Heterocyclic compounds used in drug therapy

Abstract

The present invention provides heterocyclic compounds that bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and their use in treating abnormal cell proliferation in humans or other hosts. The present invention also provides compounds that can be used as synthetic intermediates for synthesizing bifunctional compounds for targeted protein degradation.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 814,706, filed on March 6, 2019. The entire contents of that application are incorporated herein by reference. Technical Field

[0003] The present invention provides compounds that bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and can alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, leading to the degradation of intrinsic downstream proteins that mediate disease. The present invention also provides compounds that can be used as synthetic intermediates for preparing bifunctional compounds for targeted 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

[0004] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective recognition and removal of damaged, misfolded, or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). The UPP is central to regulating virtually all cellular processes, including antigen processing, apoptosis, organelle biogenesis, the cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neural and muscle degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels, and secretory pathways, responses to stress and extracellular mediators, ribosome biogenesis, and viral infection.

[0005] The covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases marks proteins for degradation by the proteasome, where they are digested into small peptides and ultimately their component amino acids, which serve as building blocks for new proteins. Defective proteasomal degradation has been linked to a variety of clinical disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0006] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, highlighting its physiological importance. Cereblon is part of an E3 ubiquitin ligase protein complex that interacts with damaged DNA-binding protein 1 (DDB1). This complex, along with Cullin4 (CUL4A) and the E2-binding protein ROC1 (also known as RBX1), forms an E3 ubiquitin ligase complex, where it functions as a substrate receptor to select proteins for ubiquitination. Through mechanisms that are not yet 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 numerous developmental processes, such as limb and auditory vesicle formation. Consequently, this E3 ubiquitin ligase complex is important for embryonic limb growth. In the absence of cereblon, DDB1 forms a complex with DDB2, which functions as a DNA damage-binding protein.

[0007] 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 the cause of thalidomide teratogenicity. After the discovery of thalidomide causing teratogenicity in the mid-1960s, although the compound and certain related structures were found to be useful as anti-inflammatory, anti-angiogenic, and anticancer agents (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 along with its structural derivatives, lenalidomide and pomalidomide, for the treatment of various 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).

[0008] The disclosure of thalidomide binding to the cereblon E3 ubiquitin ligase has led to research investigating the incorporation of thalidomide and certain derivatives into compounds for targeted protein destruction. 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; 7,820,697 ; those in 7,874,984; 7,959,566; 8,204,763; 8,315,886; 8,589,188; 8,626,531; 8,673,939; 8,735,428; 8,741,929; 8,828,427; 9,056,120; 9,101,621; and 9,101,622.

[0009] Patent applications filed by C4 Therapeutics, Inc. that describe compounds capable of binding to E3 ubiquitin ligases include: WO 2019 / 236483, entitled “Spirocyclic Compounds”; WO 2019 / 191112, entitled “Cereblon Binders for the Degradation of Ikaros”; WO 2019 / 099868, entitled “Degraders and Degrons for Targeted Protein Degradation”; WO 2018 / 237026, entitled “N / O-Linked Degrons and Degronimers for Protein Degradation”; WO 2017 / 197051, entitled “Amine-Linked C3-Glutarimide Degronimers for Target Protein Degradation”; WO 2017 / 197055, entitled “Heterocytic Degronimers for Target Protein Degradation”; and WO 2017 / 197036, entitled “Spirocyclic Degronimers for Target Protein Degradation”; WO 2017 / 197046 20, entitled “C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation”; and WO 2017 / 197056, entitled “Bromodomain Targeting Degronimers for Target Protein Degradation”.

[0010] Patent applications filed by C4 Therapeutics, Inc. and Hoffmann-La Roche describing compounds capable of binding to E3 ubiquitin ligases include: WO 2019 / 121562, entitled “Bifunctional Inhibitors with EGFR having a E3 Ubiquitin Ligase Moiety”; WO 2019 / 149922, entitled “Compounds Which Cause Degradation of EGFR, for use Against Cancer”; WO 2018 / 220149, entitled “Compounds”; and WO 2018 / 115218, entitled “2-Benzopyrazinyl-N-heteroaryl-2-phenyl-acetamide Compounds.”

[0011] Other compound publications include: WO 2011 / 035124; WO 02 / 072576; WO 2010 / 085684; WO2014 / 134240; WO 2011 / 130628; WO 2007 / 065518; WO 2016 / 176640; WO 2009 / 135651; WO2011 / 156245; WO 2017 / 046318; WO 2010 / 130794; WO 2012 / 021382; WO 2005 / 060967; WO2012 / 174199; EP385850; WO 2016 / 176449; WO 2016 / 040508;WO 00 / 20358; 2009 / 050232; WO 2018 / 93569; Terefenk et al., Bioorg.Med.Chem.Lett.2005,15(15):3600-03; Smolyar et al., Russian Journal ofOrganic Chemistry 2011,47(8):119-3; Jun Yon Choi et al., J. Med. Chem. 2012, 55(13): 852-70.

[0012] There is a need for new compounds, compositions and uses thereof that bind to the E3 ligase protein cereblon to treat various medical conditions, particularly abnormal cell proliferation. There is also a need for new compounds that can be used to prepare bifunctional molecules for degrading proteins involved in disease processes. Summary of the Invention

[0013] In a first aspect, compounds that bind cereblon and modify the ubiquitination of proteins by cereblon-containing E3 ubiquitin ligases, and their uses and preparation are provided. In a second aspect, compounds containing a chemical moiety capable of binding cereblon are provided, which can be used as synthetic intermediates for preparing bifunctional compounds that cause degradation of selected proteins via the ubiquitin proteosome pathway (UPP).

[0014] The compounds described herein can be administered to a host in need thereof, such as a human, in an effective amount, optionally as a pharmaceutically acceptable salt, and optionally in a pharmaceutically acceptable composition. The compounds can be administered for any therapeutic indication that is treated by modulating the function or activity of a cereblon-containing E3 ubiquitin ligase protein complex, including but not limited to the treatment of abnormal cell proliferation, such as cancer or tumors, or other known uses of the cereblon binders thalidomide, pomalidomide, and lenalidomide. In certain embodiments, the compounds described herein can modulate the natural activity of cereblon.

[0015] The present invention includes novel compounds of Formula I, II-a to II-k, III, IV-a to IV-j, V, VI, VII-a to VII-e, VIII-a to VIII-i, IX-a to IX-j, Xa to Xi, XI-a to XI-i, XII, and XIII-a to XIII-I. Furthermore, the present invention includes the use of compounds of Formula XIV 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 of Formula XIV (1) for preparing bifunctional compounds that degrade target proteins via the ubiquitin proteasome pathway (UPP). The present invention also includes compounds of formula I(1), formula II(1)-a to II(1)-k, formula III(1), formula IV(1)-a to IV(1)-j, formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1) and formula XIII(1)-a to XIII(1)-i.

[0016] In one aspect, compounds of formula I are provided:

[0017]

[0018] or a pharmaceutically acceptable salt thereof;

[0019] in:

[0020] A 1 is selected from the group consisting of -O-, -S-, -CH2-, -CF2-, and -NH-, and A 2 is -CH2-; or

[0021] A 1 is selected from the group consisting of -O-, -S-, -CH2-, and -CF2-, and A 2 is -NH-;

[0022] W is CH or N;

[0023] R 3 independently selected at each occurrence from: 10 Substituted -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; 10 Substituted -(CH2) 0-1 -aryl; -(CH2) 0-1 -aryl; 10 Substituted -(CH2) 0-1 -C 3-7 Cycloalkyl; -(CH2) 0-1 -C 3-7 Cycloalkyl; R 9 Substituted -(CH2) 0-1 -heteroaryl; -(CH2) 0-1 -heteroaryl; -(CH2) 0-1 -heterocycloalkyl; -C(=O)C 1-6 Alkyl; -(CH2) 0-2 -C(=O)-N(R 7 ,R 8 ); -C(=O)OC 1-6 Alkyl; -C 1-6 Alkoxy; -C 1-6 Alkyl; -OH; -NO2; -C 1-6 Alkyl-N(R 11 )-C(=O)-R 12 ; by R 10 Substituted -CH2-O-(CH2) 0-1-aryl; -CH2-O-(CH2) 0-1 -aryl; -O-(CH2) 0-1 -Aryl; -Halogen; -Halogen-C 1-6 Alkyl; -hydroxy-C 1-6 Alkyl; -hydroxy-C 1-6 Alkyl-aryl; -N(R 5 ,R 6 ); -NH-C(=O)C 1-6 Alkyl; -NH-C(=O)OC 1-6 Alkyl; and =O, if valence permits;

[0024] m is 0, 1, or 2;

[0025] R 5 and R 6 independently selected at each occurrence from H, C 1-6 Alkyl and phenyl groups;

[0026] or R 5 and R 6 together with the nitrogen to which they are attached, form a heterocycloalkyl ring;

[0027] R 7 and R 8 independently selected at each occurrence from H and C 1-6 alkyl;

[0028] or R 7 and R 8 together with the nitrogen to which they are attached, form a heterocycloalkyl ring;

[0029] R 9 In each occurrence, independently selected from C 1-6 Alkoxy, C 1-6 Alkyl, halogen, halogen-C 1-6 Alkyl, heteroaryl and C 1-6 Alkyl or C 1-6 alkoxy-substituted heteroaryl;

[0030] R 10 In each occurrence, independently selected from C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Alkyl-C 1-6 Alkoxy, halogen and halogen-C 1-6 alkyl;

[0031] R 11 independently selected at each occurrence from H and C 1-6 alkyl; and

[0032] R 12independently selected at each occurrence from H, C 1-6 Alkyl and C 3-7 Cycloalkyl.

[0033] In another aspect, a compound having one of the following formulae is provided:

[0034]

[0035]

[0036] or a pharmaceutically acceptable salt thereof;

[0037] in:

[0038] R 4 independently selected at each occurrence from: 10 Substituted -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; 10 Substituted -(CH2) 0-1 -aryl; -(CH2) 0-1 -aryl; 10 Substituted -(CH2) 0-1 -C 3-7 Cycloalkyl; -(CH2) 0-1 -C 3-7 Cycloalkyl; R 9 Substituted -(CH2) 0-1 -heteroaryl; -(CH2) 0-1 -heteroaryl; =O, valence permitting; -C(=O)C 1-6 Alkyl; -C(=O)-N(R 7 ,R 8 ); -C(=O)OC 1-6 Alkyl; -C 1-6 Alkoxy; -C 1-6 Alkyl; R 10 Substituted -CH2-O-(CH2) 0-1 -aryl; -CH2-O-(CH2) 0-1 -Aryl; -Halogen; -Halogen-C 1-6 Alkyl; -hydroxy-C 1-6 Alkyl; -N(R 5 ,R 6 ); and -NH-C(=O)C 1-6 alkyl;

[0039] n is 1 or 2; and

[0040] All other variables are as defined herein.

[0041] In another aspect, compounds of formula III are provided:

[0042]

[0043] or a pharmaceutically acceptable salt thereof;

[0044] wherein all variables are as defined herein.

[0045] In another aspect, a compound having one of the following formulae is provided:

[0046]

[0047] or a pharmaceutically acceptable salt thereof;

[0048] wherein all variables are as defined herein.

[0049] In another aspect, compounds of Formula V are provided:

[0050]

[0051] or a pharmaceutically acceptable salt thereof;

[0052] wherein all variables are as defined herein.

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

[0054]

[0055] or a pharmaceutically acceptable salt thereof;

[0056] in:

[0057] R 2 independently selected at each occurrence from: 10 Substituted -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; 10 Substituted -(CH2) 0-1 -aryl; -(CH2) 0-1 -aryl; 10 Substituted -(CH2) 0-1 -C 3-7 Cycloalkyl; -(CH2) 0-1 -C 3-7 Cycloalkyl; R 9 Substituted -(CH2) 0-1 -heteroaryl; -(CH2)0-1 -heteroaryl; -C(=O)C 1-6 Alkyl; -C(=O)-N(R 7 ,R 8 ); -C(=O)OC 1-6 Alkyl; -C 1-6 Alkoxy; -C 1-6 Alkyl; R 10 Substituted -CH2-O-(CH2) 0-1 -aryl; -CH2-O-(CH2) 0-1 -aryl; -O-(CH2) 0-1 -Aryl; -Halogen; -Halogen-C 1-6 Alkyl; -hydroxy-C 1-6 Alkyl; -N(R 5 ,R 6 );-NO2;-NH-C(=O)C 1-6 Alkyl; and -SO2-N(R 5 ,R 6 );and

[0058] All other variables are as defined herein.

[0059] In another aspect, a compound having one of the following formulae is provided:

[0060]

[0061] or a pharmaceutically acceptable salt thereof;

[0062] wherein all variables are as defined herein.

[0063] In another aspect, a compound having one of the following formulae is provided:

[0064]

[0065] or a pharmaceutically acceptable salt thereof;

[0066] wherein all variables are as defined herein.

[0067] In another aspect, a compound having one of the following formulae is provided:

[0068]

[0069]

[0070] or a pharmaceutically acceptable salt thereof;

[0071] wherein all variables are as defined herein.

[0072] In another aspect, a compound having one of the following formulae is provided:

[0073]

[0074]

[0075] or a pharmaceutically acceptable salt thereof;

[0076] wherein all variables are as defined herein.

[0077] In another aspect, a compound having one of the following formulae is provided:

[0078]

[0079] or a pharmaceutically acceptable salt thereof;

[0080] wherein all variables are as defined herein.

[0081] In another aspect, provided is a compound of Formula XII:

[0082]

[0083] or a pharmaceutically acceptable salt thereof;

[0084] in:

[0085] A is selected from: optionally with one or two R 2 substituted aryl; optionally substituted by one or two R 3 Heteroaryl substituted with one or two R 4 Heterocycloalkyl substituted with a group; -NH-C(=O)-C 1-6 Alkyl; and cycloalkyl; and

[0086] All other variables are as defined herein.

[0087] In another aspect, a compound having one of the following formulae is provided:

[0088]

[0089]

[0090] or a pharmaceutically acceptable salt thereof;

[0091] wherein all variables are as defined herein.

[0092] In another aspect, provided is a compound of formula XIV:

[0093]

[0094] or a pharmaceutically acceptable salt thereof for treating a condition that can be treated by modulating the function or activity of a cereblon-containing E3 ubiquitin ligase protein complex;

[0095] Wherein Z is selected from: covalent bond; carbonyl; -(CH2) 0-2 -NR 1 -(CH2) 0-2 -;-(NR 1 ) 0-1 -C(=O)-(NR 1 ) 0-1 -;-(NR 1 ) 0-1 -C(=O)-(CH2) 1-3 -;-O-(CH2) 0-2 -C(=O)-NR 1 -;-(CH2) 1-3 -;-(CH2) 1-3 -;-(CH2) 0-2 -O-(CH2) 0-2 ; and -(NR 1 ) 0-1 -SO 0,2 -(NR 1 ) 0-1 -;or

[0096] In an alternative embodiment, Z is selected from alkylene, alkenylene, alkynylene, arylene, heteroarylene, heterocyclyl, or carbocyclyl;

[0097] Each occurrence of R 1 Independently selected from H or C 1-6 alkyl; and

[0098] All other variables are as defined herein.

[0099] Compounds of Formula I, II-a to II-k, III, IV-a to IV-j, V, VI, VII-a to VII-e, VIII-a to VIII-i, IX-a to IX-j, Xa to Xi, XI-a to XI-i, XII, XHI-a to XIII-i, and XIV can activate, reduce, or alter the natural activity of cereblon. These compounds of Formula I, II-a to II-k, III, IV-a to IV-j, V, VI, VII-a to VII-e, VIII-a to VIII-i, IX-a to IX-j, Xa to Xi, XI-a to XI-i, XII, XHI-a to XIII-i, and XIV, when administered in an effective amount to a host, typically a human, are useful as therapeutic agents 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, Walden's giant cell disease, Hypergammaglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorder; immune disorders, including autoimmune diseases such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type 1 diabetes; cardiac dysfunction, including hypercholesterolemia; infectious diseases, including viral or bacterial infections; inflammatory diseases, including asthma, chronic peptic ulcer disease, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn's disease, or hepatitis; or any condition treatable with thalidomide, pomalidomide, or lenalidomide.

[0100] In certain embodiments, the present invention provides for treating a patient, e.g., a human, with an infectious disease by administering an effective amount of a compound of Formula I, II-a to II-k, III, IV-a to IV-j, V, VI, VII-a to VII-e, VIII-a to VIII-i, IX-a to IX-j, Xa to Xi, XI-a to XI-i, XII, XHI-a to XIII-i, and XIV, wherein the treatment acts by binding to cereblon or its E3 ubiquitin 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 agent or other exogenous agent, such as a virus (as a non-limiting example, HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola, flavivirus, pestivirus, rotavirus, influenza, coronavirus, EBV, viral pneumonia, drug-resistant virus, avian influenza, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, or hepatitis virus), bacteria (including but not limited to Gram-negative, Gram-positive, atypical, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, meningitis, gonorrhea, Chlamydiaceae, Mycoplasmaceae, etc.), fungus, protozoa, helminth, worm, prion, parasite, or other microorganism.

[0101] In another aspect, the disclosed compounds 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 to produce a bifunctional compound as described above that can cause degradation of the selected protein via the UPP.

[0102] Thus, provided is a compound of formula XIV (1) or a pharmaceutically acceptable salt thereof, which can be used to prepare a bifunctional compound that causes degradation of a selected protein via UPP:

[0103]

[0104] in:

[0105] A B Selected from optionally one or two R 2 substituted arylene group, optionally substituted by one or two R 3 A heteroarylene group substituted with one or two R 4 Heterocycloalkylene substituted with a group, -NH-C(=O)-C 1-6 Alkylene- and cycloalkylene;

[0106] 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 degrader, or

[0107] 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;

[0108] In one embodiment, the "tail" is

[0109] X 1 Selected from bond, NR 34 , CH2, CHR 34 、C(R 34 )2, O and S;

[0110] X 22 is a functional group that can be used as a linker to a protein-binding moiety; or X 22 is a valency-capping group and is generally not a linking group; X 22 Representative examples include, but are not limited to, halogen, -NH2, -NHR 34 、-N(R 34 )2、hydroxyl、thiol、-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)olefins, -NR 34 C(O)alkyne, cyano, -SC(O)alkyl, OC(O)alkyl, heterocycle, -C(O)OH, hydrogen, alkyl, aryl, heteroaryl, aliphatic, heteroaliphatic, and carbocycle;

[0111] 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 ;

[0112] 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;

[0113] 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 groups, -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’ -, alkene, haloalkyl, alkoxy, alkynylheteroarylalkyl, aryl, arylalkyl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, carbocyclic ring, -(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 1-6 can independently be 1, 2, 3, 4, 5 or 6, wherein 1-12 can independently be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein one or more CH2 or NH groups can be modified by replacing H with methyl, ethyl, cyclopropyl, F (if on carbon), etc., as described herein, and optionally, heteroatoms, heteroalkyl, aryl, heteroaryl or alicyclic 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.

[0114] Each R 20 、R 21 、R 22 、R 23 and R 24 Optionally, one or more selected from R 101 substituted by a substituent, or as described in the definition section; wherein R 20 、R 21 、R 22 、R 23 and R 24 At least one of is not a key;

[0115] R 101 is independently selected at each occurrence from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, 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;

[0116] R 26 is selected from the group consisting of hydrogen, alkyl, silane, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic;

[0117] 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-membered, 5-membered or 6-membered spiroheterocycle containing 1 or 2 heteroatoms selected from N and O, or form 1 or 2 carbon bridged rings;

[0118] R 40at each occurrence selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl, or heterocycle), -N(alkyl)SO2(aryl, heteroaryl, or heterocycle)-NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocycle, and carbocycle; and

[0119] All other variables are as defined herein.

[0120] In another aspect, novel compounds are provided comprising compounds of Formula I, II-a to II-k, III, IV-a to IV-j, V, VI, VII-a to VII-e, VIII-a to VIII-i, IX-a to IX-j, Xa to Xi, XI-a to XI-i, XII and XIII-a to XIII-I, wherein one of the free hydrogens on the molecule has been replaced by a "tail" group as defined herein. Therefore, new compounds of formula I(1), formula II(1)-a to II(1)-k, formula III(1), formula IV(1)-a to IV(1)-j, formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1) and formula XIII(1)-a to XIII(1)-i are also provided.

[0121] In one aspect, there is provided a compound of formula I(1)

[0122]

[0123] wherein all variables are as defined herein.

[0124] In one aspect, a compound having one of the following formulae is provided:

[0125]

[0126]

[0127]

[0128] wherein all variables are as defined herein.

[0129] In one aspect, provided is a compound of formula III (1):

[0130]

[0131] wherein all variables are as defined herein.

[0132] In one aspect, a compound having one of the following formulae is provided:

[0133]

[0134]

[0135] wherein all variables are as defined herein.

[0136] In one aspect, provided is a compound of formula V(1):

[0137] wherein all variables are as defined herein.

