 mg, 69.7 μl, 399 μmol, eq. 4) was added. The reaction mixture was shaken at room temperature for 3 hours. According to LC / MS, the reaction was complete. Water and dichloromethane were added. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluent: 0 to 20% methanol / dichloromethane) to obtain 8-(2-((R)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)octanamide (39.8 mg, 49.1 μmol, 49.2% yield) as an off-white solid. MS (ISP): 811.3 ([M+H] + ).

[1760] Embodiment 58

[1761] (S)-8-(1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

[1762]

[1763] HATU (449 mg, 1.18 mmol, eq. 2.0) and DIPEA (229 mg, 310 μl, 1.77 mmol, eq. 3.0) were added to a solution of 1,3,8-triazaspiro[4.5]decane-2,4-dione (CAS13625-39-3, 100 mg, 591 μmol, eq. 1) and (S)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (CAS85977-52-2, 109 mg, 621 μmol, eq. 1.05) in N,N-dimethylformamide (1 ml) at room temperature. The reaction mixture was stirred for 15 hours and then partitioned between ethyl acetate (50 ml) and water (30 ml). The layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 20 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by reverse phase HPLC and then lyophilized to give (S)-8-(1,2,3,4-tetrahydronaphthalene-1-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (45 mg, 137 μmol, 23.3%) as a white solid. MS (ISP): 328.0 ([M+H] + ).

[1764] Embodiment 59

[1765] (R)-8-(1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

[1766]

[1767] Analogously to Example 58, using (R)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (CAS 23357-47-3) instead of (S)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, the title compound was obtained as a white solid. MS (ISP): 328.0 ([M+H] + ).

[1768] Embodiment 60

[1769] 8-Benzoyl-1,3,8-triazaspiro[4.5]decane-2,4-dione

[1770]

[1771] Analogously to Example 58, using benzoic acid (CAS 65-85-0) instead of (S)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, the title compound was obtained as a white solid. MS (ISP): 274.1 ([M+H] + ).

[1772] Embodiment 61

[1773] 8-(Benzo[d]thiazol-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

[1774]

[1775] To a suspension of 1,3,8-triazaspiro[4.5]decane-2,4-dione (CAS 13625-39-3, 20 mg, 118 μmol, eq. 1) and DIPEA (45.8 mg, 61.9 μl, 355 μmol, eq. 3) in N,N-dimethylformamide (0.5 ml) was added 2-chlorobenzo[d]thiazole (22.1 mg, 130 μmol, eq. 1.1). The reaction mixture was stirred at 120° C. for 2 hours. The reaction mixture was poured into a mixture of ethyl acetate / tetrahydrofuran (1:1) and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, eluent: 0 to 5% methanol / dichloromethane) to give 8-(benzo[d]thiazol-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (11 mg, 36.4 μmol, 30.8%) as a white solid. MS (ISP): 303.1 ([M+H] + ).

[1776] Embodiment 62

[1777] 8-(Thiazolo[4,5-b]pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

[1778]

[1779] Analogously to Example 62, using 2-chlorothiazolo[4,5-b]pyridine (CAS 152170-30-4) instead of 2-chlorobenzo[d]thiazole, the title compound was obtained as a brown solid. MS (ISP): 304.1 ([M+H] + ).

[1780] Embodiment 63

[1781] 6-(2,4-dioxo-1,3,8-triazaspiro[4.5]dec-8-yl)nicotinate

[1782]

[1783] Analogously to Example 62, using methyl 6-chloronicotinate (CAS 73781-91-6) instead of 2-chlorobenzo[d]thiazole and stirring for 16 hours instead of 2 hours, the title compound was obtained as a brown solid. MS (ISP): 305.1 ([M+H] + ).

[1784] Embodiment 64

[1785] N-(4-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)phenyl)acetamide

[1786]

[1787] To a solution of 1,3,8-triazaspiro[4.5]decane-2,4-dione (36 mg, 213 μmol, eq. 1) and 4-acetamidobenzoic acid (CAS 556-08-1, 40 mg, 223 μmol, eq. 1.05) in N,N-dimethylformamide (1 ml) was added DIPEA (110 mg, 149 μl, 851 μmol, eq. 4) and HATU (121 mg, 319 μmol, eq. 1.5). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ethyl acetate / tetrahydrofuran (1: 1) and extracted with water, then 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 N-(4-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)phenyl)acetamide (10 mg, 30.3 μmol, 14.2%) as a white solid. MS (ISP): 331.1 ([M+H] + ).