[0138] In one aspect, a compound of formula VI (1) is provided:

[0139] wherein all variables are as defined herein.

[0140] In one aspect, a compound having one of the following formulae is provided:

[0141]

[0142] wherein all variables are as defined herein.

[0143] In one aspect, a compound having one of the following formulae is provided:

[0144]

[0145]

[0146]

[0147] wherein all variables are as defined herein.

[0148] In one aspect, a compound having one of the following formulae is provided:

[0149]

[0150]

[0151] wherein all variables are as defined herein.

[0152] In one aspect, a compound having one of the following formulae is provided:

[0153]

[0154]

[0155] wherein all variables are as defined herein.

[0156] In one aspect, a compound having one of the following formulae is provided:

[0157]

[0158]

[0159]

[0160] wherein all variables are as defined herein.

[0161] In one aspect, a compound of formula XII(1) is provided:

[0162] wherein all variables are as defined herein.

[0163] In one aspect, a compound having one of the following formulae is provided:

[0164]

[0165]

[0166] wherein all variables are as defined herein.

[0167] In a first aspect, the present invention provides formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-i, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-i, formula XII, formula XHI-a to XIII-i, formula XIV, formula I(1), formula II(1)-a to II(1)-k, formula III(1), Compounds of formula IV(1)-a to IV(1)-j, formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) for use as therapeutically active substances.

[0168] In another aspect, the present invention provides a pharmaceutical composition comprising Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula I A compound of formula II(1), formula IV(1)-a to IV(1)-j, formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) and a therapeutically inert carrier.

[0169] In certain embodiments, Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula The compounds of formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) have at least one desired atomic isotope substituted in an amount greater than the natural abundance of that isotope, i.e., enriched. In one embodiment, Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1 )-a to IV(1)-j, Formula V(1), Formula VI(1), Formula VII(1)-a to VII(1)-e, Formula VIII(1)-a to VIII(1)-i, Formula IX(1)-a to IX(1)-j, Formula X(1)-a to X(1)-i, Formula XI(1)-a to XI(1)-i, Formula XII(1), Formula XIII(1)-a to XIII(1)-i or Formula XIV(1) includes one or more deuterium atoms.

[0170] Other features and advantages of the present application will be apparent from the following detailed description and from the claims.

[0171] Therefore, the present invention includes at least the following features:

[0172] a) Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1) )-a to IV(1)-j, Formula V(1), Formula VI(1), Formula VII(1)-a to VII(1)-e, Formula VIII(1)-a to VIII(1)-i, Formula IX(1)-a to IX(1)-j, Formula X(1)-a to X(1)-i, Formula XI(1)-a to XI(1)-i, Formula XII(1), Formula XIII(1)-a to XIII(1)-i, or a pharmaceutically acceptable salt thereof;

[0173] b) Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V(1), Formula VI(1), Formula VII(1)-a to VII(1)-e, Formula VIII(1-a to VI Use of a compound of formula II(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i, or formula XIV(1), or a pharmaceutically acceptable salt thereof, in an effective amount to treat a patient, typically a human, having a condition responsive to such treatment, including by modulating cereblon-based ubiquitination of proteins, such as abnormal cell proliferation, such as a tumor or cancer; an immune or autoimmune or inflammatory disease, a cardiac disease, an infectious disease, or other disease responsive to such treatment;

[0174] c) Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V(1), Use of a compound of Formula VI(1), Formula VII(1)-a to VII(1)-e, Formula VIII(1)-a to VIII(1)-i, Formula IX(1)-a to IX(1)-j, Formula X(1)-a to X(1)-i, Formula XI(1)-a to XI(1)-i, Formula XII(1), Formula XIII(1)-a to XIII(1)-i, or Formula XIV(1), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a medical condition, as further described herein;

[0175] d) a method for preparing a medicament for therapeutic treatment of a host condition characterized by a compound of formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-i, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-i, formula XII, formula XIII-a to XIII-i, formula XIV, formula I(1), formula II(1)-a to II(1)-k, formula I The compound of formula II (1), formula IV (1)-a to IV (1)-j, formula V (1), formula VI (1), formula VII (1)-a to VII (1)-e, formula VIII (1)-a to VIII (1)-i, formula IX (1)-a to IX (1)-j, formula X (1)-a to X (1)-i, formula XI (1)-a to XI (1)-i, formula XII (1), formula XIII (1)-a to XIII (1)-i or formula XIV (1) is used for the preparation;

[0176] e) Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V(1), Formula a compound of Formula VI(1), Formula VII(1)-a to VII(1)-e, Formula VIII(1)-a to VIII(1)-i, Formula IX(1)-a to IX(1)-j, Formula X(1)-a to X(1)-i, Formula XI(1)-a to XI(1)-i, Formula XII(1), Formula XIII(1)-a to XIII(1)-i, or Formula XIV(1), 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;

[0177] f) Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V(1), Formula VI( 1), use of a compound of Formula VII(1)-a to VII(1)-e, Formula VIII(1)-a to VIII(1)-i, Formula IX(1)-a to IX(1)-j, Formula X(1)-a to X(1)-i, Formula XI(1)-a to XI(1)-i, Formula XII(1), Formula XIII(1)-a to XIII(1)-i or Formula XIV(1) 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;

[0178] g) A method for preparing a medicament for therapeutic use to treat abnormal cell proliferation in a host, such as cancer (including any cancer described herein), characterized by Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I (1), Formula II (1) -a to II(1)-k, formula III(1), formula IV(1)-a to IV(1)-j, formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) is used for the preparation;

[0179] h) Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V(1) ), a compound of formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1), or a pharmaceutically acceptable salt thereof, which can be used to treat a tumor in a host, including any tumor described herein;

[0180] i) Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V(1), Formula Use of a compound of Formula VI(1), Formula VII(1)-a to VII(1)-e, Formula VIII(1)-a to VIII(1)-i, Formula IX(1)-a to IX(1)-j, Formula X(1)-a to X(1)-i, Formula XI(1)-a to XI(1)-i, Formula XII(1), Formula XIII(1)-a to XIII(1)-i, or Formula XIV(1), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a tumor in a host, including any tumor described herein;

[0181] j) A method for preparing a medicament for therapeutic use in treating a tumor (including any tumor described herein) in a host characterized by Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to I The compound of formula I(1)-k, formula III(1), formula IV(1)-a to IV(1)-j, formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) is used for the preparation;

[0182] k) Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V( 1), a compound of formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1), or a pharmaceutically acceptable salt thereof, which can be used to treat an immune, autoimmune or inflammatory disease of a host;

[0183] l) Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V(1), Use of a compound of formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an immune, autoimmune or inflammatory disease of a host;

[0184] m) A method for preparing a medicament for therapeutic use in treating an immune, autoimmune or inflammatory disease of a host, characterized by formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-i, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-i, formula XII, formula XIII-a to XIII-i, formula XIV, formula I (1), formula II (1)-a to II (2)-a (1)-k, formula III (1), formula IV (1)-a to IV (1)-j, formula V (1), formula VI (1), formula VII (1)-a to VII (1)-e, formula VIII (1)-a to VIII (1)-i, formula IX (1)-a to IX (1)-j, formula X (1)-a to X (1)-i, formula XI (1)-a to XI (1)-i, formula XII (1), formula XIII (1)-a to XIII (1)-i or formula XIV (1) is used for the preparation;

[0185] n) a pharmaceutical preparation comprising an effective amount of formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-i, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-i, formula XII, formula XIII-a to XIII-i, formula XIV, formula I(1), formula II(1)-a to II(1)-k, formula III(1), formula IV(1)-a to IV(1)-j, Formula V(1), Formula VI(1), Formula VII(1)-a to VII(1)-e, Formula VIII(1)-a to VIII(1)-i, Formula IX(1)-a to IX(1)-j, Formula X(1)-a to X(1)-i, Formula XI(1)-a to XI(1)-i, Formula XII(1), Formula XIII(1)-a to XIII(1)-i or Formula XIV(1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent;

[0186] o) Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(2)-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV( Compounds of formula (1)-j, formula (1), formula (1), formula (1)-a to formula (1)-e, formula (1)-a to formula (1)-i, formula (1)-a to formula (1)-j, formula (1)-a to formula (1)-i, formula (1)-a to formula (1)-i, formula (1)-b to formula (1)-c), formula (1)-d to formula (1)-i, formula (1)-d to formula (1)-i, formula (1)-e to formula (1)-i, formula (1)-f), formula (1)-g to formula (1)-g, formula (1)-h to formula (1)-h), formula (1)-h to formula (1)-i, formula (1)-i ...

[0187] p) preparing a mixture containing an effective amount of Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I (1), Formula II (1)-a to II (1)-k, Formula III (1), Formula IV (1)-a to methods of treating a compound of formula IV(1)-j, formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1), or a pharmaceutically acceptable salt thereof; and

[0188] q) A method for preparing a bifunctional compound that causes degradation of a selected protein via the ubiquitin proteasome pathway, characterized by Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k , compounds of formula III(1), formula IV(1)-a to IV(1)-j, formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) are used to prepare the bifunctional compound. DETAILED DESCRIPTION

[0189] I. Definition

[0190] Unless otherwise defined, all technical and scientific terms used herein are the same as those generally understood by those skilled in the art to which this application belongs. In the specification, the singular also includes the plural, unless the context clearly provides otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this application, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not considered to be the prior art of the claimed application. In the event of a conflict, this specification (including definitions) shall prevail. In addition, materials, methods and embodiments are illustrative only and not restrictive.

[0191] 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.

[0192] 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, unless specifically described, each of which is excluded by the context.

[0193] The terms "one" and "an" do not represent a quantitative limitation, but rather represent that there is at least one reference item. The term "or" refers to "and / or". Unless otherwise stated herein, the reference to a range of values is only intended to be used as a shorthand method for quoting each individual value falling within the range, and each individual value is incorporated into the specification as if it were quoted separately herein. The endpoints of all ranges are included within the range and can be independently combined. Unless otherwise stated herein or clearly contradictory to the context, all methods described herein can be performed in a suitable order. The use of examples or exemplary language (e.g., "such as") is only intended to better illustrate the present invention and is not intended to limit the scope of the present invention, unless otherwise stated.

[0194] 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 the 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. The 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 the compounds of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO. The solvate can be in liquid or solid form.

[0195] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH2 is attached through the carbon of the carbonyl (C=O).

[0196] 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.

[0197] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0198] The term "C 1-6 -alkyl", alone or in combination with other groups, represents a hydrocarbon radical which may be straight-chain or branched, with a single branch or multiple branches, wherein the alkyl radical generally contains 1 to 6 carbon atoms, for example methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (tert-butyl), isopentyl, 2-ethyl-propyl (2-methyl-propyl), 1,2-dimethyl-propyl, etc. A specific radical is methyl.

[0199] The term "halogen-C 1-6 -alkyl", alone or in combination with other groups, refers to C 1-6 -alkyl, which is substituted by one or more halogens, in particular 1 to 5 halogens, more in particular 1 to 3 halogens. Particular halogen is fluorine. Particular "halogen-C 1-6 -alkyl" is a fluoro-C 1-6 -alkyl, and particularly "halogen-C 1-3 -alkyl" is a fluoro-C 1-3 -alkyl. Examples are trifluoromethyl, difluoromethyl, fluoromethyl, etc.

[0200] In one embodiment, the "halogen-C 1-6 -alkyl" has one carbon.

[0201] In one embodiment, the "halogen-C 1-6 -alkyl" has one carbon and one halogen.

[0202] In one embodiment, the "halogen-C 1-6 -alkyl" has one carbon and two halogens.

[0203] In one embodiment, the "halogen-C 1-6 -alkyl" has one carbon and three halogens.

[0204] In one embodiment, the "halogen-C 1-6 -alkyl" has two carbons.

[0205] In one embodiment, the "halogen-C 1-6 An "-alkyl" group has three carbon atoms.

[0206] In one embodiment, the "halogen-C 1-6 An "-alkyl" group has four carbon atoms.

[0207] In one embodiment, the "halogen-C 1-6 An "-alkyl" group has five carbon atoms.

[0208] In one embodiment, the "halogen-C 1-6 An "-alkyl" group has six carbons.

[0209] "Halogen-C 1-6 Non-limiting examples of "-alkyl" include:

[0210] "Halogen-C 1-6 Other non-limiting examples of "-alkyl" include:

[0211] "Halogen-C1-6 Other non-limiting examples of "-alkyl" include:

[0212] "Halogen-C 1-6 Other non-limiting examples of "-alkyl" include:

[0213] The term "hydroxy-C 1-6 -alkyl", alone or in combination with other groups, refers to C 1-6 -alkyl, which is substituted by one or more hydroxyl groups, in particular by 1 hydroxyl group. Examples are -CH2OH, -CH2CH2OH, etc.

[0214] The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 10 ring carbon atoms, particularly a monovalent saturated monocyclic hydrocarbon radical of 3 to 8 ring carbon atoms. Bicyclic refers to a radical consisting of two carbocyclic rings having one or more carbon atoms in common, one of which is saturated and the other of which may be aromatic. Specific cycloalkyl groups are monocyclic. Examples of monocyclic cycloalkyl groups are "C 3-7 "cycloalkyl", for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of saturated bicyclic cycloalkyl are bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl. Examples of bicyclic cycloalkyl in which one ring is aromatic are 1H-indenyl or 1,2,3,4-tetrahydronaphthyl.

[0215] The term "hydroxy", alone or in combination with other groups, refers to OH.

[0216] The term "Bz" represents a benzyl group (ie, phenyl-CH2-).

[0217] The term "halogen", alone or in combination with other groups, means chlorine (Cl), iodine (I), fluorine (F) and bromine (Br). A specific group is F.

[0218] The term "heteroaryl" refers to a monovalent heterocyclic 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, wherein at least one ring is 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

[0014] The term "benzotriazolyl" refers to a benzothiophene, an indolinyl, an indolyl, an isoindolyl, an isobenzofuranyl, a benzimidazolyl, a benzoxazolyl, a benzisoxazolyl, a benzothiazolyl, a benzisothiazolyl, a benzoxadiazolyl, a benzothiadiazolyl, a benzotriazolyl, a purinyl, a quinolinyl, an isoquinolinyl, a quinazolinyl, a quinoxalinyl, or a 2,3-dihydropyrrolo[2,3-b]pyridinyl group. Specific examples include benzimidazolyl, pyridyl, thiazolyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydroquinolinyl, benzofuranyl, furanyl, imidazolyl, isoindolyl, and quinolinyl.

[0219] In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0220] 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.

[0221] Other non-limiting examples of 5-membered "heteroaryl" groups include:

[0222]

[0223]

[0224] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0225] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include:

[0226] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0227] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0228] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0229]

[0230] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0231]

[0232] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0233]

[0234] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0235] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0236] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0237]

[0238] In another embodiment, "heteroaryl" is optionally substituted with 1, 2, 3, or 4 substituents.

[0239] The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 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 groups 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 oxazepanyl. Examples of bicyclic saturated heterocycloalkyl groups are 8-aza-bicyclo[3.2.1]octyl, quinuclidine, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl or dihydropyranyl. Specific examples include piperazinyl, piperidinyl, pyrrolidinyl and 3,8-diazabicyclo[3.2.1]octyl.

[0240] In one embodiment, "heterocycloalkyl" refers to a ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0241] In one embodiment, "heterocycloalkyl" refers to a ring having one nitrogen and one oxygen, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0242] In one embodiment, "heterocycloalkyl" refers to a ring having two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0243] In one embodiment, "heterocycloalkyl" refers to a ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0244] In one embodiment, "heterocycloalkyl" refers to a ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0245] Non-limiting examples of "heterocycloalkyl" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0246] Other non-limiting examples of "heterocycloalkyl" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0247] Other non-limiting examples of "heterocycloalkyl" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0248] Other non-limiting examples of "heterocycloalkyl" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiazane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0249] Other non-limiting examples of "heterocycloalkyl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is on the heterocycle.

[0250] For example, is a heterocycloalkyl group.

[0251] However, is an aryl group.

[0252] Non-limiting examples of "heterocycloalkyl" also include:

[0253]

[0254] Other non-limiting examples of "heterocycloalkyl" include:

[0255]

[0256] Other non-limiting examples of "heterocycloalkyl" include:

[0257]

[0258] Non-limiting examples of "heterocycloalkyl" also include:

[0259]

[0260] Non-limiting examples of "heterocycloalkyl" also include:

[0261]

[0262] Other non-limiting examples of "heterocycloalkyl" include:

[0263]

[0264] Other non-limiting examples of "heterocycloalkyl" include:

[0265]

[0266] In another embodiment, "heterocycloalkyl" is optionally substituted with 1, 2, 3, or 4 substituents.

[0267] The term "C 1-6 -alkoxy", alone or in combination with other groups, represents -OC 1-6 -alkyl, which may be linear or branched, with a single branch or multiple branches, wherein the alkyl group generally contains 1 to 6 carbon atoms, for example methoxy (OMe, MeO), ethoxy (OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (isobutoxy), 2-butoxy (sec-butoxy), t-butoxy (tert-butoxy), isopentyl (i-pentyloxy), etc. In particular, "C 1-6 "-Alkoxy" is a group having 1 to 4 carbon atoms. A specific group is methoxy.

[0268] The term "aryl" refers to a monovalent aromatic carbocyclic monocyclic or bicyclic ring system containing 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl (Ph) and naphthyl. A specific "aryl" group is phenyl.

[0269] In one embodiment, "aryl" is a 6 carbon aromatic group (phenyl).

[0270] In one embodiment, "aryl" is a 10 carbon aromatic group (naphthyl).

[0271] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a heterocycle, wherein the point of attachment is the aromatic ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is on the aromatic ring.

[0272] For example, is an "aryl" group.

[0273] However, is a "heterocycloalkyl" group.

[0274] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl group, wherein the point of attachment is the aromatic ring. Non-limiting examples of "aryl" include dihydroindane and tetrahydronaphthalene, wherein the point of attachment of each group is on the aromatic ring.

[0275] For example, is an "aryl" group.

[0276] However, is a "cycloalkyl" group.

[0277] In another embodiment, "aryl" is optionally substituted with 1, 2, 3, or 4 substituents.

[0278] The term "optionally substituted" means that the groups herein are substituted with, but are 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 Alkylsulfonyl, arylsulfonyl, C1-C 10 Alkyl imino, aryl imino, C1-C 10 Alkylsulfonimino, arylsulfonimino, hydroxyl, halogen, thio, C1-C 10 Alkylthio, arylthio, C1-C 10 Partial substitution with alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminosulfonyl, amidino, guanidino, ureido, cyano, nitro, azido, acyl, sulfonyl, acyloxy, carboxyl, and carboxylate.

[0279] In another embodiment, any suitable group may be present in a "substituted" or "optionally substituted" position if it indicates the formation of a stable molecule and meets the desired objectives of the present invention and includes, but is not limited to, for example, halogen (which can independently be F, Cl, Br or I); cyano; hydroxy; nitro; azido; alkanoyl (e.g., 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 being substituted or unsubstituted); aralkyl, including those with, for example, 1 to 3 separate or fused rings and 6 to about 14 or 18 ring carbon atoms, wherein benzyl is an exemplary aralkyl group; arylalkoxy, for example, having 1 to 3 separate or fused rings, wherein benzyloxy is an exemplary arylalkoxy group; or a saturated or partially unsaturated heterocycle having 1 to 3 separate or fused rings and one or more N, O or S atoms, or a heteroaryl having 1 to 3 separate or fused rings and one or more N, O or S atoms, such as coumarin, quinolyl, isoquinolyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl and pyrrolidinyl. These groups can be further substituted by, for example, hydroxyl, alkyl, alkoxy, halogen and amino. In certain embodiments, "optionally substituted" includes one or more independently selected from halogen, hydroxy, 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, hydroxy C1-C6 alkyl, ester, carbamate, urea, sulfonamide, -C1-C6 alkyl(heterocyclic), 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 can be monovalent, divalent, or trivalent to form stable molecules and meet the desired objectives of the present invention.

[0280] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with one substituent.

[0281] In one embodiment, a group described herein as substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.

[0282] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with three substituents.

[0283] In one embodiment, a group described herein as substituted with 1, 2, 3, or 4 substituents is substituted with four substituents.

[0284] A term such as "abx substituted with R" means that the "x" portion of the moiety is substituted with R. For example, "abx substituted with R 10 Substituted -(CH2) 0-1 -aryl" means that the "aryl" portion of the moiety is replaced by R 10 Replaced by R 10 Substituted -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl" means that the "aryl" portion of the moiety is replaced by R 10 Replaced by R 9 Substituted -(CH2) 0-1 -heteroaryl" means that the "heteroaryl" portion of the moiety is replaced by R 9 Replaced by R 10 Substituted -CH2-O-(CH2) 0-1 -aryl" means that the "aryl" portion of the moiety is replaced by R 10 replace.

[0285] The term "pharmaceutically acceptable" refers to the property of materials useful in preparing pharmaceutical compositions that are generally safe, not unacceptably toxic, and neither biologically nor otherwise undesirable. In one aspect, the material is acceptable for veterinary as well as human pharmaceutical use.

[0286] The term "pharmaceutically acceptable salt" refers to salts suitable for contact with human and animal tissues. Examples of suitable salts formed with inorganic and organic acids include, but are not limited to, 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. Specific acids include formic acid, trifluoroacetic acid, and hydrochloric acid. Specific acids include hydrochloric acid, trifluoroacetic acid, and fumaric acid.

[0287] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of the parent compound formed, for example, 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, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared 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) wherein n is 0-4 n -COOH, etc., or using a different acid that produces the same counterion. Lists of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985).

[0288] 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.

[0289] A "therapeutically effective amount," when administered to a subject for the treatment of a disease state, will vary depending on the compound, the disease state being treated, the severity or condition being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0290] When referring to a variable, the terms "as defined herein" and "as described herein" incorporate by reference the broad definition of the variable, as well as particular, more particular, and most particular definitions, if any.

[0291] The terms "treating," "contacting," and "reacting," when referring to a chemical reaction, refer to the addition or mixing of two or more reagents under appropriate conditions to produce a specified and / or desired product. It should be understood that a reaction that produces a specified and / or desired product does not necessarily result directly from the combination of the two reagents initially added, i.e., one or more intermediates may be produced in the mixture that ultimately lead to the formation of the specified and / or desired product.

[0292] The term "aromatic" refers to the traditional 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).

[0293] The term "pharmaceutically acceptable excipient" means any therapeutically inactive and non-toxic ingredient such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant or lubricant used to formulate a pharmaceutical product.

[0294] All individual embodiments can be combined.

[0295] As used herein, the term "treating" includes: (1) inhibiting a condition, disease, or disorder (e.g., arresting, reducing, or delaying the progression of the disease, or, in the case of maintenance therapy, the recurrence of at least one clinical or subclinical symptom); and / or (2) ameliorating a condition (i.e., causing regression of the condition, disease, or disorder, or at least one clinical or subclinical symptom thereof). However, it should be understood that when a drug is administered to a patient to treat a disease, the result may not always be effective treatment.

[0296] As used herein, the term "preventing" includes preventing or delaying the appearance of clinical symptoms of a condition, disease or disorder that develops in a mammal, especially a human, who may have or be susceptible to the condition, disease or disorder but does not experience or display clinical or subclinical symptoms of the condition, disease or disorder.

[0297] Isotope substitution

[0298] The present invention includes formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-i, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-i, formula XII, formula XIII-a to XIII-i, formula XIV, formula I (1), formula II (1)-a to II (1)-k, formula III (1), formula IV (1)-a to IV (1)-j, formula V ( 1), a compound of formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1), which has at least one desired isotopic substitution of an atom in an amount greater than the natural abundance of that isotope, i.e., enrichment. Isotopes are atoms with the same atomic number but different mass numbers, i.e., atoms with the same number of protons but different numbers of neutrons.

[0299] Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, e.g. 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 35 S. 36 Cl and 125 In one non-limiting embodiment, isotope-labeled compounds can be used in metabolic studies (e.g., using 14 C), reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET), or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution analysis, or for radiotherapy of patients. In particular, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by following the procedures disclosed in the Schemes or Examples and Preparations described below by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0300] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution refers to that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is enriched in 90%, 95% or 99% or more of the isotope at any position of interest. In a non-limiting embodiment, deuterium is enriched in 90%, 95% or 99% at the desired position.

[0301] In a non-limiting embodiment, the present invention can be carried out in the following manner: Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula I In any of the compounds of Formulas V(1)-a to IV(1)-j, V(1), VI(1), VII(1)-a to VII(1)-e, VIII(1)-a to VIII(1)-i, IX(1)-a to IX(1)-j, X(1)-a to X(1)-i, XI(1)-a to XI(1)-i, XII(1), XIII(1)-a to XIII(1)-i, or XIV(1), a deuterium atom is provided. In a non-limiting embodiment, the replacement of a hydrogen atom by a deuterium atom occurs within one or more groups selected from the variables described herein. For example, when any group is or comprises, for example, by substitution, a methyl, ethyl, or methoxy group, the alkyl residue may be deuterated (in non-limiting embodiments, 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 may be deuterated.

[0302] II. Compounds of the Invention

[0303] The present invention provides formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-i, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-i, formula XII, formula XIII-a to XIII-i, formula XIV, formula I (1), formula II (1)-a to II (1)-k, formula III (1), formula IV The present invention also provides a compound of formula XIV or formula XIV(1) and a pharmaceutically acceptable salt thereof. The present invention also provides a compound of formula XIV or formula XIV(1) as further described herein.

[0304] Embodiments of Formulas I-XIII

[0305] In one embodiment, there is provided a compound of formula I:

[0306]

[0307] wherein all variables are as defined herein.

[0308] In one embodiment, a compound of formula I is provided selected from:

[0309]

[0310] wherein all variables are as defined herein.

[0311] In one embodiment, a compound of formula I is provided selected from:

[0312]

[0313] wherein all variables are as defined herein.

[0314] In one embodiment of Formula I, Selected from:

[0315]

[0316]

[0317] In one embodiment, compounds of Formula II-a and Formula II-b are provided:

[0318]

[0319] wherein all variables are as defined herein.

[0320] In one embodiment, compounds of Formula II-c and Formula II-d are provided:

[0321]

[0322] wherein all variables are as defined herein.

[0323] In one embodiment, a compound having one of the following formulae is provided:

[0324]

[0325]

[0326] wherein all variables are as defined herein.

[0327] In any one of the embodiments of Formulae II-a to II-k, Selected from:

[0328]

[0329] In one embodiment, a compound of Formula III is provided:

[0330]

[0331] wherein all variables are as defined herein.

[0332] In one embodiment, the compound of formula III is selected from:

[0333]

[0334]

[0335] wherein all variables are as defined herein.

[0336] In one embodiment, the compound of formula III is selected from:

[0337]

[0338] wherein all variables are as defined herein.

[0339] In one embodiment of Formula III, Selected from:

[0340]

[0341]

[0342] In one embodiment, compounds of Formula IV-a and Formula IV-b are provided:

[0343]

[0344] wherein all variables are as defined herein.

[0345] In one embodiment, a compound having one of the following formulae is provided:

[0346]

[0347] wherein all variables are as defined herein.

[0348] In one embodiment, a compound selected from Formula IV-g and Formula IV-h is provided:

[0349]

[0350] wherein all variables are as defined herein.

[0351] In one embodiment, a compound selected from Formula IV-i and Formula IV-j is provided:

[0352]

[0353] wherein all variables are as defined herein.

[0354] In some embodiments of any one of Formulae IV-a to IV-j, Selected from:

[0355] In one embodiment, a compound of Formula V is provided:

[0356]

[0357] wherein all variables are as defined herein.

[0358] In one embodiment, the compound of formula V is selected from:

[0359]

[0360] In one embodiment, the compound of formula V is selected from:

[0361]

[0362] In one embodiment of Formula V, Selected from:

[0363]

[0364] In one embodiment, a compound having Formula VI is provided:

[0365]

[0366] wherein all variables are as defined herein.

[0367] In one embodiment, the compound of formula VI is selected from:

[0368]

[0369]

[0370] wherein all variables are as defined herein.

[0371] In one embodiment, the compound of formula VI is selected from:

[0372]

[0373] wherein all variables are as defined herein.

[0374] In one embodiment of Formula VI, Selected from:

[0375]

[0376] In one embodiment, the compound of formula VII-a is selected from:

[0377]

[0378]

[0379] wherein all variables are as defined herein.

[0380] In one embodiment, compounds of Formula VII-b, Formula VII-c, and Formula VII-d are provided:

[0381]

[0382] wherein all variables are as defined herein.

[0383] In one embodiment, a compound of Formula VII-e is provided:

[0384]

[0385] wherein all variables are as defined herein.

[0386] In one embodiment of any one of Formulae VII-a to VII-e, Selected from:

[0387]

[0388] In one embodiment, a compound having one of the following formulae is provided:

[0389]

[0390] wherein all variables are as defined herein.

[0391] In one embodiment, a compound having the formula VIII-e) is provided:

[0392]

[0393] wherein all variables are as defined herein.

[0394] In one embodiment, compounds of Formula VIII-f and Formula VIII-g are provided:

[0395]

[0396] wherein all variables are as defined herein.

[0397] In one embodiment, compounds of Formula VIII-h and VIII-i are provided:

[0398]

[0399] wherein all variables are as defined herein.

[0400] In any one of the embodiments of Formulae VIII-a to VIII-i, Selected from:

[0401]

[0402] In one embodiment, a compound having the formula:

[0403]

[0404] wherein all variables are as defined herein.

[0405] In one embodiment, a compound having the formula IX-e is provided:

[0406]

[0407] wherein all variables are as defined herein.

[0408] In one embodiment, compounds of Formula IX-f and IX-g are provided:

[0409]

[0410] wherein all variables are as defined herein.

[0411] In one embodiment, compounds of Formula IX-h and IX-i are provided:

[0412]

[0413] wherein all variables are as defined herein.

[0414] In one embodiment, a compound having the formula IX-j is provided:

[0415]

[0416] wherein all variables are as defined herein.

[0417] In one embodiment, a compound having one of the following formulae is provided:

[0418]

[0419] wherein all variables are as defined herein.

[0420] In one embodiment, a compound having the formula Xd or Xe is provided:

[0421]

[0422] wherein all variables are as defined herein.

[0423] In one embodiment, a compound having one of the following formulae is provided:

[0424]

[0425] wherein all variables are as defined herein.

[0426] In one embodiment, a compound of formula Xi is provided:

[0427]

[0428] wherein all variables are as defined herein.

[0429] In one embodiment, a compound having one of the following formulae is provided:

[0430]

[0431]

[0432] wherein all variables are as defined herein.

[0433] In one embodiment, a compound having one of the following formulae is provided:

[0434]

[0435] wherein all variables are as defined herein.

[0436] In one embodiment, a compound of formula XI-i is provided:

[0437]

[0438] wherein all variables are as defined herein.

[0439] In one embodiment, a compound having Formula XII is provided:

[0440]

[0441] wherein all variables are as defined herein.

[0442] In one embodiment, there is provided a compound of formula XII selected from the group consisting of:

[0443]

[0444] In one embodiment, there is provided a compound of formula XII selected from the group consisting of:

[0445]

[0446] In one embodiment, a compound having one of the following formulae is provided:

[0447]

[0448]

[0449] wherein all variables are as defined herein.

[0450] In one embodiment, a compound having Formula XIII-e is provided:

[0451]

[0452] wherein all variables are as defined herein.

[0453] In one embodiment, a compound having one of the following formulae is provided:

[0454]

[0455] wherein all variables are as defined herein.

[0456] In one embodiment, a compound having Formula XIII-i is provided:

[0457]

[0458] wherein all variables are as defined herein.

[0459] In any one of the embodiments of Formulae IX-a through IX-j, Xa through Xi, XI-a through XI-i, or XHI-a through XIII-I, Can be selected from:

[0460]

[0461] Embodiments of Formula XIV

[0462] In a first aspect (A1), the present invention provides a compound of formula XIV

[0463]

[0464] or a pharmaceutically acceptable salt thereof, wherein:

[0465] wherein all variables are as defined herein.

[0466] The present invention also provides the following embodiment (E):

[0467] E1: In one embodiment, the present invention provides a compound of formula XIV according to A1, or a pharmaceutically acceptable salt thereof, wherein Z is selected from the group consisting of:

[0468] i) covalent bonds,

[0469] ii) a carbonyl group,

[0470] iii)-NR 1 -,

[0471] iv) -O-CH2-C(=O)-NR 1 -,

[0472] v) -C(=O)-NR 1 -,and

[0473] vi)-NR 1 -C(=O)-.

[0474] E2: In one embodiment, the present invention provides a compound of formula XIV according to any one of A1 or E1, or a pharmaceutically acceptable salt thereof, wherein R 1 For hydrogen.

[0475] E3: In one embodiment, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E2, or a pharmaceutically acceptable salt thereof, wherein each R 2 -C 1-6 Alkyl or -N(R 5 ,R 6 ).

[0476] E4: In one aspect, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E2, or a pharmaceutically acceptable salt thereof, wherein each R 2 is methyl or -N(R 5 ,R 6 ).

[0477] E5: In one embodiment, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E4, or a pharmaceutically acceptable salt thereof, wherein each R 3 Selected from -C(=O)-N(R 7 ,R 8 ),-C 1-6 A group consisting of alkyl, -OH and -NO2.

[0478] E6: In one embodiment, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E4, or a pharmaceutically acceptable salt thereof, wherein each R 3 Selected from -C(=O)-N(R 7 ,R 8 ), a group consisting of isopropyl, -OH and -NO2.

[0479] E7: In one embodiment, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E6, or a pharmaceutically acceptable salt thereof, wherein each R 4 -C(=O)C 1-6 alkyl.

[0480] E8: In one aspect, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E6, or a pharmaceutically acceptable salt thereof, wherein each R 4 It is acetyl.

[0481] E9: In one embodiment, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E8, or a pharmaceutically acceptable salt thereof, wherein each R 5 For hydrogen.

[0482] E10: In one embodiment, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E9, or a pharmaceutically acceptable salt thereof, wherein each R 6 For hydrogen.

[0483] E11: In one embodiment, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E10, or a pharmaceutically acceptable salt thereof, wherein each R 7 C 1-6 alkyl.

[0484] E12: In one embodiment, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E10, or a pharmaceutically acceptable salt thereof, wherein each R 7 It is a methyl group.

[0485] E13: In one embodiment, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E12, or a pharmaceutically acceptable salt thereof, wherein each R 8 For hydrogen.

[0486] E14: In one embodiment, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E13, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

[0487] i) By R 2 substituted aryl groups,

[0488] ii) an aryl group,

[0489] iii) by one or two R 3 substituted heteroaryl,

[0490] iv) heteroaryl, and

[0491] v) by R 4 Substituted heterocycloalkyl.

[0492] E15: In one aspect, the present invention provides a compound of formula XIV according to any one of A1 and E1 to E13, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

[0493] i) By R 2 substituted phenyl,

[0494] ii) phenyl,

[0495] iii) tetralin-1-yl,

[0496] iv) by one or two R 3 Substituted benzimidazol-1-yl,

[0497] v) by R 3 Substituted isoindoline-2-yl,

[0498] vi) 2-furyl,

[0499] vii) indolin-1-yl,

[0500] viii) benzofuran-3-yl,

[0501] ix) 2,3-dihydropyrrolo[2,3-b]pyridin-1-yl, and

[0502] x) is R 4 Substituted 4-piperidinyl.

[0503] E16: In one embodiment, the present invention provides a compound of formula XIV according to A1 or a pharmaceutically acceptable salt thereof, wherein:

[0504] A 1 is selected from the group consisting of -O-, -S-, -CH2-, -CF2-, and -NH-; and A 2 is -CH2-; or

[0505] A 1 is selected from the group consisting of: -O-, -S-, -CH2-, and -CF2-; and A 2 is -NH-;

[0506] Z is selected from the following group:

[0507] i) covalent bonds,

[0508] ii) a carbonyl group,

[0509] iii) -NH-,

[0510] iv) -O-CH2-C(=O)-NH-,

[0511] v) -C(=O)-NH-, and

[0512] vi) -NH-C(=O)-;

[0513] W is CH or N;

[0514] A is selected from the group consisting of:

[0515] i) By R 2 substituted aryl groups,

[0516] ii) an aryl group,

[0517] iii) by one or two R 3 substituted heteroaryl,

[0518] iv) heteroaryl, and

[0519] v) by R 4 substituted heterocycloalkyl;

[0520] R 2 Yes-C1-6 Alkyl or -NH2;

[0521] R 3 Selected from the group consisting of: -C(=O)-NH-C 1-6 Alkyl, -C 1-6 Alkyl, -OH and -NO2; and

[0522] R 4 is -C(=O)C 1-6 alkyl.

[0523] E17: In one aspect, the present invention provides a compound of formula XIV according to A1 or a pharmaceutically acceptable salt thereof, wherein:

[0524] A 1 is selected from the group consisting of -O-, -S-, -CH2-, -CF2-, and -NH-; and A 2 is -CH2-; or

[0525] A 1 is selected from the group consisting of: -O-, -S-, -CH2-, and -CF2-; and A 2 is -NH-;

[0526] Z is selected from the following group:

[0527] i) covalent bonds,

[0528] ii) a carbonyl group,

[0529] iii) -NH-,

[0530] iv) -O-CH2-C(=O)-NH-,

[0531] v) -C(=O)-NH-, and

[0532] vi) -NH-C(=O)-;

[0533] W is CH or N;

[0534] A is selected from the group consisting of:

[0535] i) By R 2 substituted phenyl,

[0536] ii) phenyl,

[0537] iii) tetralin-1-yl,

[0538] iv) by one or two R 3 Substituted benzimidazol-1-yl,

[0539] v) by R 3 Substituted isoindoline-2-yl,

[0540] vi) 2-furyl,

[0541] vii) indolin-1-yl,

[0542] viii) benzofuran-3-yl,

[0543] ix) 2,3-dihydropyrrolo[2,3-b]pyridin-1-yl, and

[0544] x) is R 4 substituted 4-piperidinyl;

[0545] R 2 is methyl or -NH2;

[0546] R 3 is selected from the group consisting of -C(=O)-NH-CH3, isopropyl, -OH, and -NO2; and R 4 It's acetyl.

[0547] E18: In one embodiment, the present invention provides a compound of formula XIV according to A1 or a pharmaceutically acceptable salt thereof, wherein:

[0548] A 1 A is selected from -O-, -S-, -CH2-, -CF2- and -NH-; 2 is -CH2-; or

[0549] A 1 Selected from -O-, -S-, -CH2- and -CF2-; A 2 is -NH-; and

[0550] W is CH or N.

[0551] E19: In one embodiment, the present invention provides a compound of formula XIV according to A1 or a pharmaceutically acceptable salt thereof, wherein:

[0552] A is selected from the group consisting of:

[0553] i) By R 2 substituted aryl groups,

[0554] ii) an aryl group,

[0555] iii) by one or two R 3 substituted heteroaryl,

[0556] iv) heteroaryl, and

[0557] v) by R 4 substituted heterocycloalkyl;

[0558] R2 Yes-C 1-6 Alkyl or -NH2;

[0559] R 3 Selected from the group consisting of: -C(=O)-NH-C 1-6 Alkyl, -C 1-6 Alkyl, -OH and -NO2; and

[0560] R 4 is -C(=O)C 1-6 alkyl.

[0561] E20: In one aspect, the present invention provides a compound of formula XIV according to A1 or a pharmaceutically acceptable salt thereof, wherein:

[0562] A is selected from the group consisting of:

[0563] i) By R 2 substituted phenyl,

[0564] ii) phenyl,

[0565] iii) tetralin-1-yl,

[0566] iv) by one or two R 3 Substituted benzimidazol-1-yl,

[0567] v) by R 3 Substituted isoindoline-2-yl,

[0568] vi) 2-furyl,

[0569] vii) indolin-1-yl,

[0570] viii) benzofuran-3-yl,

[0571] ix) 2,3-dihydropyrrolo[2,3-b]pyridin-1-yl, and

[0572] x) is R 4 substituted 4-piperidinyl;

[0573] R 2 is methyl or -NH2;

[0574] R 3 is selected from the group consisting of -C(=O)-NH-CH3, isopropyl, -OH, and -NO2; and R 4 It's acetyl.

[0575] E21: In one embodiment, the present invention provides a compound of formula XIV according to A1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula XIV is selected from the group consisting of:

[0576] 2-Isopropyl-N-methyl-1-(2-oxoindolin-6-yl)benzimidazole-5-carboxamide;

[0577] 2-Isopropyl-N-methyl-1-(2-oxoindolin-5-yl)benzimidazole-5-carboxamide;

[0578] 6-(2-aminoaniline)-3H-1,3-benzothiazol-2-one;

[0579] 6-(2-isopropylbenzimidazol-1-yl)-3H-1,3-benzothiazol-2-one;

[0580] 6-(2-aminoaniline)-3H-1,3-benzoxazol-2-one;

[0581] 6-(2-isopropylbenzimidazol-1-yl)-3H-1,3-benzoxazol-2-one;

[0582] N-(l-acetyl-4-piperidinyl)-2-oxo-3H-1,3-benzoxazole-6-carboxamide;

[0583] 6-(2,3-dihydropyrrolo[2,3-b]pyridine-1-carbonyl)-3H-1,3-benzoxazol-2-one;

[0584] 6-(Indoline-1-carbonyl)-3H-1,3-benzothiazol-2-one;

[0585] 5-(Indolin-1-carbonyl)indolin-2-one;

[0586] 2-Oxo-N-phenyl-3H-oxazolo[4,5-b]pyridine-6-carboxamide;

[0587] N-(l-acetyl-4-piperidinyl)-2-oxo-3H-oxazolo[4,5-b]pyridine-6-carboxamide;

[0588] 5-(Indolin-1-carbonyl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one;

[0589] 3,3-Difluoro-5-(2-isopropylbenzimidazol-1-yl)indolin-2-one;

[0590] 6-(4-Hydroxyisoindoline-2-carbonyl)-3H-1,3-benzoxazol-2-one;

[0591] 6-(4-nitroisoindoline-2-carbonyl)-3H-1,3-benzoxazol-2-one;

[0592] N-(3,3-difluoro-2-oxo-indolin-5-yl)tetralin-1-carboxamide;

[0593] N-(3,3-difluoro-2-oxo-indolin-5-yl)benzofuran-3-carboxamide;

[0594] 2-Isopropyl-N-methyl-1-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-5-yl)benzimidazole-5-carboxamide;

[0595] 5-(2-isopropylbenzimidazol-1-yl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one;

[0596] N-(2-Oxo-3H-1,3-benzoxazol-6-yl)benzamide;

[0597] N-(2-oxoindolin-5-yl)furan-2-carboxamide;

[0598] 2-(2-methylphenoxy)-N-(2-oxo-3H-1,3-benzothiazol-6-yl)acetamide;

[0599] 2-Oxo-N-phenylindoline-5-carboxamide;

[0600] 2-Oxo-N-phenyl-3H-1,3-benzoxazole-6-carboxamide;

[0601] 6-(Indoline-1-carbonyl)-3H-1,3-benzoxazol-2-one; and

[0602] 2-Oxo-N-phenyl-3H-1,3-benzothiazole-6-carboxamide.