[1788] Embodiment 65

[1789] N-(3-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)phenyl)acetamide

[1790]

[1791] Analogously to Example 64, using 3-acetamidobenzoic acid (CAS 587-48-4) instead of 4-acetamidobenzoic acid, the title compound was obtained as a white solid. MS (ISP): 329.1 ([MH]- ).

[1792] Embodiment 66

[1793] 8-(Benzofuran-3-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

[1794]

[1795] To a solution of 1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (CAS13625-48-4, 30 mg, 146 μmol, eq.1) and benzofuran-3-carboxylic acid (CAS26537-68-8, 31.6 mg, 195 μmol, eq.1.1) in N,N-dimethylformamide (0.5 ml) was added DIPEA (68.8 mg, 92.9 μl, 532 μmol, eq.3) and HATU (169 mg, 443 μmol, eq.2.5). The reaction mixture was stirred at room temperature for 2 hours and poured into ethyl acetate / tetrahydrofuran (2:1) (30 ml). The aqueous layer was extracted with two portions of ethyl acetate (2 x 20 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% methanol / dichloromethane) followed by preparative RP-HPLC and lyophilized to afford 8-(benzofuran-3-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (3.3 mg, 10.5 μmol, 7.22%) as a yellow solid. MS (ISP): 314.1 ([M+H] + ).

[1796] Embodiment 67

[1797] 8-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

[1798]

[1799] Analogously to Example 66, using pyrazolo[1,5-a]pyridine-3-carboxylic acid (CAS 16205-46-2) instead of benzofuran-3-carboxylic acid, the title compound was obtained as a white solid. MS (ISP): 314 ([M+H] + ).

[1800] Embodiment 68

[1801] 8-(Thiazolo[4,5-b]pyridin-2-yl)-2,8-diazaspiro[4.5]decane-1,3-dione

[1802]

[1803] Analogously to Example 61, using 2-chlorothiazolo[4,5-b]pyridine (CAS 152170-30-4) instead of 2-chlorobenzo[d]thiazole and using 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (CAS 2696-03-9) instead of 1,3,8-triazaspiro[4.5]decane-2,4-dione, the title compound was obtained as a grey solid. MS (ISP): 303.1 ([M+H] + ).

[1804] Embodiment 69

[1805] 8-(5-Nitropyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

[1806]

[1807] Analogously to Example 61, using 2-chloro-5-nitropyridine (CAS 4548-45-2) instead of 2-chlorobenzo[d]thiazole, the title compound was obtained as a yellow solid. MS (ISP): 292.1 ([M+H] + ).

[1808] Embodiment 70

[1809] 8-(5-Nitropyridin-2-yl)-2,8-diazaspiro[4.5]decane-1,3-dione

[1810]

[1811] Analogously to Example 61, using 2-chloro-5-nitropyridine (CAS 4548-45-2) instead of 2-chlorobenzo[d]thiazole and 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (CAS 2696-03-9) instead of 1,3,8-triazaspiro[4.5]decane-2,4-dione, the title compound was obtained as a grey solid. MS (ISP): 291.1 ([M+H] + ).

[1812] Embodiment 71

[1813] 8-(Benzo[d]thiazol-2-yl)-2,8-diazaspiro[4.5]decane-1,3-dione

[1814]

[1815] Analogously to Example 61, 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (CAS 2696-03-9) was used instead of 1,3,8-triazaspiro[4.5]decane-2,4-dione to obtain the title compound as a grey solid. MS (ISP): 302.0 ([M+H] + ).

[1816] Embodiment 72

[1817] 8-(4-Nitrophenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

[1818]

[1819] Analogously to Example 61, using 1-fluoro-4-nitrobenzene (CAS 350-46-9) instead of 2-chlorobenzo[d]thiazole, the title compound was obtained as a yellow solid. MS (ISP): 291.0 ([M+H] + ).