[0603] E22: In one embodiment, the present invention provides a compound of formula XIV according to A1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula XIV is selected from the group consisting of:

[0604] 2-Isopropyl-N-methyl-1-(2-oxoindolin-6-yl)benzimidazole-5-carboxamide;

[0605] 2-Isopropyl-N-methyl-1-(2-oxoindolin-5-yl)benzimidazole-5-carboxamide;

[0606] 6-(2-aminoaniline)-3H-1,3-benzothiazol-2-one;

[0607] 6-(2-isopropylbenzimidazol-1-yl)-3H-1,3-benzothiazol-2-one;

[0608] 6-(2-isopropylbenzimidazol-1-yl)-3H-1,3-benzoxazol-2-one;

[0609] N-(1-acetyl-4-piperidinyl)-2-oxo-3H-1,3-benzoxazole-6-carboxamide;

[0610] 6-(2,3-dihydropyrrolo[2,3-b]pyridine-1-carbonyl)-3H-1,3-benzoxazol-2-one;

[0611] 6-(Indoline-1-carbonyl)-3H-1,3-benzothiazol-2-one;

[0612] 2-Oxo-N-phenyl-3H-oxazolo[4,5-b]pyridine-6-carboxamide;

[0613] N-(1-acetyl-4-piperidinyl)-2-oxo-3H-oxazolo[4,5-b]pyridine-6-carboxamide;

[0614] 5-(Indolin-1-carbonyl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one;

[0615] 3,3-Difluoro-5-(2-isopropylbenzimidazol-1-yl)indolin-2-one;

[0616] 6-(4-Hydroxyisoindoline-2-carbonyl)-3H-1,3-benzoxazol-2-one;

[0617] 6-(4-nitroisoindoline-2-carbonyl)-3H-1,3-benzoxazol-2-one;

[0618] N-(3,3-difluoro-2-oxo-indolin-5-yl)tetralin-1-carboxamide;

[0619] N-(3,3-difluoro-2-oxo-indolin-5-yl)benzofuran-3-carboxamide;

[0620] 2-isopropyl-N-methyl-1-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-5-yl)benzimidazole-5-carboxamide; and

[0621] 5-(2-Isopropylbenzimidazol-1-yl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one.

[0622] E23: In one embodiment, R 3 independently selected at each occurrence from: 10 Substituted -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; 10 Substituted -(CH2)0-1 -C 3-7 Cycloalkyl; -(CH2) 0-1 -C 3-7 Cycloalkyl; -(CH2) 0-1 -heterocycloalkyl; -C(=O)C 1-6 Alkyl; -(CH2) 0-2 -C(=O)-N(R 7 ,R 8 ); -C(=O)OC 1-6 Alkyl; -C 1-6 Alkoxy; -C 1-6 Alkyl; -OH; -NO2; -C 1-6 Alkyl-N(R 11 )-C(=O)-R 12 ; by R 10 Substituted -CH2-O-(CH2) 0-1 -aryl; -CH2-O-(CH2) 0-1 -aryl; -O-(CH2) 0-1 -Aryl; -Halogen; -Halogen-C 1-6 Alkyl; -hydroxy-C 1-6 Alkyl; -N(R 5 ,R 6 ); -NH-C(=O)C 1-6 Alkyl; and -NH-C(=O)OC 1-6 alkyl.

[0623] E24: In one embodiment, R 2 independently selected at each occurrence from: 10 Substituted -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; 10 Substituted -(CH2) 0-1 -C 3-7 Cycloalkyl; -(CH2) 0-1 -C 3-7 Cycloalkyl; -(CH2) 0-1 -heterocycloalkyl; -C(=O)C 1-6 Alkyl; -(CH2) 0-2 -C(=O)-N(R 7 ,R 8 ); -C(=O)OC 1-6 Alkyl; -C 1-6 Alkoxy; -C 1-6 Alkyl; -OH; -NO2; -C 1-6 Alkyl-N(R11 )-C(=O)-R 12 ; by R 10 Substituted -CH2-O-(CH2) 0-1 -aryl; -CH2-O-(CH2) 0-1 -aryl; -O-(CH2) 0-1 -Aryl; -Halogen; -Halogen-C 1-6 Alkyl; -hydroxy-C 1-6 Alkyl; -N(R 5 ,R 6 ); -NH-C(=O)C 1-6 Alkyl; and -NH-C(=O)OC 1-6 alkyl.

[0624] E25: A compound according to any one of the above embodiments, wherein A 1 is selected from -O- and -NH-, and A 2 It is -CH2-.

[0625] E26: A compound according to any one of the above embodiments, wherein A 1 is selected from the group consisting of -O-, -S-, -CH2-, -CF2-, and A 2 It is -NH-.

[0626] E27: A compound according to any of the previous embodiments, wherein W is CH.

[0627] E28: A compound according to any of the previous embodiments, wherein W is N.

[0628] E29: A compound according to any one of the above embodiments, wherein R 2 is independently selected at each occurrence from: -halogen; -halogen-C 1-6 Alkyl; -hydroxy-C 1-6 Alkyl; -N(R 5 ,R 6 );-NO2;-NH-C(=O)C 1-6 Alkyl; and -SO2-N(R 5 ,R 6 ).

[0629] E30: A compound according to any one of the above embodiments, wherein R 2 independently selected at each occurrence from: 10 Substituted -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; 10 Substituted -(CH2)0-1 -C 3-7 Cycloalkyl; -(CH2) 0-1 -C 3-7 Cycloalkyl; -C(=O)C 1-6 Alkyl; -C(=O)-N(R 7 ,R 8 ); -C(=O)OC 1-6 Alkyl; -C 1-6 Alkoxy; -C 1-6 Alkyl; R 10 Substituted -CH2-O-(CH2) 0-1 -aryl; -CH2-O-(CH2) 0-1 -aryl; and -O-(CH2) 0-1 -aryl.

[0630] E31: A compound according to any one of the above embodiments, wherein R 3 is independently selected at each occurrence from: -C(=O)C 1-6 Alkyl; -(CH2) 0-2 -C(=O)-N(R 7 ,R 8 ); -C(=O)OC 1-6 Alkyl; -C 1-6 Alkoxy; -C 1-6 Alkyl; -OH; -NO2; -C 1-6 Alkyl-N(R 11 )-C(=O)-R 12 ; by R 10 Substituted -CH2-O-(CH2) 0-1 -aryl; -CH2-O-(CH2) 0-1 -aryl; -O-(CH2) 0-1 -Aryl; -Halogen; -Halogen-C 1-6 Alkyl; -hydroxy-C 1-6 Alkyl; -hydroxy-C 1-6 Alkyl-aryl; -N(R 5 ,R 6 ); -NH-C(=O)C 1-6 Alkyl; -NH-C(=O)OC 1-6 alkyl; and =0.

[0631] E32: A compound according to any one of the above embodiments, wherein R 3 independently selected at each occurrence from: 10 Substituted -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; -(CH2) 0-1 -(C3-7 Cycloalkyl)-aryl; 10 Substituted -(CH2) 0-1 -C 3-7 Cycloalkyl; -(CH2) 0-1 -C 3-7 Cycloalkyl; -R 9 Substituted (CH2) 0-1 -heteroaryl; and -(CH2) 0-1 -heterocycloalkyl.

[0632] E33: A compound according to any one of the above embodiments, wherein R 4 is independently selected at each occurrence from: -C(=O)C 1-6 Alkyl; -C(=O)-N(R 7 ,R 8 ); -C(=O)OC 1-6 Alkyl; -C 1-6 Alkoxy; -C 1-6 Alkyl; R 10 Substituted -CH2-O-(CH2) 0-1 -aryl; -CH2-O-(CH2) 0-1 -Aryl; -Halogen; -Halogen-C 1-6 Alkyl; -hydroxy-C 1-6 Alkyl; -N(R 5 ,R 6 ); and -NH-C(=O)C 1-6 alkyl.

[0633] E34: A compound according to any one of the above embodiments, wherein R 4 independently selected at each occurrence from: 10 Substituted -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; -(CH2) 0-1 -(C 3-7 Cycloalkyl)-aryl; 10 Substituted -(CH2) 0-1 -C 3-7 Cycloalkyl; and -(CH2) 0-1 -C 3-7 Cycloalkyl.

[0634] E35: A compound according to any one of the above embodiments, wherein R 5 and R 6 independently selected at each occurrence from H, C 1-6 Alkyl and phenyl.

[0635] E36: A compound according to any one of the above embodiments, wherein R 5and R 6 Together with the nitrogen to which they are attached they form a heterocycloalkyl ring.

[0636] E37: A compound according to any one of the above embodiments, wherein R 7 and R 8 independently selected at each occurrence from H and C 1-6 alkyl.

[0637] E38: A compound according to any one of the above embodiments, wherein R 7 and R 8 Together with the nitrogen to which they are attached they form a heterocycloalkyl ring.

[0638] E39: A compound according to any one of the above embodiments, wherein X 1 Select from bond or NR 34 .

[0639] E40: A compound according to any one of the above embodiments, wherein X 22 Selected from halogen, -NH2, -NHR 34 、-N(R 34 )2、hydroxyl、thiol、-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)olefins, -NR 34 C(O)alkyne, cyano, -SC(O)alkyl, OC(O)alkyl, heterocycle, -C(O)OH, hydrogen, alkyl, aryl, heteroaryl, aliphatic, heteroaliphatic, and carbocycle.

[0640] E41: A compound according to any one of the above embodiments, wherein R 20 、R 21 、R 22 、R 23 and R 24 independently selected from the group consisting of: a bond, an alkyl group, -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 R34’ )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' -, alkene, haloalkyl, alkoxy, alkynylheteroarylalkyl, aryl, aralkyl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, carbocyclic ring, -(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-, where R 20 、R 21 、R 22 、R 23 and R 24 At least one of is not a key.

[0641] E42: A compound according to any one of the above embodiments, wherein R 20 、R 21 、R 22 、R 23 and R 24 At least two of them are not keys.

[0642] E43: A compound according to any one of the above embodiments, wherein R 20 、R 21 、R 22 、R 23 and R 24 At least three of them are not keys.

[0643] E44: A compound according to any one of the above embodiments, wherein R 20 、R 21 、R 22、R 23 and R 24 At least four of them are not bonds.

[0644] In one embodiment, the present invention provides a pharmaceutically acceptable salt or ester of a compound of formula XIV as described herein. In a specific embodiment, the present invention provides a pharmaceutically acceptable salt, especially a hydrochloride, of a compound of formula XIV as described herein. In another specific embodiment, the present invention provides a pharmaceutically acceptable ester of a compound of formula XIV as described herein. In yet another specific embodiment, the present invention provides a compound of formula XIV as described herein.

[0645] 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 of formula XIV.

[0646] Formula XIV compound can contain one or more asymmetric centers and therefore can exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomeric forms. Depending on the nature of the various substituents on the molecule, additional asymmetric centers may exist. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereoisomers in the expected 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 diastereoisomers or their chromatographic separations can be achieved by appropriately modifying the method disclosed herein as known in the art. Their absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, and if desired, the crystalline product or crystalline intermediate can be derivatized with a reagent containing an asymmetric center of known absolute configuration. If desired, the racemic mixture of the compound can be separated to separate each enantiomer. Separation can be achieved by methods well known in the art, such as 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.

[0647] In embodiments providing optically pure enantiomers, an optically pure enantiomer means that the compound contains >90% by weight of the desired isomer, particularly >95% by weight of the desired isomer, or 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.

[0648] In one embodiment of Formula XIV, Z is a covalent bond.

[0649] In another embodiment of Formula XIV, Z is C(=O).

[0650] In another embodiment of Formula XIV, Z is selected from:

[0651]

[0652] In another embodiment of Formula XIV, Z is selected from:

[0653]

[0654] In another embodiment of Formula XIV, Z is selected from:

[0655]

[0656] In another embodiment of Formula XIV, Z is selected from:

[0657]

[0658] In another embodiment of Formula XIV, Z is selected from:

[0659]

[0660] In another embodiment of Formula XIV, Z is selected from:

[0661]

[0662] In another embodiment of Formula XIV, Z is selected from:

[0663]

[0664] In one embodiment of Formula XIV, yes

[0665] In one embodiment of Formula XIV, yes

[0666] In one embodiment of Formula XIV, Selected from:

[0667]

[0668] In one embodiment of Formula XIV, Selected from:

[0669]

[0670]

[0671] In one embodiment of Formula XIV, Selected from:

[0672]

[0673] In one embodiment of Formula XIV, Selected from:

[0674]

[0675] In one embodiment of Formula XIV, Selected from:

[0676]

[0677] In one embodiment of Formula XIV, Selected from:

[0678]

[0679] In one embodiment of Formula XIV, Selected from:

[0680]

[0681] In one embodiment of Formula XIV, Selected from:

[0682]

[0683] In one embodiment of XIV, Selected from:

[0684]

[0685] Embodiments of Formula XIV (1)

[0686] In one aspect, the compound of formula XIV(1) is selected from:

[0687]

[0688]

[0689] In one aspect, the compound of formula XIV(1) is selected from:

[0690]

[0691] In one aspect, the compound of formula XIV(1) is selected from:

[0692]

[0693]

[0694] In one aspect, the compound of formula XIV(1) is selected from:

[0695]

[0696]

[0697]

[0698] In one aspect, the compound of formula XIV(1) is selected from:

[0699]

[0700]

[0701] In one aspect, the compound of formula XIV(1) is selected from:

[0702]

[0703]

[0704] In one aspect, the compound of formula XIV(1) is selected from:

[0705]

[0706]

[0707]

[0708] In one aspect, the compound of formula XIV(1) is selected from:

[0709]

[0710]

[0711]

[0712] In one aspect, the compound of formula XIV(1) is selected from:

[0713]

[0714]

[0715]

[0716] In one aspect, the compound of formula XIV(1) is selected from:

[0717]

[0718]

[0719]

[0720] In one aspect, the compound of formula XIV(1) is selected from:

[0721]

[0722]

[0723]

[0724] In one aspect, the compound of formula XIV(1) is selected from:

[0725]

[0726]

[0727]

[0728] In one aspect, the compound of formula XIV(1) is selected from:

[0729]

[0730]

[0731]

[0732] In one aspect, the compound of formula XIV(1) is selected from:

[0733]

[0734]

[0735]

[0736] Embodiments of Formulas I(1)-XIII(1)

[0737] In one aspect, there is provided a compound of formula I(1)

[0738]

[0739] wherein all variables are as defined herein.

[0740] In one embodiment of formula I(1), Selected from:

[0741]

[0742] where T is

[0743] In one aspect, a compound having one of the following formulae is provided:

[0744]

[0745]

[0746]

[0747] wherein all variables are as defined herein.

[0748] In any of the embodiments of Formulae II(1)a-II(1)k, Selected from:

[0749] where T is

[0750] In one aspect, provided is a compound of formula III (1):

[0751]

[0752] wherein all variables are as defined herein.

[0753] In one embodiment of formula III (1), Selected from:

[0754]

[0755]

[0756] where T is

[0757] In one aspect, a compound having one of the following formulae is provided:

[0758]

[0759]

[0760] wherein all variables are as defined herein.

[0761] In one embodiment of any one of Formulae IV(1)-a to IV(1)-J, Selected from:

[0762]

[0763] where T is

[0764] In one aspect, provided is a compound of formula V(1):

[0765]

[0766] wherein all variables are as defined herein.

[0767] In one embodiment of formula V (1), Selected from:

[0768]

[0769]

[0770] where T is

[0771] In one aspect, a compound of formula VI (1) is provided:

[0772]

[0773] wherein all variables are as defined herein.

[0774] In one embodiment of formula VI (1), Selected from:

[0775]

[0776]

[0777] where T is

[0778] In one aspect, a compound having one of the following formulae is provided:

[0779]

[0780]

[0781] wherein all variables are as defined herein.

[0782] In one embodiment of any of Formulae VII(1)a-VII(1)e, Selected from:

[0783] where T is

[0784] In one aspect, a compound having one of the following formulae is provided:

[0785]

[0786]

[0787]

[0788] wherein all variables are as defined herein.

[0789] In one embodiment of any one of Formulae VIII(1)-a to VIII(1)-I, Selected from:

[0790] where T is

[0791] In one aspect, a compound having one of the following formulae is provided:

[0792]

[0793]

[0794]

[0795] wherein all variables are as defined herein.

[0796] In one aspect, a compound having one of the following formulae is provided:

[0797]

[0798]

[0799] wherein all variables are as defined herein.

[0800] In one aspect, a compound having one of the following formulae is provided:

[0801]

[0802]

[0803]

[0804] wherein all variables are as defined herein.

[0805] In one aspect, there is provided a compound of formula XII(1):

[0806]

[0807] wherein all variables are as defined herein.

[0808] In one aspect, a compound having one of the following formulae is provided:

[0809]

[0810]

[0811]

[0812] wherein all variables are as defined herein.

[0813] In one embodiment of any one of the compounds of Formulae IX(1)-1 to IX(1)-j, X(1)-a to X(1)-i, XI(1)-a to XI(1)-i, and XIII(1)-a to XIII(1)-i, Selected from:

[0814] where T is

[0815] III. Tail Implementation

[0816] In one embodiment, the "tail" is a moiety selected from Formula T1, Formula T-II, Formula T-III, Formula T-IV, Formula TV, Formula T-VI, and Formula T-VII:

[0817]

[0818]

[0819] where all variables are defined as above.

[0820] In another embodiment, the "tail" is a moiety selected from the group consisting of Formulae T-VIII, T-IX, and TX:

[0821]

[0822] 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.

[0823] The following are non-limiting examples of "tail" portions that may be used in the present invention. Based on this description, those skilled in the art will understand how to use the full width of the "tail" portion to achieve the goals of the present invention.

[0824] 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:

[0825]

[0826]

[0827]

[0828] In another embodiment, the "tail" is selected from:

[0829]

[0830] In another embodiment, the "tail" is selected from:

[0831]

[0832]

[0833] R 20 、R 21 、R 22 、R 23 and R 24 Some non-limiting examples include:

[0834]

[0835] R 20 、R 21 、R 22 、R 23 and R 24 Other non-limiting examples of parts include:

[0836]

[0837] R 20 、R 21 、R 22 、R 23 and R 24 Other non-limiting examples of parts include:

[0838]

[0839]

[0840] 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 side-joined, 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 having a size range of about 1 to about 12 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to about 6 ethylene glycol units, about 2 to 5 ethylene glycol units, about 2 to 4 ethylene glycol units. In any embodiment of the compounds described herein, the "tail" group can be any suitable part described herein.

[0841] In further embodiments, the "tail" is selected from:

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

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

[0844] -NR 61 (CH2) n1 -(cycloalkyl)-(lower alkyl)-OCH2-X 22 ,-NR 61 (CH2) n1 -(Heterocycloalkyl)-X 22 ,

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

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

[0847] -NR 61 (CH2CH2O) n1 -Aryl-O-CH2-X 22 ,-NR 61 (CH2CH2O) n1 -(Heteroaryl)-O-CH2-X 22 ,

[0848] -NR 61 (CH2CH2O) n1 -(cycloalkyl)-O-(heteroaryl)-O-CH2-X 22 ,

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

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

[0851] -NR 61 (CH2CH2O) n1 -(lower alkyl)-O-aryl-CH2-X 22 ,

[0852] -NR 61 (CH2CH2O) n1 -cycloalkyl-O-aryl-X 22 ,-NR 61 (CH2CH2O) n1 -cycloalkyl-O-heteroaryl-X 22 ,

[0853] -NR 61 (CH2CH2) n1 -(cycloalkyl)-O-(heterocycle)-CH2-X 22 ,

[0854] -NR 61 (CH2CH2) n1 -(Heterocycle)-(Heterocycle)-CH2-X 22 , and -NR 61 -(Heterocyclic)-CH2-X 22 ;

[0855] wherein n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0856] R 61 It is H, methyl or ethyl.

[0857] In further embodiments, the "tail" is selected from:

[0858] -N(R 61 )-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-X 22 ,

[0859] -O-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-X 22 ,

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

[0861] -N(R 61 )-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OH;

[0862] -(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OH;

[0863] -(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1-O(CH2) q1 -O(CH2) r1 -OCH2-X 22 ;

[0864] -O(CH2) m1 O(CH2) n2 O(CH2) p1 O(CH2) q1 OCH2-X 22 ;

[0865] -O(CH2) m1 O(CH2) n2 O(CH2) p1 O(CH2) q1 OCH2-X 22 ;

[0866] wherein m1, n2, o1, p1, q1 and r1 are independently 1, 2, 3, 4 or 5; and

[0867] R 61 It is H, methyl or ethyl.

[0868] In further embodiments, the "tail" is selected from:

[0869]

[0870]

[0871] m1, n2, o1, p1, q2 and r1 are independently 1, 2, 3, 4 or 5.

[0872] In further embodiments, the "tail" is selected from:

[0873]

[0874]

[0875] In further embodiments, the "tail" is selected from:

[0876]

[0877] In further embodiments, the "tail" is selected from:

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884] where R 71 is -O-, -NH, N-alkyl, heteroaliphatic, aliphatic or -NMe.

[0885] In further embodiments, the "tail" is selected from:

[0886]

[0887]

[0888]

[0889]

[0890]

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

[0892]

[0893]

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

[0895]

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

[0897]

[0898]

[0899] In further embodiments, the "tail" is selected from:

[0900]

[0901] In the above embodiment, select X 22 The compound is sufficiently stable or produces the intended use result.

[0902] In further embodiments, the "tail" is selected from:

[0903]

[0904]

[0905] In certain embodiments, the "tail" is selected from:

[0906]

[0907] In certain embodiments, the "tail" is selected from:

[0908]

[0909]

[0910] In the above structure, represent

[0911] In certain embodiments, the "tail" can be a straight chain of 4-24 carbon atoms, wherein one or more carbon atoms in the straight chain can be replaced or substituted by oxygen, nitrogen, amide, fluorinated carbon, etc., such as the following:

[0912]

[0913]

[0914] In certain embodiments, the "tail" may be non-linear, and may be or include an aliphatic or aromatic or heteroaromatic cyclic moiety.

[0915] In certain embodiments, the "tail" can include a continuous, partially continuous, or non-continuous group of ethylene glycol units ranging in size from about 1 to about 12 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to about 6 ethylene glycol units, about 2 to 5 ethylene glycol units, about 2 to 4 ethylene glycol units, e.g., 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11, or 12 ethylene glycol units.

[0916] 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 "tail" moieties include:

[0917]

[0918] X 22 Representative examples include:

[0919]

[0920] In certain embodiments, the length can be adjusted as needed or as required for the desired application.

[0921] IV. Treatment Methods

[0922] Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V(1), Formula VI(1 ), compounds of Formula VII(1)-a to VII(1)-e, Formula VIII(1)-a to VIII(1)-i, Formula IX(1)-a to IX(1)-j, Formula X(1)-a to X(1)-i, Formula XI(1)-a to XI(1)-i, Formula XII(1), Formula XIII(1)-a to XIII(1)-i or Formula XIV(1) can be used to treat a host in need thereof (including humans) in an effective amount, optionally in a pharmaceutically acceptable carrier to treat any of the conditions described herein.

[0923] As used herein, the term "treatment" and the like refers to any effect that provides a benefit to a patient to whom a compound of the invention is administered, including the treatment of any disease state or condition modulated by a protein to which the compound of the invention binds. Exemplary non-limiting disease states or conditions that can be treated using compounds according to the invention include cancer, as described above.

[0924] When combined with Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V(1), Formula VI(1), Formula VII(1)-a to VII(1)-e, Formula VIII( When used in combination with a compound of formula (I)-a to VIII(I)-i, formula (IX)-a to IX(I)-j, formula (X)-a to X(I)-i, formula (XI)-a to XI(I)-i, formula (XII)-1, formula (XIII)-a to XIII(I)-i, or formula (XIV)-1, the term "disease state or condition" refers to any therapeutic indication that can be treated by decreasing the activity of cereblon or an E3 ligase containing cereblon, including but not limited to the use of known cereblon binders thalidomide, pomalidomide, or lenalidomide. Non-limiting examples 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 disorders, such as B-cell or T-cell lymphoma, Walden's macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorder; immune disorders, including autoimmune diseases, such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, arthritis, especially rheumatoid arthritis, lupus, or type 1 diabetes; cardiac dysfunction disorders, including hypercholesterolemia; infectious diseases, including viral and / or bacterial infections, as generally described herein; inflammatory diseases, including asthma, chronic peptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis, and ulcerative colitis.

[0925] In certain embodiments, the present invention provides a method for treating a molecule of formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-i, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-i, formula XII, formula XIII-a to XIII-i, formula XIV, formula I(1), formula II(1)-a to II(1)-k, formula III(1), formula IV(1)-a to IV(1)-j, formula V( 1), a compound of formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) is administered to a patient, such as a human, suffering from an infectious disease, wherein the treatment targets a protein of the infectious agent, optionally in combination with another biologically active agent. The disease state or disorder can be a disease caused by a microbial agent or other exogenous agent, such as a virus (as a non-limiting example, HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola, flavivirus, pestivirus, rotavirus, influenza, coronavirus, EBV, viral pneumonia, drug-resistant virus, avian influenza, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, or hepatitis virus), bacteria (Gram-negative, Gram-positive, fungi, protozoa, helminths, worms, prions, parasites, or other microorganisms) or can be a disease state caused by the overexpression of a protein that causes the disease state and / or disorder.

[0926] In certain embodiments, the conditions treated with the compounds of the present invention are conditions 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 diseases, and induction of benign or malignant tumors.

[0927] There are many skin diseases associated with excessive cell proliferation. For example, psoriasis is a benign disease of the human skin characterized by patches of skin covered with thickened scales. The disease is caused by an unexplained increase in the proliferation of epidermal cells. Chronic eczema is also associated with significant overproduction of epidermal cells. Other diseases caused by excessive skin cell proliferation include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratoses, basal cell carcinoma, and squamous cell carcinoma.

[0928] Other hyperproliferative cellular diseases include angiogenic disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancer.

[0929] Vascular proliferative disorders include angiogenic disorders and vasculogenic disorders. The proliferation of smooth muscle cells during plaque formation 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.

[0930] Fibrotic conditions are generally caused by abnormal formation of the extracellular matrix. Examples of fibrotic conditions include cirrhosis and mesangial proliferative cell disorders. Cirrhosis is characterized by an increase in extracellular matrix components, leading to scarring of the liver. Hardening of the liver can lead to 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 cirrhosis.

[0931] Mesangial diseases are caused by abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell diseases include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection, and glomerulopathy.

[0932] Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease, thought to be associated with the activity of autoreactive T cells and caused by autoantibodies produced against collagen and IgE.

[0933] Other disorders that may include an abnormal cell proliferation component include Bechet syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammatory conditions.

[0934] Skin contact allergies and asthma are just two examples of immune reactions that can be associated with significant morbidity. Others include atopic dermatitis, eczema, Sjögren's syndrome, including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions due to arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative conjunctivitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may cause any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulcers, pain, scaling, cracking, hair loss, scarring, or drainage involving the skin, eyes, or mucous membranes.

[0935] 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 in sites other than the skin, such as the airways of asthmatics and the tear glands of eyes with keratoconjunctivitis sicca.

[0936] In one non-limiting embodiment, the compounds of the present invention are used as topical agents for the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjögren's syndrome (Sjögren's syndrome), including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions caused by 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 into the skin in diseases such as fungal diseases. These compounds can also be used to treat patients experiencing water-deficient dry eyes (e.g., immune-mediated keratoconjunctivitis) by applying the compounds topically to the eyes.

[0937] Disease states in which the compounds according to the present invention can be used to treat disorders include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease 1 (PKD1) or 2 (PKD2) Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome.

[0938] Other disease states or conditions that can be treated by the compounds of the present invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette syndrome, vasculitis.

[0939] Other disease states or conditions treatable by the compounds of the present invention include aceruloplasminemia, type II chondrodysplasia, achondroplasia, acrofacial malformations, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis, ALA dehydratase deficiency, adenylate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkali aciduria, Alexander disease, homogentisate ocheropathy, alpha 1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, amyloidosis syndrome, Alexander disease, amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, diffuse angiokeratoma body, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, spider fingers (Marfan syndrome), Stickler syndrome, arthrogryposis congenita (Ehlers-Danlos syndrome, arthrochalasia type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson skin gyrations, Mediterranean fever, familial leukemia, Benjamin syndrome, beta-thalassemia, bilateral auditory neurofibromatosis (neurofibromatosis type II), factor VLeiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion diseases, Birt-Hogg-Dube syndrome, brittle bone disease (osteogenesis imperfecta), Rubinstein-Taybi syndrome, bronze diabetes / bronze cirrhosis (hemochromatosis), bulbospinal myopathy Atrophy (Kennedy disease), Burger-Grutz syndrome (lipoprotein lipase deficiency), chronic granulomatous disease (CGD), Campomelic dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), Cry-du-chat syndrome, CAVD (congenital absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, chondrodystrophy syndrome (achondroplasia), auris hypertrophic epiphyseal dysplasia, Lesch-Nyhan syndrome Symptoms include: galactosemia, Ehlers-Danlos syndrome, thanatoplasia, 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, conotofacial syndrome, Cooley anemia (beta-thalassemia), copper storage disease (Wilson disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, and craniofacial joint disorders. (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Beare-Stevenson skin gyration syndrome, primary hyperoxaluria, spondylodysplasia (Strudwick type), muscular dystrophy, Duchenne and Becker types (DBMD), Usher syndrome, degenerative neurological diseases including dementiaGrouchy syndrome and Dejerine-Sottas syndrome, developmental disabilities, distal spinal muscular atrophy, androgen insensitivity syndrome type V, diffuse glomerulosclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, erythropoietic 5-aminolevulinic acid synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polymyalgia Porphyria cutanea tarda, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrocystic disease, fragile X syndrome, galactosemia, hereditary brain disorders, giant cell hepatitis (neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudoxanthoma elasticum), Gunther disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, achondroplasia, 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 disorders including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, lacunar dementia, Langer-Saldino chondrodysplasia, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome Symptoms include: motion sickness, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrodysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary Alzheimer's disease, prion disease, progeria (Hutchinson'sGilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen disease (neurofibromatosis type 1), relapsing polypsoralen, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe achondroplasia and acanthosis nigricans with developmental delay (SADDAN), Li-Fraumeni syndrome, sarcoma, breast cancer, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis), SDAT, congenital SED (spondyloepiphyseal dysplasia congenita), SED Strudwick (spondyloepiphyseal dysplasia, Strudwick type), SEDc (spondyloepiphyseal dysplasia congenita), SEMD, Strudwick type, Shprintzen syndrome, skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South African hereditary porphyrias (variable porphyrias), ascending hereditary spastic paralysis of the infantile type, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, tomaculous neuropathy (hereditary neuropathy with pressure palsy), Treacher Collins syndrome, Triple X syndrome, Trisomy 21 (Down syndrome), Trisomy X syndrome, VHL syndrome (von Hippel-Lindau syndrome) Hippel-Lindau disease), visual impairment and blindness (Alstrom syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo Fledelius syndrome, Weissenbacher-Zweymiiller syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disease, Weissenbacher-Zweymiiller syndrome and xeroderma pigmentosum, among others.

[0940] As used throughout this specification, the terms "neoplasia" or "cancer" refer to the pathological process that leads to the formation and growth of cancerous or malignant tumors, i.e., abnormal tissue that grows through cellular proliferation, often more rapidly than normal tissue, and continues to grow after the stimulus that initiated new growth has ceased. Malignant tumors exhibit partial or complete lack of structural organization and functional coordination with accompanying normal tissue, most often invade surrounding tissues, metastasize to multiple sites, and are likely to recur after attempted resection and result in patient death unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous 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 present invention, alone or in combination with at least one additional anticancer agent, include: squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular 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, particularly Burkitts lymphoma and non-Hodgkin lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, and leukemia. Liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, astrocytoma, ganglioneuroma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma and schwannoma; colorectal 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-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphocytic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0941] Other cancers that can be treated using the compounds disclosed herein include, for example, acute myeloid leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical cancer, 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 , estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, HER2-negative breast cancer, HER2-positive or -negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, 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 cancer, invasive / infiltrating breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastasis, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal, Mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous neck cancer, mixed glioma, monocutaneous teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, fungal disease, myelodysplastic syndrome, nasal cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, eye melanoma, oligodendroglioma, mouth cancer, oral cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian primary peritoneal cancer, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,Pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, vertebral cancer, spinal cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma / thymic cancer, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine carcinoma, 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-BALL, Pre-B lymphoma, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma tumors; mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, unclassifiable splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain disorders, such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicle center lymphoma , T cell / histiocyte-rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, ALK+ large B-cell lymphoma of the leg, plasmablastic lymphoma; large B-cell lymphoma caused by HHV8-related multicentric disease, Castleman disease; B-cell lymphoma, unclassifiable and characterized as intermediate between diffuse large B-cell lymphoma; or B-cell lymphoma, unclassifiable and characterized as intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0942] In one embodiment, the cancer is a NUT midline cardiac tumor.

[0943] In one embodiment, the cancer is adenoid cystic carcinoma.

[0944] The term "biologically active agent" is used to describe an agent other than a compound according to the invention that 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 using the compounds of the invention. Preferred biologically active agents for use herein include those having pharmacological activities similar to those of the use or administration of the compounds of the invention, and include, for example, anticancer agents, antiviral agents, particularly including anti-HIV agents and anti-HCV agents, antimicrobial agents, antifungal agents, and the like.

[0945] V. Combination Therapy

[0946] Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V The compounds of formula (1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) can be used alone or in combination in an effective amount to treat a host, such as a human, suffering from a condition described herein.

[0947] The compounds disclosed herein can be used in an effective amount alone or in combination with another compound of the invention or another biologically active agent to treat a host, such as a human, suffering from a condition described herein.

[0948] The term "biologically active agent" is used to describe an agent, other than a compound selected according to the present invention, that can be used in combination or in conjunction with a compound of the present invention to achieve a desired therapeutic outcome. In one embodiment, the compound of the present invention and the biologically active agent are administered in such a manner that they are active in vivo over overlapping time periods, e.g., have overlapping Cmax, Tmax, AUC, or other pharmacokinetic parameters. In another embodiment, the compound of the present invention and the biologically active agent are administered to a host in need thereof with no overlapping pharmacokinetic parameters, however, one has a therapeutic impact on the therapeutic efficacy of the other.

[0949] In one aspect of this embodiment, bioactive agent is immunomodulator, including but not limited to check point inhibitor, including as non-limiting example PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, T cell activated V domain Ig inhibitor (VISTA) inhibitor, small molecule, peptide, nucleotide or other inhibitor.In some aspects, immunomodulator is antibody, such as monoclonal antibody.

[0950] VI. Pharmaceutical Compositions

[0951] As disclosed herein, Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V(1), Formula VI(1), Formula VI(2), Formula VI(3), Formula VI(4), Formula VI(5), Formula VI(6), Formula VI(7), Formula VI(8), Formula VI(9), Formula VI(10), Formula VI(11), Formula VI(12), Formula VI(13), Formula VI(14), Formula VI(15), Formula VI(16), Formula VI(17), Formula VI(18), Formula VI(19), Formula VI(20), Formula VI(21), Formula VI(22), Formula VI(23), Formula VI(24), Formula VI(25), Formula VI(26), Formula VI(27), Formula VI(28), Formula VI(29), Formula VI(30), Formula VI(31), Formula VI(32), Formula VI(33), Formula VI(34), Formula VI(35), Formula VI(36), Formula VI(37), Formula VI(38), Formula VI(39), Formula VI(40), Formula VI(41), Formula VI(42), Formula VI(43), Formula VI(44), Formula VI(45), Formula VI(46), Formula VI(47), Formula VI(48), Formula VI(49), Formula VI(50), Formula VI(51), Formula VI(52), Formula VI(53), The compounds of formula I(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i, or formula XIV(1) can be administered as pure chemicals, but are more typically administered as pharmaceutical compositions comprising an amount effective for a host (typically a human) in need of such treatment for any of the diseases described herein. Accordingly, the present disclosure provides pharmaceutical compositions for any of the uses described herein, comprising an effective amount of a compound or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier. The pharmaceutical composition can contain the compound or salt as the sole active agent, or in alternative embodiments, the pharmaceutical composition can contain the compound and at least one additional active agent.

[0952] In certain embodiments, the dosage form of the pharmaceutical composition comprises an active compound of 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 in a unit dose and optionally an additional active agent of 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. Examples are dosage forms having at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound or a salt thereof. The pharmaceutical composition may also include a certain molar ratio of the active compound and the additional active agent. For example, the pharmaceutical composition may include an anti-inflammatory agent or immunosuppressant in a molar ratio 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 can be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implants including ocular implants, transdermally, by oral administration, rectally, as eye drops, by injection including ocular injection, intravenously, intraaortically, intracranially, subcutaneously, intraperitoneally, in the subcutaneous tissue layer, nasally, sublingually or rectally or by other means in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For ocular delivery, the compound can be administered, for example, via intravitreal, intrastromal, intracameral, subtenon, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior scleral, peripheral or lacrimal injection or through mucus, mucin or mucosal barriers, in an immediate release or controlled release manner or by an ocular device.

[0953] The pharmaceutical composition can be formulated into any pharmaceutically useful form, such as an aerosol, cream, gel, pill, injection or infusion solution, capsule, tablet, syrup, transdermal patch, subcutaneous patch, dry powder, inhalation formulation, medical device, suppository, oral or sublingual formulation, parenteral formulation or eye drops. Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing an appropriate amount of the active ingredient, such as an effective amount to achieve the desired purpose.

[0954] The carrier includes an excipient and a diluent and must be of sufficiently high purity and sufficiently low toxicity to make it suitable for administration to the patient being treated. The carrier may be inert or 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 administration per unit dose of the compound.

[0955] Carrier categories include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one category; for example, a vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder, 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.

[0956] 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, 0.1-99 weight percent (wt.%) of the compound and typically at least about 5 wt.% of the compound. Some embodiments contain from about 25 wt.% to about 50 wt.% or from about 5 wt.% to about 75 wt.% of the compound.

[0957] 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, for example, cocoa butter, and shaping the resulting mixture.

[0958] 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 glycol, alcohol, transdermal enhancers and combinations of two or more thereof.

[0959] Preparations suitable for transdermal administration can be in the form of discrete patches suitable for maintaining close contact with the epidermis of the recipient for a long time. Preparations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6): 318 (1986)) and are generally in the form of optional buffered aqueous solutions of the active compound. In one embodiment, a microneedle patch or device is provided for delivering the drug through or into biological tissue, particularly the skin. The microneedle patch or device allows the drug to be delivered through or into the skin or other tissue barriers at a clinically relevant rate with minimal or no stimulation to the damage, pain or irritation of the tissue.

[0960] Preparations suitable for pulmonary administration can be delivered by a variety of passive respiratory actuation and active power-driven single-dose / multi-dose dry powder inhalers (DPIs). The equipment most commonly used in respiratory delivery includes nebulizers, metered dose inhalers, and dry powder inhalers. Various types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of suitable lung delivery devices depends on the following parameters, such as the properties of the drug and its preparation, site of action, and the pathophysiology of the lung.

[0961] 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, administration can also be performed rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

[0962] The compounds described herein and their pharmaceutically acceptable salts can be processed together with pharmaceutically inert, inorganic or organic carriers to prepare pharmaceutical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as 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 properties of the active substance, a carrier is generally not required in the case of soft gelatin capsules. Suitable carriers for preparing 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.

[0963] 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 with therapeutic value.

[0964] The present invention further provides medicaments containing a compound of the invention or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, as well as a process for their production, which comprises formulating one or more compounds of formula I and / or a pharmaceutically acceptable salt thereof and one or more other therapeutically valuable substances (if desired) together with one or more therapeutically inert carriers into a galenical administration form.

[0965] The dosage can vary over a wide range and, of course, must be adjusted according to the individual needs in each particular case. In the case of oral administration, the dosage for an adult can vary within the range of about 0.01 mg to about 1000 mg per day of a compound of Formula XIV or a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose can be administered in a single dose or in divided doses, and the upper limit may be exceeded if it is found necessary to do so.

[0966] The following examples illustrate the invention without limiting it but are merely representative thereof. The pharmaceutical preparations conveniently contain about 1 to 500 mg, in particular 1 to 100 mg, of a compound of formula XIV.