[1820] Embodiment 73

[1821] 8-(4-Nitrophenyl)-2,8-diazaspiro[4.5]decane-1,3-dione

[1822]

[1823] Analogously to Example 61, using 1-fluoro-4-nitrobenzene (CAS 350-46-9) instead of 2-chlorobenzo[d]thiazole and 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (CAS 2696-03-9) instead of 1,3,8-triazaspiro[4.5]decane-2,4-dione, the title compound was obtained as a grey solid. MS (ISP): 291.1 ([M+H] + ).

[1824] Embodiment 74

[1825] 6-(1,3-Dioxo-2,8-diazaspiro[4.5]dec-8-yl)nicotinate

[1826]

[1827] Analogously to Example 61, using methyl 6-chloronicotinate (CAS 73781-91-6) instead of 2-chlorobenzo[d]thiazole and 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (CAS 2696-03-9) instead of 1,3,8-triazaspiro[4.5]decane-2,4-dione, the title compound was obtained as an off-white solid. MS (ISP): 304.1 ([M+H] + ).

[1828] Embodiment 75

[1829] 8-Benzoyl-2,8-diazaspiro[4.5]decane-1,3-dione

[1830]

[1831] Benzoyl chloride (CAS 98-88-4, 49.5 mg, 40.9 μl, 352 μmol, eq.1.2) was added to a solution of 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (60 mg, 293 μmol, eq.1) and triethylamine (89 mg, 123 μl, 880 μmol, eq.3) in tetrahydrofuran (1.5 ml) at 5 °C. The reaction mixture was stirred for 3 hours. LC / MS showed that the reaction was complete. The reaction mixture was distributed between ethyl acetate / tetrahydrofuran 1:1 (20 ml) and brine (25 ml). The layers were separated. The aqueous layer was extracted with a portion of ethyl acetate (15 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was subjected to flash chromatography (silica gel, 4 g, 0% to 10% methanol / dichloromethane) to afford 8-benzoyl-2,8-diazaspiro[4.5]decane-1,3-dione (25.2 mg, 92.5 μmol, 31.6%) as a white solid. MS (ISP): 273.1 ([M+H] + ).

[1832] Embodiment 76

[1833] 8-(Benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione

[1834]

[1835] 1-Chloro-N,N,2-trimethyl-1-propenamine (47 mg, 46.5 μl, 352 μmol, Eq. 1.2) was added to a suspension of benzo[d]thiazole-5-carboxylic acid (55.2 mg, 308 μmol, eq. 1.05) in tetrahydrofuran (1 ml). The mixture was stirred for 1.5 hours and added to a pre-stirred suspension of 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (60 mg, 293 μmol, eq. 1) and DIPEA (114 mg, 154 μl, 880 μmol, eq. 3.0) in tetrahydrofuran (1 ml) at room temperature in one portion. The reaction mixture was stirred for 1.5 hours. LC / MS showed that the reaction was complete. The reaction mixture was distributed between ethyl acetate (30 ml) and 1M aqueous sodium carbonate solution (15 ml). The aqueous layer was extracted with a portion of ethyl acetate (30 ml). The combined organic layers were washed with a portion of brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by preparative RP-HPLC and then lyophilized to give 8-(benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione (16 mg, 48.6 μmol, 16.6%) as a white solid. MS (ISP): 330.1 ([M+H] + ).

[1836] Embodiment 77

[1837] (S)-8-(1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione (or enantiomer)

[1838] a) (R)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl chloride

[1839]

[1840] To a solution of (R)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (250 mg, 1.42 mmol, eq. 1) in dichloromethane (11 ml) was added thionyl chloride (203 mg, 124 μl, 1.7 mmol, eq. 1.2) and a catalytic amount of N,N-dimethylformamide at room temperature. The reaction mixture was stirred for 3 hours. The solvent was concentrated in vacuo to give (R)-1,2,3,4-tetrahydronaphthalene-1-carbonyl chloride (276 mg, 1.42 mmol, 99.9%) as a colorless oil, which was used in the next step without further purification. b) 8-(Benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione

[1841] To a suspension of 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (60 mg, 293 μmol, eq. 1) and triethylamine (89 mg, 123 μl, 880 μmol, eq. 3.0) in tetrahydrofuran (1.5 ml) was added dropwise (R)-1,2,3,4-tetrahydronaphthalene-1-carbonyl chloride (62.8 mg, 322 μmol, eq. 1.1) at 0°C-5°C. The cooling bath was removed after 5 minutes and the reaction mixture was stirred for 15 hours. The reaction was quenched by the addition of 2M aqueous sodium carbonate solution (5 ml). The reaction mixture was distributed between ethyl acetate (30 ml) and 2M aqueous sodium carbonate solution (15 ml). The layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. Analytical chiral HPLC of the product showed that some racemization occurred during the reaction. The crude material was purified by flash column chromatography (silica gel, 4 g, 0% to 5% methanol / dichloromethane) to give 8-(1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione (16 mg, 41.7 μmol, 14.2%) as a white solid. MS (ISP): 327.1 ([M+H] + ).

[1842] c) (S)-8-(Benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione (or enantiomer)

[1843] The enantiomers of 8-(benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione were separated using chiral HPLC (column: Reprosil Chiral-NR, eluent: heptane / ethanol+NH4OAc (60:40), pressure: 18 bar; flow rate: 35 ml / min) to give (S)-8-(benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione (or enantiomer) (9.4 mg, white solid), retention time = 8.87 min. MS (ISP): 327.1 ([M+H] + ).

[1844] Embodiment 78

[1845] (R)-8-(1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione (or enantiomer)

[1846]

[1847] The enantiomers of 8-(benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione were separated using chiral HPLC (column: Reprosil Chiral-NR, eluent: heptane / ethanol+NH4OAc (60:40), pressure: 18 bar; flow rate: 35 ml / min) to give (R)-8-(benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione (or enantiomer) (9.4 mg, white solid), retention time = 11.28 min. MS (ISP): 327.1 ([M+H] + ).

[1848] Embodiment 79

[1849] 8-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione

[1850]

[1851] 1-Chloro-N,N,2-trimethylpropenamine (39.6 mg, 39.2 μl, 296 μmol, Eq. 1.2) was added to a suspension of pyrazolo[1,5-a]pyridine-3-carboxylic acid (CAS 68867-17-4) 40 mg, 247 μmol, eq. 1) in tetrahydrofuran (0.5 ml) at 0°C-5°C. The reaction mixture was stirred at 0°C for 30 minutes to obtain a white suspension. The reaction mixture was stirred at room temperature for 15 minutes and then added to a suspension of 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (50.5 mg, 247 μmol, eq. 1) and DIPEA (95.7 mg, 129 μl, 740 μmol, eq. 3) in tetrahydrofuran (0.5 ml). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ethyl acetate / tetrahydrofuran (1:3) and extracted with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4g, 0% to 10% MeOH / dichloromethane) to give 8-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione (42mg, 134μmol, 54.5%) as a white solid. MS (ISP): 313.1 ([M+H] + ).

[1852] Embodiment 80

[1853] 8-(Benzofuran-3-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione

[1854]

[1855] Analogously to Example 79, benzofuran-3-carboxylic acid (CAS 26537-68-8) was used instead of pyrazolo[1,5-a]pyridine-3-carboxylic acid to obtain the title compound as a yellow solid. MS (ISP): 291.0 ([M+H] + ).

[1856] Embodiment 81

[1857] 8-(Benzo[d]thiazole-5-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

[1858]

[1859] Analogously to Example 66, using benzo[d]thiazole-5-carboxylic acid (CAS 68867-17-4) instead of benzofuran-3-carboxylic acid and stirring overnight instead of 2 hours, the title compound was obtained as a white solid. MS (ISP): 331.1 ([M+H] + )

[1860] Pharmacological tests

[1861] The compounds described herein and their pharmaceutically acceptable salts possess valuable pharmacological properties. The compounds were investigated according to the tests given below.