[0967] Examples of compositions according to the invention are:

[0968] Example A

[0969] Tablets of the following composition are prepared in the usual manner:

[0970]

[0971]

[0972] Table 1: Possible tablet compositions

[0973] Preparation steps

[0974] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

[0975] 2. Dry the granules at 50°C.

[0976] 3. Pass the granules through suitable grinding equipment.

[0977] 4. Add ingredient 5 and stir for three minutes; compress on a suitable tablet press.

[0978] Example B-1

[0979] Prepare capsules of the following composition:

[0980]

[0981] Table 2: Possible capsule composition

[0982] Preparation steps

[0983] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[0984] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[0985] 3. Fill into suitable capsules.

[0986] The compound of formula XIV, lactose, and corn starch are first mixed in a blender and then in a mill. The mixture is returned to the blender; talc is added and mixed thoroughly. The mixture is then filled by machine into suitable capsules, such as hard gelatin capsules.

[0987] Example B-2

[0988] Prepare soft gelatin capsules of the following composition:

[0989] Element mg / capsule Compound of formula XIV 5 Yellow wax 8 hydrogenated soybean oil 8 Partially hydrogenated vegetable oil 34 soybean oil 110 total 165

[0990] Table 3: Possible soft gelatin capsule composition

[0991] 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

[0992] Table 4: Possible soft gelatin capsule compositions

[0993] Preparation steps

[0994] The compound of formula XIV is dissolved in the warm melted other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are processed according to the usual procedures.

[0995] Example C

[0996] Prepare suppositories of the following composition:

[0997] Element mg / suppository Compound of formula XIV 15 Suppository block 1285 total 1300

[0998] Table 5: Possible suppository compositions

[0999] Preparation steps

[1000] The suppository mass is melted in a glass or steel container, mixed thoroughly, and cooled to 45°C. Subsequently, the finely powdered compound of formula XIV is added and stirred until it is completely dispersed. The mixture is poured into a suppository mold of appropriate size and allowed to cool; the suppositories are then removed from the mold and individually wrapped in wax paper or metal foil.

[1001] Example D

[1002] Prepare an injection solution of the following composition:

[1003] Element mg / injection solution Compound of formula XIV 3 polyethylene glycol 400 150 Acetic acid qsad pH 5.0 Water for injection solution ad 1.0ml

[1004] Table 6: Possible compositions of injection solutions

[1005] Preparation steps

[1006] The compound of formula XIV is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 with acetic acid. The volume is adjusted to 1.0 ml by adding the remaining amount of water. The solution is filtered, filled into vials using an appropriate excess, and sterilized.

[1007] Example E

[1008] Prepare a sachet of the following composition:

[1009] Element mg / sachet Compound of formula XIV 50 Lactose, finely powdered 1015 Microcrystalline cellulose (AVICEL PH 102) 1400 Sodium carboxymethyl cellulose 14 Polyvinylpyrrolidone K 30 10 magnesium stearate 10 flavoring additives 1 total 2500

[1010] Table 7: Possible sachet compositions

[1011] Preparation steps

[1012] The compound of formula XIV 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.

[1013] VII. Uses of the Compounds

[1014] Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I (1), Formula II (1)-a to II (1)-k, Formula III (1), Formula IV (1)-a to IV (1)-j, Formula V ( Compounds of formula 1, VI(1), VII(1)-a to VII(1)-e, VIII(1)-a to VIII(1)-i, IX(1)-a to IX(1)-j, X(1)-a to X(1)-i, XI(1)-a to XI(1)-i, XII(1), XIII(1)-a to XIII(1)-i, or XIV(1) bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, leading to the degradation of intrinsic downstream proteins. Therefore, the compounds of the present invention can be used to treat or prevent various cancers.

[1015] In one aspect, the present invention provides Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Compounds of formula IV(1)-a to IV(1)-j, formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) are used as therapeutically active substances.

[1016] In another aspect, the present invention provides Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Compounds of formula IV(1)-a to IV(1)-j, formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) for use in treating or preventing cancer.

[1017] In another aspect, the present invention provides a compound of formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-i, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-i, formula XII, formula XIII-a to XIII-i, formula XIV, formula I(1), formula II(1)-a to II(1)-k, formula III(1), formula Use of a compound of formula IV(1)-a to IV(1)-j, formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) for treating or preventing cancer.

[1018] In another aspect, the present invention provides a method for treating or preventing cancer, comprising administering a therapeutically effective amount of Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-a )-k, III(1), IV(1)-a to IV(1)-j, V(1), VI(1), VII(1)-a to VII(1)-e, VIII(1)-a to VIII(1)-i, IX(1)-a to IX(1)-j, X(1)-a to X(1)-i, XI(1)-a to XI(1)-i, XII(1), XIII(1)-a to XIII(1)-i or XIV(1) is administered to a subject.

[1019] In another aspect, the present invention provides a method of preparing a composition of formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-i, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-i, formula XII, formula XIII-a to XIII-i, formula XIV, formula I(1), formula II(1)-a to II(1)-k, formula III(1), formula IV(1) -a to IV(1)-j, formula V(1), formula VI(1), formula VII(1)-a to VII(1)-e, formula VIII(1)-a to VIII(1)-i, formula IX(1)-a to IX(1)-j, formula X(1)-a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) for the preparation of a medicament for treating or preventing cancer.

[1020] Formula I, Formula II-a to II-k, Formula III, Formula IV-a to IV-j, Formula V, Formula VI, Formula VII-a to VII-e, Formula VIII-a to VIII-i, Formula IX-a to IX-j, Formula Xa to Xi, Formula XI-a to XI-i, Formula XII, Formula XIII-a to XIII-i, Formula XIV, Formula I(1), Formula II(1)-a to II(1)-k, Formula III(1), Formula IV(1)-a to IV(1)-j, Formula V(1), Formula VI(1), Formula VII(1)-a to VII(1)-e, Formula VIII(1)-a to VIII(1)-i, Formula IX(1)-a to IX(1)-j, Formula X(1)- Compounds of formula a to X(1)-i, formula XI(1)-a to XI(1)-i, formula XII(1), formula XIII(1)-a to XIII(1)-i or formula XIV(1) can also be used to prepare bifunctional degrader compounds by linking them to protein targeting moieties that bind to target proteins or target polypeptides, similar to the bifunctional compounds described in WO2013020557, WO2013063560, WO2013106643, WO2015160845, WO2016011906, WO2016105518, WO2017007612, WO2017024318, WO2017117473.

[1021] VIII. General Synthesis and Preparation Process

[1022] The compounds described herein can be prepared by methods known to those skilled in the art. In one non-limiting example, the disclosed compounds can be prepared by the schemes provided below.

[1023] The preparation of the compounds of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is described in the following Schemes 1-3 and 27 specific examples. The skills required to carry out the reactions and purification of 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.

[1024] In more detail, the compounds described herein can be prepared by the methods given below, by the methods given in the examples, or by similar methods. 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 Schemes 1-3, however, the sequence of reaction steps can be freely changed depending on the starting materials and their respective reactivity. The starting materials are commercially available or can be prepared by methods similar to those given below, by methods described in the references cited in the specification or examples, or by methods known in the art.

[1025] Solution 1

[1026]

[1027] Step A: Nitroaminoarene compound 3 can be synthesized by aromatic nucleophilic substitution (S) between 1,2-fluoro-nitro-arene 1 and aromatic amine compound 2. N Ar) reaction was obtained.

[1028] Examples of suitable 1,2-fluoro-nitro-arenes 1 include, but are not limited to, 1-fluoro-2-nitrobenzene (CAS 1493-27-2), 4-fluoro-N-methyl-3-nitrobenzamide (CAS 475216-25-2), and 4-fluoro-3-nitro-benzoic acid methyl ester (CAS 185629-31-6).

[1029] Examples of suitable aromatic amine compounds 2 include, but are not limited to, 6-amino-3H-1,3-benzoxazol-2-one (CAS 22876-17-1), 6-amino-3H-1,3-benzothiazol-2-one (CAS 56354-98-4), 5-aminoindolin-2-one (CAS 20876-36-2), 5-amino-3,3-difluoro-indolin-2-one (CAS 813424-17-8), 6-aminoindolin-2-one (CAS 150544-04-0) and 5-amino-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (CAS 869371-00-6).

[1030] S N The Ar reaction is carried out in the presence of an organic base such as N,N-diisopropylethylamine, triethylamine, or N-methylmorpholine in a polar aprotic organic solvent such as N-methyl-2-pyrrolidone or N,N-dimethylformamide at elevated temperature. Preferred conditions are N,N-diisopropylethylamine in N-methyl-2-pyrrolidone at 120°C for 3 hours.

[1031] Step B: Reduction of nitro-amino-arene compounds 3 to diamino-arene 4 can be carried out by hydrogenation with hydrogen in the presence of a catalyst such as PtO2, Pd-C or Raney nickel in a polar solvent such as MeOH, EtOH, dioxane, THF or a mixture thereof at atmospheric or elevated pressure.

[1032] Preferred conditions are 1 atmosphere of hydrogen in the presence of 10% palladium on carbon in a mixture of methanol and THF at room temperature for 12 hours.

[1033] Step C: Benzimidazole 7 can be obtained by cyclization of diaminoarenes 4 with aldehydes 5 in the presence of sodium metabisulfite. The cyclization reaction is carried out in a polar aprotic organic solvent such as N-methyl-2-pyrrolidone or N,N-dimethylformamide 1 at elevated temperature. Preferred conditions are N,N-dimethylformamide 1 at 120°C for 1 hour.

[1034] Benzimidazole 7 can also be obtained by cyclization of diaminoarenes 4 with carboxylic acids 6 in the presence of another acid. The cyclization reaction is carried out in aqueous solutions of strong acids such as HCl or H2SO4. The preferred conditions are 6M aqueous HCl at 120°C for 12 hours.

[1035] Option 2

[1036]

[1037] R, R' = H, aryl, heterocycloalkyl, heteroaryl or together with the nitrogen to which they are attached form heterocycloalkyl or heteroaryl as defined herein;

[1038] W.A. 1 、A 2 =As described in this article

[1039] Step A: The formation of an amide bond can be achieved by coupling a suitable carboxylic acid 8 and a primary or secondary amine 9 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 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-dimethylacetamide at room temperature or elevated temperature for 2-18 hours.

[1040] Examples of suitable carboxylic acids 8 include, but are not limited to, 2-oxo-3H-1,3-benzoxazole-6-carboxylic acid (CAS 54903-16-1), 2-oxo-3H-1,3-benzothiazole-6-carboxylic acid (CAS 99615-68-6), 2-oxoindoline-5-carboxylic acid (CAS 102359-00-2), 2-oxo-3H-oxazolo[4,5-b]pyridine-6-carboxylic acid (CAS 1555998-02-1), and 2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-5-carboxylic acid (CAS 1260665-66-4).

[1041] Preferred conditions are HATU with N,N-diisopropylethylamine in N,N-dimethylformamide at room temperature for 4 hours.

[1042] Option 3

[1043]

[1044] R = as defined herein

[1045] W, A 1 , A 2 =As described in this article

[1046] Step A: Amide bond formation can be achieved by coupling a suitable amine 2 and a carboxylic acid 11 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 or N-methylmorpholine in a halogenated solvent such as dichloromethane or 1,2-dichloroethane or an ethereal 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.

[1047] Alternatively, amide bond formation can be achieved by coupling a suitable amine 2 and carboxylic acid 11 in the presence of a coupling agent (eg, DMTMM) in an alcoholic solvent (eg, methanol, ethanol, n-propanol, or isopropanol) at room temperature for 1-4 hours.

[1048] Examples of suitable aromatic amine compounds 2 include, but are not limited to, 6-amino-3H-1,3-benzoxazol-2-one (CAS 22876-17-1), 6-amino-3H-1,3-benzothiazol-2-one (CAS 56354-98-4), 5-aminoindolin-2-one (CAS 20876-36-2), 5-amino-3,3-difluoro-indolin-2-one (CAS 813424-17-8), 6-aminoindolin-2-one (CAS 150544-04-0) and 5-amino-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (CAS 869371-00-6).

[1049] Preferred conditions are DMTMM in methanol at room temperature for 4 hours.

[1050] Option 4

[1051]

[1052] Compounds of formula XIV (1) can be prepared as shown in Scheme 4 by reacting intermediate 14 (wherein X 1 It is NR 34, O or S) is coupled with intermediate 13 for 1-24 hours to synthesize, wherein LG 1 A suitable leaving group such as a halogen (eg, Cl, Br, or I) or a sulfonate (eg, -O(SO2)CH3, -O(SO2)CF3, or -O(SO2)(4-methylphenyl)) will be understood by those skilled in the art.

[1053] Option 5

[1054]

[1055] Compounds of formula XIV (1) can be prepared as shown in Scheme 5 by reacting a compound having CG in an organic solvent at elevated temperature (e.g., reflux of the organic solvent) in the presence of a palladium catalyst (e.g., Pd(PPh3)4, PdCl2(PPh3)2, or a similar catalyst that would be appropriately selected by one skilled in the art). 1 The intermediate 16 of the group and the CG 2 The intermediate 17 of the group was synthesized by coupling for 1-48 hours. 1 NR 34 In some embodiments of , O or S, CG 1 H and CG 2 Can be selected from -B(OH)2, -Zn(halogen) or Sn(alkyl)3. In some embodiments, wherein X 1 It is CH2, CHR 34 or C(R 34 )2, CG 1 Selected from halogen or sulfonate and CG 2 Can be selected from -B(OH)2, -Zn(halogen) or Sn(alkyl)3. In other embodiments, wherein X 1 CH2, CHR 34 or C(R 34 )2, CG 1 Can be selected from -B(OH)2, -Zn(halogen) or Sn(alkyl)3 and CG 2 Can be selected from halogen or sulfonate.

[1056] Option 6

[1057]

[1058] Compound 21 of formula XIV (1) can be synthesized by sequential Heck reactions and subsequent hydrogenation or other suitable reduction as shown in Scheme 6. In step A, a mixture containing CG is reacted in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2 or a similar catalyst that would be appropriately selected by one skilled in the art) and a base (e.g., sodium carbonate) at elevated temperature (e.g., 80° C.) in an organic solvent (e.g., 1,4-dioxane). 1 The heterocyclic olefin 18 of the radical is reacted with bromide 19 for 1-24 hours to synthesize. In one embodiment of step A, CG 1 The group is a pinacol boron group. In step B, heterocyclic olefin 20 is reacted with a palladium-carbon catalyst in an organic solvent (e.g., ethanol) under a hydrogen atmosphere for 1-48 hours. The heterocyclic olefin group of 18 can be substituted with any cycloolefin or heterocyclic olefin group as understood by those of ordinary skill in the art to be suitable.

[1059] Option 7

[1060]

[1061] Compound 24 of formula XIV (1) can be synthesized by Heck reaction and subsequent hydrogenation or other suitable reduction as shown in Scheme 7. In step A, olefin 22 is synthesized by reacting bromide 19 in the presence of a palladium catalyst (e.g., Pd(PPh 3 ) 2 Cl 2 or a similar catalyst that would be appropriately selected by one skilled in the art) and a base (e.g., triethylamine) in an organic solvent (e.g., DMF) at elevated temperature (e.g., 90° C.) for 1-24 hours. In step B, olefin 23 is reacted with a palladium-carbon catalyst in an organic solvent (e.g., ethanol) under a hydrogen atmosphere for 1-48 hours.

[1062] Option 8

[1063]

[1064] Compound 28 of formula XIV (1) can be synthesized via an azide-alkyne Huisgen cycloaddition sequence as shown in Scheme 8. In step A, alcohol 25 is reacted with propargyl bromide in an organic solvent such as DMF in the presence of a base such as cesium carbonate at room temperature for 1-24 hours. In step B, alkyne 27 is reacted with azide 27 in an organic solvent such as DMSO in the presence of copper sulfate and sodium ascorbate.

[1065] Option 9

[1066]

[1067] Compound 30 of formula XIV (1) can be synthesized by reacting a coupling agent (e.g., 2,4,6-trichlorobenzoyl chloride and 4-dimethylaminopyridine) and a base (e.g., triethylamine) in an organic solvent (e.g., THF) at room temperature for 1-24 hours as shown in Scheme 9. In some embodiments, as will be readily appreciated by one skilled in the art, the alcohol group of 25 may be substituted with an amino group or a thiol group.

[1068] Plan 10

[1069]

[1070] Compound 32 of formula XIV(1) can be synthesized as shown in Scheme 10 by a Mitsunobu reaction of alcohol 31 with a second alcohol 25 in the presence of a phosphine (e.g., triphenylphosphine) and an azodicarboxylate (e.g., DEAD or DIAD) in an organic solvent (e.g., THF) at elevated temperature (e.g., reflux) for 1-24 hours.

[1071] Plan 11

[1072]

[1073] Compounds 35 of formula XIV (1) can be synthesized by reductive amination of piperidine 33 with aldehyde 34 in the presence of sodium triacetoxyborohydride and acetic acid, optionally in an organic solvent (e.g., THF) at room temperature for 1-24 hours as shown in Scheme 11. In one embodiment, the piperidine group of compound 33 can be substituted with heterocyclic amine groups of varying sizes or substitutions, as will be apparent to one of ordinary skill in the art.

[1074] Plan 12

[1075]

[1076] Compound 38 of formula XIV (1) can be synthesized by reacting carboxylic acid 36 with piperidine 37 in the presence of a coupling agent (e.g., COMU) and a base (e.g., diisopropylethylamine) in an organic solvent (e.g., DMF) at room temperature for 1-24 hours as shown in Scheme 12. In one embodiment, the piperidine group of compound 37 can be substituted with a heterocyclic amine group of varying size or substitution, as will be apparent to one of ordinary skill in the art.

[1077] Plan 13

[1078]

[1079] Compound 41 of formula XIV (1) can be synthesized by reacting amine 39 with compound 40 substituted with a leaving group (LG), such as bromide, iodide, or sulfonate, in the presence of a base (e.g., diisopropylethylamine) in an organic solvent (e.g., DMF) at elevated temperature (e.g., 60° C.) for 1-24 hours as shown in Scheme 13. In some embodiments, the amino group of 39 can be substituted with an alcohol or thiol group, as will be readily appreciated by those skilled in the art.

[1080] Plan 14

[1081]

[1082] Compound 44 of formula XIV(1) can be synthesized as shown in Scheme 14 by reacting terminal alkyne 41 with bromide 43 in the presence of a copper(I) catalyst (e.g., CuI) and a palladium catalyst (e.g., Pd(PPh3)4) in the presence of a base (e.g., triethylamine) in an organic solvent (e.g., DMF) at elevated temperature (e.g., 80°C) for 1-24 hours via a Sonagashira reaction.

[1083] Isolation and purification of compounds

[1084] If desired, the compounds and intermediates described herein can be isolated and purified by any suitable separation or purification procedure, such as 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 isolation and separation procedures are provided in the preparations and examples below. However, other equivalent isolation or separation procedures can certainly be used. Racemic mixtures of chiral compounds of Formula XIV can be separated using chiral HPLC. Racemic mixtures of chiral synthetic intermediates can also be separated using chiral HPLC.

[1085] When the compound of formula XIV is alkaline, they can be converted into corresponding acid addition salts. The conversion is completed by treating with at least a stoichiometric amount of a suitable acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. and an organic acid such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Typically, the free base is dissolved in an inert organic solvent such as ether, ethyl acetate, chloroform, ethanol or methanol, and the acid is added to a similar solvent. The temperature is maintained between 0° C. and 50° C. The resulting salt will precipitate spontaneously, or it can be separated out from the solution with a less polar solvent.

[1086] Unless their preparation is described in the embodiments, the compounds of formula XIV and all intermediates can be prepared according to analogous methods or according to the methods described herein. Starting materials are commercially available, known in the art or can be prepared by methods known in the art or by methods analogous thereto.

[1087] It will be appreciated that the compounds of formula XIV of this invention may be derivatized at functional groups to provide derivatives that are capable of conversion back to the parent compound in vivo.

[1088] Stereochemistry

[1089] For convenience, compounds of the invention having stereocenters may be drawn without stereochemistry. Those skilled in the art will recognize that pure enantiomers and diastereomers can be prepared by methods known in the art. Examples of methods for obtaining optically active materials include at least the following methods.

[1090] i) Physical separation of crystals – a technique whereby macroscopic crystals of individual enantiomers are manually separated. This technique can be used if crystals of the individual enantiomers are present, i.e. the material is an aggregate and the crystals are visually distinct;

[1091] ii) Simultaneous crystallization - a technique whereby the individual enantiomers are crystallized separately from a solution of the racemate, possible only when the racemate is an agglomerate in the solid state;

[1092] iii) Enzymatic resolution - a technique by which racemates are partially or completely separated with the aid of the different reaction rates of the enantiomers with enzymes;

[1093] iv) Enzymatic asymmetric synthesis - a synthetic technique in which at least one synthetic step utilizes an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;

[1094] v) Chemical asymmetric synthesis - a synthetic technique by which the desired enantiomer is synthesized from achiral precursors under conditions that produce asymmetry (i.e. chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries;

[1095] vi) Diastereomeric separation - a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) which converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization on the basis of their now more distinct structural differences, followed by removal of the chiral auxiliary to obtain the desired enantiomer;

[1096] vii) Primary and secondary asymmetric transformations - techniques whereby diastereoisomers from the racemate equilibrate to produce a preponderance in solution of a diastereoisomer from the desired enantiomer, or whereby preferential crystallization of a diastereoisomer from the desired enantiomer disturbs the equilibrium so that ultimately, in principle, all of the material is converted to the crystalline diastereoisomer from the desired enantiomer. The desired enantiomer is then liberated from the diastereoisomers;

[1097] viii) Kinetic resolution - This technique involves the partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by the unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions;

[1098] ix) Enantiospecific synthesis of non-racemic precursors - a synthetic technique by which the desired enantiomer is obtained from achiral starting materials and the stereochemical integrity is not compromised or only minimally compromised during the synthetic process;

[1099] x) Chiral liquid chromatography - a technique by which the enantiomers of a racemate are separated in a liquid mobile phase by means of differential interactions with the stationary phase (including by chiral HPLC); the stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral materials to induce differential interactions;

[1100] xi) Chiral gas chromatography - a technique by which the racemate is volatilized and the enantiomers are separated by means of their different interactions in the gaseous mobile phase with a chromatographic column containing a stationary non-racemic chiral adsorbent phase;

[1101] xii) Extraction with chiral solvents - a technique by which enantiomers are separated by virtue of the preferential solubility of one enantiomer in a specific chiral solvent;

[1102] xiii) Transport across chiral membranes – A technique whereby a racemate is exposed to a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential results in preferential transport across the barrier. Separation occurs due to the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass.

[1103] xiv) Simulated moving bed chromatography is used in one embodiment. A variety of chiral stationary phases are commercially available.

[1104] Representative Examples of the Invention

[1105] The present invention will be more fully understood with reference to the following examples. However, the claims should not be interpreted as being limited to the scope of the examples.

[1106] Where preparations are obtained as mixtures of enantiomers, the pure enantiomers can be separated or crystallized by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (eg chiral SFC or chiral HPLC).

[1107] Unless otherwise stated, all reaction examples and intermediates were prepared under a nitrogen atmosphere.

[1108] Example 1

[1109] N-(2-Oxo-3H-1,3-benzoxazol-6-yl)benzamide

[1110]

[1111] The title compound (CAS 932474-64-1) can be purchased from commercial suppliers, for example in chemical databases such as (American Chemical Society).

[1112] Example 2

[1113] N-(2-Oxoindolin-5-yl)furan-2-carboxamide

[1114]

[1115] The title compound (CAS 921814-32-6) can be purchased from commercial suppliers, for example in chemical databases such as (American Chemical Society).

[1116] Example 3

[1117] 2-(2-Methylphenoxy)-N-(2-oxo-3H-1,3-benzothiazol-6-yl)acetamide

[1118]

[1119] The title compound (CAS 931736-40-2) can be purchased from commercial suppliers, for example in chemical databases such as (American Chemical Society) listed.

[1120] Example 4

[1121] 2-Isopropyl-N-methyl-1-(2-oxoindolin-6-yl)benzimidazole-5-carboxamide

[1122]

[1123] a) N-methyl-3-nitro-4-[(2-oxoindolin-6-yl)amino]benzamide

[1124] A stirred solution of 4-fluoro-N-methyl-3-nitrobenzamide (1264 mg, CAS 475216-25-2), 6-aminoindolin-2-one (151 mg, CAS 150544-04-0) and N,N-diisopropylethylamine (1.59 ml) in N-methyl-2-pyrrolidone (20 ml) was heated at 120° C. for three hours. The reaction mixture was then cooled to room temperature and poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and dried under vacuum to give N-methyl-3-nitro-4-[(2-oxoindolin-6-yl)amino]benzamide (1800 mg, 36%) as a black oil which was used in the next step without further purification. MS (ISP): 327.2 ([M+H] + ).

[1125] b) 3-Amino-N-methyl-4-[(2-oxoindolin-6-yl)amino]benzamide

[1126] To a stirred suspension of N-methyl-3-nitro-4-[(2-oxoindolin-6-yl)amino]benzamide (1800 mg) in methanol (20 ml) and THF (20 ml) was added 10% palladium on carbon (200 mg). The reaction mixture was stirred at room temperature for 12 hours 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: 0-10% methanol in dichloromethane) to give 3-amino-N-methyl-4-[(2-oxoindolin-6-yl)amino]benzamide (800 mg, 49%) as a brown solid. MS (ISP): 297.2 ([M+H] + ).

[1127] c) 2-Isopropyl-N-methyl-1-(2-oxoindolin-6-yl)benzimidazole-5-carboxamide

[1128] To a stirred solution of 3-amino-N-methyl-4-[(2-oxoindolin-6-yl)amino]benzamide (199 mg) and isobutyraldehyde (48.5 mg, CAS 78-84-2) in N,N-dimethylformamide (10 ml) was added sodium metabisulfite (153.4 mg) at room temperature. The reaction mixture was then heated at 120°C for 1 hour. Subsequent TLC and LC-MS analysis showed that the reaction was complete. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by preparative reverse phase HPLC to give 2-isopropyl-N-methyl-1-(2-oxoindolin-6-yl)benzimidazole-5-carboxamide (90 mg, 35%) as a brown solid. MS (ISP): 349.1 ([M+H] + ).

[1129] Example 5

[1130] 2-Isopropyl-N-methyl-1-(2-oxoindolin-5-yl)benzimidazole-5-carboxamide

[1131]

[1132] The title compound was obtained by analogy to Example 4 using 5-aminoindolin-2-one (CAS 20876-36-2) instead of 6-aminoindolin-2-one in step a. White solid MS (ISP): 349.1 ([M+H] + ).

[1133] Example 6

[1134] 6-(2-Aminoaniline)-3H-1,3-benzothiazol-2-one

[1135]

[1136] The title compound was obtained by analogy to Example 4 steps a and b, using 1-fluoro-2-nitrobenzene (CAS 1493-27-2) instead of 4-fluoro-N-methyl-3-nitrobenzamide and 6-aminobenzo[d]thiazol-2(3H)-one (CAS 56354-98-4) instead of 6-aminoindolin-2-one in step a. Brown solid MS (ISP): 258.3 ([M+H] + ).

[1137] Example 7

[1138] 6-(2-Isopropylbenzimidazol-1-yl)-3H-1,3-benzothiazol-2-one

[1139]

[1140] The title compound was obtained by analogy to step c of Example 4 using 6-(2-aminoaniline)-3H-1,3-benzothiazol-2-one instead of 3-amino-N-methyl-4-[(2-oxoindolin-6-yl)amino]benzamide. White solid MS (ISP): 310.2 ([M+H] + ).

[1141] Example 8

[1142] 6-(2-Aminoaniline)-3H-1,3-benzoxazol-2-one

[1143]

[1144] The title compound was obtained by analogy to steps a and b of Example 4 except that 1-fluoro-2-nitrobenzene (CAS 1493-27-2) was used in place of 4-fluoro-N-methyl-3-nitrobenzamide and 6-aminobenzo[d]oxazol-2(3H)-one (CAS 22876-17-1) was used in place of 6-aminoindolin-2-one in step a. Brown solid MS (ISP): 242.2 ([M+H] + ).

[1145] Example 9

[1146] 6-(2-Isopropylbenzimidazol-1-yl)-3H-1,3-benzoxazol-2-one

[1147]

[1148] The title compound was obtained by analogy to step c of Example 4 using 6-(2-aminoanilino)-3H-1,3-benzoxazol-2-one instead of 3-amino-N-methyl-4-[(2-oxoindolin-6-yl)amino]benzamide. White solid MS (ISP): 294.3 ([M+H] + ).

[1149] Example 10

[1150] 2-Oxo-N-phenylindoline-5-carboxamide

[1151]

[1152] The title compound (CAS 1168720-81-7) can be purchased from commercial suppliers, for example in chemical databases such as (American Chemical Society).

[1153] Example 11

[1154] 2-Oxo-N-phenyl-3H-1,3-benzoxazole-6-carboxamide

[1155]

[1156] The title compound (CAS 1791206-26-2) can be purchased from commercial suppliers, for example at (American Chemical Society) and other chemical databases.

[1157] Example 12

[1158] N-(1-acetyl-4-piperidinyl)-2-oxo-3H-1,3-benzoxazole-6-carboxamide

[1159]

[1160] To a mixture of 1-(4-aminopiperidin-1-yl)ethan-1-one (50 mg, CAS 160357-94-8) and 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid (69.3 mg, CAS 54903-16-1) was added N,N-diisopropylethylamine (181 μl) dropwise, followed by a solution of HATU in N,N-dimethylformamide (245 mg, 1.8 ml, 0.358 M solution). The reaction mixture was shaken at 25° C. for 4 hours. The reaction mixture was directly purified by preparative HPLC and then freeze-dried to give N-(1-acetyl-4-piperidinyl)-2-oxo-3H-1,3-benzoxazole-6-carboxamide (45.5 mg, 43%) as a white solid. MS (ISP): 304.2 ([M+H] + ).

[1161] Example 13

[1162] 6-(Indoline-1-carbonyl)-3H-1,3-benzoxazol-2-one

[1163]

[1164] The title compound (CAS 1787518-86-8) can be purchased from commercial suppliers, for example in chemical databases such as (American Chemical Society).

[1165] Example 14

[1166] 6-(2,3-dihydropyrrolo[2,3-b]pyridine-1-carbonyl)-3H-1,3-benzoxazol-2-one

[1167]

[1168] The title compound was obtained by analogy to Example 12 using 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (CAS 10592-27-5) instead of 1-(4-aminopiperidin-1-yl)ethan-1-one. White solid MS (ISP): 282.1 ([M+H] + ).

[1169] Example 15

[1170] 2-Oxo-N-phenyl-3H-1,3-benzothiazole-6-carboxamide

[1171]

[1172] The title compound (CAS 503443-01-4) can be purchased from commercial suppliers, for example in chemical databases such as (American Chemical Society).

[1173] Example 16

[1174] 6-(Indoline-1-carbonyl)-3H-1,3-benzothiazol-2-one

[1175]

[1176] The title compound was obtained by analogy to Example 12 using indoline (CAS 496-15-1) instead of 1-(4-aminopiperidin-1-yl)ethan-1-one and 2-oxo-2,3-dihydrobenzo[d]thiazole-6-carboxylic acid (CAS 99615-68-6) instead of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid. White solid MS (ISP): 297.2 ([M+H] + ).

[1177] Example 17

[1178] 5-(Indolin-1-carbonyl)indolin-2-one

[1179]

[1180] The title compound was obtained by analogy to Example 12 using indoline (CAS 496-15-1) instead of 1-(4-aminopiperidin-1-yl)ethan-1-one and 2-oxoindoline-5-carboxylic acid (CAS 102359-00-2) instead of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid. White solid MS (ISP): 279.3 ([M+H] + ).

[1181] Example 18

[1182] 2-Oxo-N-phenyl-3H-oxazolo[4,5-b]pyridine-6-carboxamide

[1183]

[1184] The title compound was obtained by analogy to Example 12 using aniline instead of 1-(4-aminopiperidin-1-yl)ethan-1-one and 2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-6-carboxylic acid (CAS 1555998-02-1) instead of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid. White solid. MS (ISP): 256.3 ([M+H] + ).

[1185] Example 19

[1186] N-(1-acetyl-4-piperidinyl)-2-oxo-3H-oxazolo[4,5-b]pyridine-6-carboxamide

[1187]

[1188] The title compound was obtained by analogy to Example 12 using 2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-6-carboxylic acid (CAS 1555998-02-1) instead of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid. White solid MS (ISP): 305.3 ([M+H] + ).

[1189] Example 20

[1190] 5-(Indoline-1-carbonyl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one

[1191]

[1192] The title compound was obtained by analogy to Example 12 using indoline (CAS 496-15-1) instead of 1-(4-aminopiperidin-1-yl)ethan-1-one and 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (CAS 1260665-66-4) instead of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid. White solid MS (ISP): 280.2 ([M+H] + ).

[1193] Example 21

[1194] 3,3-Difluoro-5-(2-isopropylbenzimidazol-1-yl)indolin-2-one

[1195]

[1196] The title compound was obtained in analogy to Example 4 by using 1-fluoro-2-nitrobenzene (CAS 1493-27-2) instead of 4-fluoro-N-methyl-3-nitrobenzamide and 5-amino-3,3-difluoroindolin-2-one (CAS 813424-17-8) instead of 6-aminoindolin-2-one in step a. White solid MS (ISP): 328.1 ([M+H] + ).

[1197] Example 22

[1198] 6-(4-Hydroxyisoindoline-2-carbonyl)-3H-1,3-benzoxazol-2-one

[1199]

[1200] The title compound was obtained by analogy to Example 12 using isoindolin-4-ol hydrochloride (CAS 72695-20-6) instead of 1-(4-aminopiperidin-1-yl)ethan-1-one. White solid MS (ISP): 295.2 ([MH] - ).

[1201] Example 23

[1202] 6-(4-Nitroisoindoline-2-carbonyl)-3H-1,3-benzoxazol-2-one

[1203]

[1204] The title compound was obtained by analogy to Example 12 using 4-nitroisoindoline hydrochloride (CAS 1159826-78-4) instead of 1-(4-aminopiperidin-1-yl)ethan-1-one. White solid MS (ISP): 326.5 ([M+H] + ).

[1205] Example 24

[1206] N-(3,3-Difluoro-2-oxo-indolin-5-yl)tetralin-1-carboxamide

[1207]

[1208] To a stirred solution of 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (47.8 mg, CAS 1914-65-4) and 5-amino-3,3-difluoroindolin-2-one (50 mg, CAS 813424-17-8) in methanol (1.67 ml) was added DMTMM (90.2 mg, CAS 3945-69-5) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then poured into 20 ml of brine and extracted twice with EtOAc / THF (1:1). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by preparative HPLC (Gemini NX, 12 nm, 5 μm, 100 x 30 mm, flow rate: 40 ml / min, eluent: CH3CN / H2O + Et3N). The product was lyophilized to afford N-(3,3-difluoro-2-oxo-indolin-5-yl)tetralin-1-carboxamide (16 mg, 17%) as a light orange solid. MS (ISP): 343.1 ([M+H] + ).

[1209] Example 25

[1210] N-(3,3-Difluoro-2-oxo-indolin-5-yl)benzofuran-3-carboxamide

[1211]

[1212] Analogously to Example 24, the title compound was obtained using benzofuran-3-carboxylic acid (CAS 26537-68-8) instead of 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid. White solid MS (ISP): 327.1 ([MH] - ).

[1213] Example 26

[1214] 2-Isopropyl-N-methyl-1-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-5-yl)benzimidazole-5-carboxamide

[1215]

[1216] a) N-methyl-3-nitro-4-(1H-pyrrolo[2.3-b]pyridin-5-ylamino)benzamide

[1217] The title compound was obtained by analogy with Example 4, step a, using 1H-pyrrolo[2,3-b]pyridin-5-amine (CAS 100960-07-4) instead of 6-aminoindolin-2-one in step a. Red solid. MS (ISP): 312.0 ([M+H] + ).

[1218] b) 4-[(3,3-dibromo-2-oxo-1H-pyrrolo[2,3-b]pyridin-5-yl)amino]-N-methyl-3-nitro Benzamide

[1219] To a stirred solution of N-methyl-3-nitro-4-(1H-pyrrolo[2,3-b]pyridin-5-ylamino)benzamide (3.0 g) in tert-butanol (100 ml) was added a small amount of pyridinium tribromide (8.32 g) over 7 minutes. The reaction was stirred at 25 ° C for 12 hours. According to TLC, the reaction was complete. The solvent was removed by vacuum concentration and the resulting residue was dissolved in a 1:1 mixture of ethyl acetate / water (400 ml). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water and saturated brine in sequence, then dried over magnesium sulfate and concentrated in vacuo to give 4-[(3,3-dibromo-2-oxo-1H-pyrrolo[2,3-b]pyridin-5-yl)amino]-N-methyl-3-nitro-benzamide (2.2 g, 18%). Brown solid MS (ISP): 485.9 ([M+H] + ).

[1220] c) 3-amino-N-methyl-4-[(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-5-yl)amino]benzoyl amine

[1221] To a 1:1 mixture of 4-[(3,3-dibromo-2-oxo-1H-pyrrolo[2,3-b]pyridin-5-yl)amino]-N-methyl-3-nitro-benzamide (1 g) in methanol / THF (20 ml) was added 10% palladium on carbon (120 mg) at room temperature. The reaction mixture was hydrogenated under a hydrogen atmosphere at room temperature. After vigorous stirring for 3 hours, the catalyst was collected by filtration and washed with methanol. The filtrate was then concentrated in vacuo. The crude material was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 1:1) to provide 3-amino-N-methyl-4-[(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-5-yl)amino]benzamide (500 mg, 89%) as a brown solid. MS (ISP): 298.8 ([M+H] + ).

[1222] d) 2-isopropyl-N-methyl-1-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-5-yl)benzimidazole- 5-Formamide

[1223] The title compound was obtained by analogy with Example 4, step c, using 3-amino-N-methyl-4-[(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-5-yl)amino]benzamide instead of 3-amino-N-methyl-4-[(2-oxoindolin-6-yl)amino]benzamide. Palm oil. MS (ISP): 350.3 ([M+H] + ).

[1224] Example 27

[1225] 5-(2-Isopropylbenzimidazol-1-yl)-1,3-dihydropyrrolo[2,3-bl-pyridin-2-one

[1226]

[1227] The title compound was obtained by analogy to Example 26 using 1-fluoro-2-nitrobenzene (CAS 1493-27-2) instead of 4-fluoro-N-methyl-3-nitrobenzamide in step a. Green solid MS (ISP): 293.3 ([M+H] + ).

[1228] Example 28

[1229] 5-(5-(Piperidin-4-yl)indoline-1-carbonyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1230]

[1231] Step 1: 5-(5-Bromoindoline-1-carbonyl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one The title compound was obtained in analogy to Example 12, using 5-bromoindoline (CAS 22190-33-6) instead of 1-(4-aminopiperidin-1-yl)ethan-1-one and 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (CAS 1260665-66-4) instead of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid.

[1232] Step 2: tert-Butyl 4-(1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)indolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1233] 5-(5-Bromoindoline-1-carbonyl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one was dissolved in a 3:1 mixture of dioxane and water (0.1 M). 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (CAS 286961-14-6, 1.3 equiv) was added, followed by sodium carbonate (2.5 equiv) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.1 equiv). The solution was degassed with nitrogen and heated at 80°C for 2 hours. The organic supernatant was separated and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide the title compound.

[1234] Step 3: tert-Butyl 4-(1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)indolin-5-yl)piperidine-1-carboxylate

[1235] Tert-butyl 4-(1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)indolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate was dissolved in ethanol (0.1 M) and 10% palladium on carbon was added to the reaction mixture. The vessel was sealed and placed under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give the title compound.

[1236] Step 4: 5-(5-(piperidin-4-yl)indoline-1-carbonyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1237] Tert-butyl 4-(1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)indolin-5-yl)piperidine-1-carboxylate was dissolved in 1,4-dioxane:methanol (1:1), and hydrogen chloride (4M, 1,4-dioxane solution) was added. The reaction mixture was stirred at 40° C. for 2 hours, and the reaction mixture was evaporated under reduced pressure to give the title compound.

[1238] Example 29

[1239] 3-(1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)indolin-6-yl)propanoic acid

[1240]

[1241] Step 1: 5-(6-Bromoindoline-1-carbonyl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one The title compound was obtained in analogy to Example 12, using 6-bromoindoline (CAS 63839-24-7) instead of 1-(4-aminopiperidin-1-yl)ethan-1-one and 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (CAS 1260665-66-4) instead of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid.

[1242] Step 2: (E)-tert-Butyl 3-(1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)indolin-6-yl)acrylate

[1243] 5-(6-Bromoindoline-1-carbonyl)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one was dissolved in N,N-dimethylformamide. Tert-butyl acrylate (1.3 equiv.), triethylamine (2.5 equiv.), and bis(triphenylphosphine)palladium(II) dichloride (0.1 equiv.) were added, and the reaction mixture was degassed with nitrogen for 10 minutes. The reaction mixture was heated at 90°C for 4 hours. The reaction mixture was diluted with ethyl acetate, washed twice with brine, and the organic layer was evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography to give tert-butyl (E)-3-(1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)indoline-6-yl)acrylate.

[1244] Step 3: tert-Butyl 3-(1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)indolin-6-yl)propanoate

[1245] Tert-butyl (E)-3-(1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)indolin-6-yl)acrylate was dissolved in ethanol (0.1 M), and 10% palladium on carbon was added to the reaction mixture. The vessel was sealed and placed under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure to provide the title compound.