[1862] Fluorescence direct binding protocol

[1863] 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. Corrections for protein dilution and filter effects were made to the fluorescence intensity (Birdsall, B., King, RW, Wheeler, MR, Lewis, CAJr, Goode, SR, Dunlap, RB & Roberts, GC (1983). Anal. Biochem. 132, 353–361). Corrected fluorescence intensity was plotted against ligand concentration and fitted using a four-parameter Sigmoidal function, from which the equilibrium dissociation constant K was calculated using the law of mass action (assuming a 1:1 protein-ligand complex).d (Eftink, Methods Enzymol. 1997; 278: 221-57). The method includes the following:

[1864] 1) Optimize measurement parameters to minimize protein consumption and minimize dilution effects and DMSO content

[1865] 2) Titration measurements of the protein against the ligand were performed in at least 12 titration steps to obtain an S-curve fit

[1866] 3) Repeat the same titration measurement with the ligand alone for calibration

[1867] 4) Check the stability of the protein by titration against DMSO alone

[1868] 5) Determine the molar extinction coefficient of the ligand at 280 and 340 nm using a UV spectrophotometer

[1869] 6) Use Excel template to correct the raw data of the measurement

[1870] 7) Quadratic binding fitting and KD estimation were performed using GraphPad Prism software.

[1871] Table 8. Parameters for the fluorescent direct binding protocol

[1872]

[1873] Table 2. ISS-PC1 device settings

[1874] Excitation wavelength [nm] 280 Emission wavelength [nm] 340 Colorimetric cup Hellma 115F-QS Volume [μL] 500

[1875] Table 9. Protein preparation

[1876] Protein volume [μL] Buffer volume [μL] Protein concentration [M] 1.8@2.54mg / ml 498.2 5.0E-8

[1877] Table 10. Titration steps for determining S-curve fit

[1878]

[1879] Table 11A. Affinity of selected compounds for Cereblon

[1880]

[1881]

[1882]

[1883]

[1884]

[1885]

[1886]

[1887]

[1888]

[1889]

[1890]

[1891]

[1892] Table 5B. Affinity of selected compounds for Cereblon

[1893]

[1894]

[1895]

[1896]

[1897]

[1898]

[1899] 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.

[1900] 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: A is selected from CH2 and NH; X 1a is selected from aromatic groups and R 2a substituted aryl; X 1b is selected from aromatic groups and R 2b substituted aryl; X 1c Selected from aryl and R 2c substituted aryl; X 1d is selected from aryl and R 2d substituted aryl; X 2a is selected from heterocyclic groups, R 3 Substituted heterocyclic group, heteroaryl group, R 4 substituted heteroaryl, and C 1-6 -alkyl; X 3a is selected from hydrogen, heterocyclic, R 3 Substituted heterocyclic group, heteroaryl group, R 4 substituted heteroaryl, and C 1-6 -alkyl; X 4a is selected from hydrogen, aryl, R 2 Substituted aryl, heterocyclic, R 3 Substituted heterocyclic group, heteroaryl group, R 4 substituted heteroaryl, and C 1-6 -alkyl; X 5a For R 6a substituted aryl; X 6a is an aryl group substituted with -C(=O)-OH; X 7a is selected from heteroaryl and R 7 substituted heteroaryl; X 8a For R 7a substituted heteroaryl; X B Selected from: aryl; 6 substituted aryl; heteroaryl; and 7 substituted heteroaryl; Y B Absent or –C(=O)-; R 1 Does not exist or is =O; R 2 Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; -OH; and –NO2; R 2a Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; -OH; and –NO2; R 2b Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; and –NO2; R 2c Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; and –NO2; R 2d Selected from: -C(=O)-OC 1-6 -alkyl; -NH-C(=O)-C 1-6 -alkyl; -NH2; and –NO2; R 3 Selected from -C(=O)-C 1-6 -alkyl and =O; R 4 Selected from -C(=O)-OC 1-6 -alkyl; C 1-6 Alkyl; -NH2; -NH-C(=O)-C 1-6 -alkyl; and –NO2; R 5 C 1-6 -alkyl; R 6 Selected from: -C(=O)-OH; -NH-C(=O)-C 1-6 -alkyl; -NH2; and –NO2; R 6a Selected from: -C(=O)-OH; -NH-C(=O)-C 1-6 -alkyl; and –NO2; R 7 Selected from: -C(=O)-OH; -C(=O)-OC 1-6 -alkyl; -NH2; and -NO2; and R 7a Selected from -C(=O)-OH and -C(=O)-OC 1-6 -alkyl.

Images