[1246] Step 4: 3-(1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)indolin-6-yl)propanoic acid

[1247] Dissolve tert-butyl 3-(1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)indolin-6-yl)propanoate in dichloromethane (0.1 M) and add trifluoroacetic acid. Stir the reaction mixture at 35°C for 24 hours. Evaporate the volatiles under reduced pressure to yield the title compound.

[1248] Example 30

[1249] 5-(4-((1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)indoline-1-carbonyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1250]

[1251] Step 1: 5-(4-Hydroxyindolin-1-carbonyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1252] The title compound was obtained in analogy to Example 12 using indolin-4-ol (CAS 85926-99-4) instead of 1-(4-aminopiperidin-1-yl)ethan-1-one and 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (CAS 1260665-66-4) instead of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid.

[1253] Step 2: 5-(4-(prop-2-yn-1-yloxy)indoline-1-carbonyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1254] 5-(4-Hydroxyindoline-1-carbonyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one was dissolved in N,N-dimethylformamide, and cesium carbonate (1.1 equivalents) and propargyl bromide were added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was partitioned between ethyl acetate and sodium bicarbonate, and the organic layer was evaporated under reduced pressure. The crude residue was purified by silica gel chromatography to give 5-(4-(prop-2-yn-1-yloxy)indoline-1-carbonyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.

[1255] Step 3: 5-(4-((1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)indoline-1-carbonyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1256] 5-(4-(prop-2-yn-1-yloxy)indoline-1-carbonyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one was dissolved in DMSO (0.1 M), 2-azidoethanol (2.0 equivalents, CAS 1517-05-1) was added, and the reaction mixture was degassed with nitrogen. Aqueous copper sulfate (1 M, 1.0 equivalents) and aqueous sodium ascorbate (2 M, 2.0 equivalents) were added dropwise to the reaction mixture. The compound was purified by column chromatography to obtain the title compound.

[1257] Example 31

[1258] 2-(2-Oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)isoindolin-4-ylpiperidine-4-carboxylate

[1259]

[1260]

[1261] Step 1: 1-(tert-Butyl)4-(2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)isoindolin-4-yl)piperidine-1,4-dicarboxylate

[1262] 1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (CAS84358-13-4, 1 equivalent), 2,4,6-trichlorobenzoyl chloride (CAS4136-95-2, 1 equivalent) and 6-(4-hydroxyisoindoline-2-carbonyl)benzo[d]oxazol-2(3H)-one (1 equivalent) were dissolved in anhydrous THF (0.1M). Triethylamine (2 equivalents) was slowly added, followed by DMAP (25 mol%). The reaction mixture was stirred at room temperature until the reaction was complete and then quenched with 10% hydrochloric acid solution. The solution was extracted twice with ethyl acetate. The combined organic phases were washed twice with saturated sodium bicarbonate solution, dried and purified by flash column chromatography on silica gel to give the title compound.

[1263] Step 2: 2-(2-Oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)isoindolin-4-ylpiperidine-4-carboxylate

[1264] 1-(tert-Butyl)-4-(2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)isoindolin-4-yl)piperidine-1,4-dicarboxylate (1 equivalent) was dissolved in DCM (0.2 M) and a 4 M solution of HCl in dioxane (0.2 M) was added at room temperature. The reaction was stirred at room temperature until completion. The mixture was concentrated and lyophilized to provide the title compound.

[1265] Example 32

[1266] 3-((2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)isoindolin-4-yl)oxy)propanoic acid

[1267]

[1268] Step 1: tert-Butyl 3-((2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)isoindolin-4-yl)oxy)propanoate

[1269] A solution of diisopropyl azodicarboxylate (1.3 equivalents) in toluene was added dropwise to a solution of 6-(4-hydroxyisoindoline-2-carbonyl)benzo[d]oxazol-2(3H)-one (1 equivalent), tert-butyl 3-hydroxypropionate (CAS 59854-11-4, 1 equivalent) and Ph3P (1.3 equivalents) in THF (0.2M) at 0°C. The reaction mixture was heated at reflux until complete. The reaction mixture was cooled and concentrated and purified by flash chromatography on silica gel to give the title compound.

[1270] Step 2: 3-((2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)isoindolin-4-yl)oxy]propanoic acid

[1271] Tert-butyl 3-((2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)isoindolin-4-yl)oxy)propanoate (1 equivalent) was dissolved in DCM (0.2 M) and TFA (0.2 M) was added at room temperature. The reaction was stirred at room temperature until completion. The mixture was concentrated and lyophilized to give the title compound.

[1272] Example 33

[1273] 6-(4-Hydroxy-5-((4-(hydroxymethyl)piperidin-1-yl)methyl)isoindoline-2-carbonyl)benzo[d]oxazol-2(3H)-one

[1274]

[1275] Step 1: 4-Hydroxy-2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)isoindoline-5-carbaldehyde

[1276] 6-(4-Hydroxyisoindoline-2-carbonyl)benzo[d]oxazol-2(3H)-one (1 equivalent) and hexamethylenetetramine (CAS 100-97-0, 4 equivalents) were dissolved in TFA (0.5 M). The reaction mixture was refluxed using a dean stark system until the reaction was complete. The mixture was then cooled to room temperature. Water was added and the reaction was heated to 80° C. for 2 hours. After cooling to room temperature, the mixture was filtered and the precipitate was purified by flash chromatography on silica gel to give the title compound.

[1277] Step 2: 6-(4-Hydroxy-5-((4-(hydroxymethyl)piperidin-1-yl)methyl)isoindoline-2-carbonyl)benzo[d]oxazol-2(3H)-one

[1278] 4-Hydroxy-2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)isoindoline-5-carbaldehyde (1 equivalent) and 4-piperidinol (CAS 6457-49-4, 1.1 equivalents) were dissolved in THF (0.4 M). Acetic acid (drops) was added, followed by sodium triacetoxyborohydride (1.3 equivalents). The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride, and the organic layer was evaporated under reduced pressure. The crude residue was purified by silica gel chromatography to give the title compound.

[1279] Example 34

[1280] 5-(5-(1-(5-hydroxypentanoyl)piperidin-4-yl)-2-isopropyl-1H-benzo[d]imidazol-1-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1281]

[1282] Step 1: tert-Butyl 4-(4-fluoro-3-nitrophenyl)piperidine-1-carboxylate

[1283] 4-(4-Fluorophenyl)piperidine hydrochloride (1 equivalent) was dissolved in concentrated sulfuric acid (0.5M reaction concentration). The mixture was cooled to 0°C and concentrated nitric acid (1.5 equivalents) was slowly added dropwise. The solution was slowly warmed to room temperature and then heated to 50°C. The solution was stirred for 24 hours. The mixture was then cooled to room temperature, poured into ice water, and treated with 1M NaOH until alkaline. The product was then extracted from the solution with ether (3x). The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure.

[1284] The crude material is then dissolved in THF (0.1M reaction concentration). DMAP (0.1 equivalent) is added, followed by Boc anhydride (1 equivalent). The mixture is stirred for two hours. Then diluted with ethyl acetate and washed with water. The organic layer is then washed with salt water and dried over sodium sulfate, followed by concentrating under reduced pressure. Column chromatography using the ethyl acetate gradient in hexane provides 4-(4-fluoro-3-nitrophenyl) piperidine-1-tert-butyl formate.

[1285] Step 2: tert-Butyl 4-(3-nitro-4-((2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)amino)phenyl)piperidine-1-carboxylate

[1286] The title compound was synthesized in analogy to Example 4 using tert-butyl 4-(4-fluoro-3-nitrophenyl)piperidine-1-carboxylate instead of 4-fluoro-N-methyl-3-nitrobenzamide.

[1287] Step 3: tert-Butyl 4-(3-amino-4-((2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)amino)phenyl)piperidine-1-carboxylate

[1288] The title compound was synthesized in analogy to Example 4 using tert-butyl 4-(3-nitro-4-((2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)amino)phenyl)piperidine-1-carboxylate instead of N-methyl-3-nitro-4-[(2-oxoindolin-6-yl)amino]benzamide.

[1289] Step 4: tert-Butyl 4-(2-isopropyl-1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate

[1290] The title compound was synthesized in analogy to Example 4 using tert-butyl 4-(3-amino-4-((2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)amino)phenyl)piperidine-1-carboxylate instead of 3-amino-N-methyl-4-[(2-oxoindolin-6-yl)amino]benzamide.

[1291] Step 5: 5-(2-Isopropyl-5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one trifluoroacetate

[1292] Tert-butyl 4-(2-isopropyl-1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (1 equivalent) was dissolved in dichloromethane (0.2 M reaction concentration). Trifluoroacetic acid (10 equivalents) was then added, and the mixture was stirred at room temperature for 24 hours. The mixture was then concentrated under reduced pressure to provide the title compound.

[1293] Step 6: 5-(5-(1-(5-hydroxypentanoyl)piperidin-4-yl)-2-isopropyl-1H-benzo[d]imidazol-1-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1294] 5-(2-Isopropyl-5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)-1,3-dihydro-2H-pyrrolo[2,3b]pyridin-2-one trifluoroacetate (1 eq) and 5-hydroxypentanoic acid (1 eq) were dissolved in DMF (0.1 M reaction concentration). Hunig's base (3 eq) was added, followed by COMU (1.1 eq). The mixture was stirred at room temperature for 2 hours. The mixture was then diluted with ethyl acetate and water. The organic layer was separated and the product was extracted from the aqueous layer with ethyl acetate (3x). The combined organic layers were washed with brine and dried over sodium sulfate, then concentrated. The crude material was then purified on silica using a gradient of ethyl acetate / hexane to provide the desired compound.

[1295] Example 35

[1296] 6-(((2-Isopropyl-1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-benzo[d]imidazol-4-yl)methyl)amino)hexanoic acid

[1297]

[1298] Step 1: tert-Butyl((3-fluoro-2-nitrobenzyl)oxy)dimethylsilane (3-fluoro-2-nitrophenyl)methanol (1 equivalent) was dissolved in THF (0.1M reaction concentration). Imidazole (1.2 equivalents) was added, followed by TBSCl (1.1 equivalents). The mixture was stirred for 24 hours. It was then diluted with ethyl acetate and water. The organic layer was separated and the product was extracted from the aqueous layer using ethyl acetate (3x). The combined organic layers were washed with brine and dried over sodium sulfate, then concentrated. The crude material was then purified on silica using a gradient of ethyl acetate / hexane to provide the desired compound.

[1299] Step 2: 5-((3-(((tert-Butyldimethylsilyl)oxy)methyl)-2-nitrophenyl)amino)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1300] The title compound was synthesized in analogy to Example 4 using tert-butyl((3-fluoro-2-nitrobenzyl)oxy)dimethylsilane instead of 4-fluoro-N-methyl-3-nitrobenzamide.

[1301] Step 3: 5-((2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1302] The title compound was synthesized in analogy to Example 4 using 5-((3-((tert-butyldimethylsilyl)oxy)methyl)-2-nitrophenyl)amino)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one instead of N-methyl-3-nitro-4-[(2-oxoindolin-6-yl)amino]benzamide.

[1303] Step 4: 5-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-isopropyl-1H-benzo[d]imidazol-1-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1304] The title compound was synthesized in analogy to Example 4 using 5-((2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one instead of 3-amino-N-methyl-4-[(2-oxoindolin-6-yl)amino]benzamide.

[1305] Step 5: 5-(4-(Hydroxymethyl)-2-isopropyl-1H-benzo[d]imidazol-1-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1306] 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2-isopropyl-1H-benzo[d]imidazol-1-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1 equivalent) was dissolved in THF (0.1M reaction concentration) and cooled to 0°C. TBAF (1 equivalent) was added and the mixture was stirred for 2 hours. The mixture was then diluted with water. The product was extracted with ethyl acetate (x3). The combined organic layers were then washed with brine and dried over sodium sulfate. The crude material was then purified on silica using a gradient of ethyl acetate / hexane.

[1307] Step 6: (2-Isopropyl-1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-benzo[d]imidazol-4-yl)methyl 4-methylbenzenesulfonate

[1308] 5-(4-(hydroxymethyl)-2-isopropyl-1H-benzo[d]imidazol-1-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one (1 equivalent) is dissolved in THF (0.1M reaction concentration). Hunig's base (2 equivalents) is added, followed by tosyl chloride. The mixture is stirred for 8 hours. It is then diluted with water. The product is extracted with ethyl acetate (x3). The organic layer combined is then washed with salt water and dried over sodium sulfate. The crude material is then purified on silica using a gradient of ethyl acetate / hexane to provide the desired compound.

[1309] Step 7: tert-Butyl 6-(((2-isopropyl-1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-benzo[d]imidazol-4-yl)methyl)amino)hexanoate

[1310] (2-Isopropyl-1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-benzo[d]imidazol-4-yl)methyl 4-methylbenzenesulfonate (1 eq) was dissolved in DMF (0.2 M reaction concentration). Hunig's base (3 eq) was added, followed by tert-butyl 6-aminohexanoate (1 eq). The mixture was heated to 60° C. for 8 hours. The mixture was then cooled to room temperature and diluted with ethyl acetate and 1.0 M aqueous HCl. The organic layer was separated and the product was extracted from the aqueous layer using ethyl acetate (3x). The combined organic layers were then washed with brine and dried over sodium sulfate. The crude material was then purified on silica using a methanol gradient in dichloromethane to provide the desired compound.

[1311] Step 8: 6-(((2-Isopropyl-1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-benzo[d]imidazol-4-yl)methyl)amino)hexanoic acid

[1312] tert-Butyl 6-(((2-isopropyl-1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-benzo[d]imidazol-4-yl)methyl)amino)hexanoate (1 equivalent) was dissolved in dichloromethane (0.5M reaction concentration). Trifluoroacetic acid (10 equivalents) was then added and the mixture was allowed to stir at room temperature for 24 hours. The solvent was then removed under reduced pressure and the crude material was purified on silica using a methanol gradient in dichloromethane to obtain the desired product.

[1313] Example 36

[1314] tert-Butyl 3-(2-isopropyl-1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-benzo[d]imidazol-5-yl)propiolate

[1315]

[1316] Step 1: 5-((4-bromo-2-nitrophenyl)amino)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1317] The title compound was synthesized in a similar manner to Example 4 using 4-bromo-1-fluoro-2-nitrobenzene instead of 4-fluoro-N-methyl-3-nitrobenzamide.

[1318] Step 2: 5-((2-amino-4-bromophenyl)amino)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1319] The title compound was synthesized in analogy to Example 4 using 5-((4-bromo-2-nitrophenyl)amino)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one instead of N-methyl-3-nitro-4-[(2-oxoindolin-6-yl)amino]benzamide.

[1320] Step 3: 5-(5-Bromo-2-isopropyl-1H-benzo[d]imidazol-1-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[1321] The title compound was synthesized in analogy to Example 4 using 5-((2-amino-4-bromophenyl)amino)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one instead of 3-amino-N-methyl-4-[(2-oxoindolin-6-yl)amino]benzamide.

[1322] Step 4: tert-Butyl 3-(2-isopropyl-1-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-benzo[d]imidazol-5-yl)propiolate

[1323] 5-(5-bromo-2-isopropyl-1H-benzo[d]imidazol-1-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one (1 equivalent) and tert-butyl propiolate (1.5 equivalents) were dissolved in DMF (0.2M reaction concentration). Triethylamine (5 equivalents) was added and the mixture was degassed for 20 minutes. CuI (0.05 equivalents) was then added, followed by Pd(PPh3)4 (0.1 equivalents). The mixture was degassed for another 10 minutes and then heated to 80°C. The mixture was stirred for 12 hours. It was then cooled to room temperature and diluted with ethyl acetate and water. The organic layer was separated and the product was extracted from the aqueous layer using ethyl acetate (3x). The combined organic layers were then washed with brine and dried over sodium sulfate. The crude material was then purified on silica using a methanol gradient in dichloromethane to provide the desired compound.

[1324] Pharmacological tests

[1325] The compounds described herein and their pharmaceutically acceptable salts have valuable pharmacological properties.The compounds were studied according to the tests given below.

[1326] Fluorescent direct binding protocol

[1327] principle

[1328] The affinity of the compound for proteins containing one or more tryptophans can be measured by monitoring 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 spectrofluorometer or automatically in a well plate on a fluorescence plate reader. Fluorescence titrations are performed at 20°C in the selected binding assay buffer using a defined constant protein concentration against varying ligand concentrations. Small aliquots of known ligand concentrations dissolved in DMSO are added and fluorescence excited at 280 nm is recorded at 340 nm. Fluorescence intensity is corrected for protein dilution and filter effects (Birdsall et al.). The corrected fluorescence intensity is plotted against ligand concentration and fitted using a four-parameter sigmoidal function to calculate the equilibrium dissociation constant, Kd, using the mass action law assuming a 1:1 protein-ligand complex (Eftink, 1997).

[1329] method

[1330] 1) Optimize measurement parameters to minimize protein consumption and minimize dilution effects and DMSO content;

[1331] 2) titrate the protein relative to the ligand using at least 12 titration steps to obtain a good s-curve fit;

[1332] 3) Repeat the same titration measurement using the ligand alone for calibration;

[1333] 4) Check protein stability by titrating against DMSO alone;

[1334] 5) measuring the molar extinction coefficient of the ligand at 280 nm and 340 nm using an ultraviolet spectrophotometer;

[1335] 6) Use the Excel template to correct the measured raw data.

[1336] Quadratic binding fitting and KD estimation were performed using GraphPad Prism software.

[1337]

[1338] Table 8: Protein-buffer, reference compounds: thalidomide, Contac, thalidomide

[1339]

[1340] Table 9: Settings

[1341] Protein preparation:

[1342] Volume protein [μL] Volume buffer [μL] Protein concentration [M] 1.8@2.54mg / ml 498.2 5.0E-8

[1343] Table 10: Protein preparation

[1344]

[1345] Table 11: Titration steps

[1346]

[1347] Table 12: Affinity of Examples for CRBN Protein

[1348] 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.

[1349] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art, based on the teachings of this invention, that certain changes and modifications may be made without departing from the spirit or scope of the invention as defined in the claims.

Claims

1. Compound of formula I (1): or a pharmaceutically acceptable salt thereof; in: A 1 is selected from the group consisting of -O-, -S-, -CH2-, -CF2-, and -NH-, and A 2 is -CH2-; or A 1 is selected from the group consisting of -O-, -S-, -CH2-, and -CF2-, and A 2 is -NH-; W is CH or N; R 3 is independently selected at each occurrence from: -C(=O)C 1-6 Alkyl; -C(=O)OC 1-6 Alkyl; -C 1-6 Alkyl; -halogen; -NH2; and -NH-C(=O)C 1-6 alkyl; m is 0, 1 or 2; X 1 Selected from bond, NR 34 and C(R 34 )2; X 22 Selected from halogen, -N(R 34 )2, hydroxyl and hydrogen; R 34 is independently selected at each occurrence from: hydrogen and C1-C6 alkyl; and R 20 、R 21 、R 22 、R 23 and R 24 independently selected from covalent bonds, C 1-6 Alkyl, -C(O)-, -O-, -NH- and -N(C 1-6 alkyl)-; where R 20 、R 21 、R 22 、R 23 and R 24 At least one of is not a key.

2. The compound according to claim 1, wherein A 1 is selected from -O- and -NH-, and A 2 It is -CH2-.

3. The compound according to claim 1, wherein A 1 is selected from -O-, -S-, -CH2-, -CF2-, and A 2 It is -NH-. The compound according to claim 1 , wherein W is CH. The compound according to claim 1 , wherein W is N.

6. The compound according to any one of claims 1 to 5, wherein R 3 is independently selected at each occurrence from: -C(=O)C 1-6 Alkyl; -C 1-6 alkyl; and -halogen.

7. The compound according to any one of claims 1 to 5, wherein R 3 independently selected at each occurrence from: -C 1-6 Alkyl and -halogen.

8. The compound according to any one of claims 1 to 5, wherein m is 0.

9. The compound according to any one of claims 1 to 5, wherein m is 1.

10. The compound according to any one of claims 1 to 5, wherein X 1 Select from bond or NR 34 .

11. The compound according to any one of claims 1 to 5, wherein X 22 is selected from hydrogen, halogen and -NH2.

12. The compound according to any one of claims 1 to 5, wherein R 20 、R 21 、R 22 、R 23 and R 24 independently selected from a bond, C 1-6 Alkyl, -C(O)-, -O- and -NH-, where R 20 、R 21 、R 22 、R 23 and R 24 At least one of is not a key.

13. The compound according to claim 12, wherein R 20 、R 21 、R 22 、R 23 and R 24 At least two of them are not keys.

14. The compound according to claim 12, wherein R 20 、R 21 、R 22 、R 23 and R 24 At least three of them are not keys.

15. The compound according to claim 12, wherein R 20 、R 21 、R 22 、R 23 and R 24 At least four of them are not bonds.

16. The compound according to claim 12, wherein R 20 、R 21 、R 22 、R 23 and R 24 None of them are keys.

17. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 in a pharmaceutically acceptable carrier.

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