Compounds and methods for enhancing the degradation of target proteins and other polypeptides by E3 ubiquitin ligases.

Abstract

To provide bifunctional compounds, which find utility as modulators of targeted ubiquitination and as inhibitors of a variety of polypeptides and other proteins that are degraded and / or otherwise inhibited.SOLUTION: Compounds contain on one end a VHL ligand that binds to the VHL E3 ubiquitin ligase (defined as a ubiquitin ligand binding moiety) and on the other end a moiety that binds to a target protein (defined as a protein / polypeptide targeting moiety) such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The compounds exhibit a broad range of pharmacological activities associated with dysregulated target protein activity.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Field of Invention The present invention relates to a bifunctional compound useful as a regulator of targeted ubiquitination, particularly as an inhibitor of various polypeptides and other proteins, wherein these polypeptides and proteins are degraded and / or otherwise inhibited by the bifunctional compound of the present invention. In particular, the present invention relates to a VHL ligand (ubiquitin ligand binding moiety or) that binds to VHL E3 ubiquitin ligase at one end. TIFF0007898835000001.tif10128 (defined as a group), and a portion at the other end that binds to the target protein (protein / polypeptide target-directed portion or The present invention aims to provide compounds containing a TIFF0007898835000002.tif10128 group (defined as such) such that the target protein / polypeptide is positioned in close proximity to the ubiquitin ligase to degrade (and inhibit) that protein. The present invention exhibits a broad range of pharmacological activities related to the compounds of the present invention that are consistent with the degradation / inhibition of target polypeptides.

[0002] Support through related applications and grants This application claims priority to Provisional Application US61 / 585,769, filed on 12 January 2011, under the same title, the entire contents of which are incorporated herein by reference.

[0003] This invention was made with government support under grant number AI084140 from the U.S. National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0004] Background of the Invention E3 ubiquitin ligases (of which over 600 are publicly known in humans) 1 It confers substrate specificity for ubiquitination, and due to its specificity for specific protein substrates, it is a general proteasome inhibitor. 3,4are more attractive therapeutic targets. The development of ligands for E3 ligases has proven difficult, in part due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. Protein-protein interactions are well known to be difficult to target with small molecules because their contact surfaces are large, the grooves involved are shallow, or the interfaces are flat. In contrast, most small molecule drugs bind to enzymes or receptors within narrow, well-defined pockets. 5 Since the discovery of nutlin, the first small molecule E3 ligase inhibitor, several additional compounds that target inhibitors of apoptosis proteins (IAPs), SCF, and SCF have been reported, but the field is still in its infancy. 6 One E3 ligase with very interesting therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor, which is the substrate recognition subunit of the E3 ligase complex VCB and also consists of elongin B and C, Cul2, and Rbx1. 7 The main substrate of VHL is the transcription factor hypoxia-inducible factor 1α (HIF-1α), which upregulates genes such as the angiogenesis-promoting growth factor VEGF and the erythroid-inducing cytokine erythropoietin in response to low oxygen levels. HIF-1α is constitutively expressed, but its intracellular levels are kept very low under normoxic conditions via its hydroxylation by prolyl hydroxylase domain (PHD) proteins and subsequent VHL-mediated ubiquitination (Figure 1). 8,9 SCF Met30 10 SCF Cdc4 11 Using rational design, the inventors generated the first small molecule ligand for the von Hippel-Lindau (VHL) substrate recognition subunit of the E3 ligase VCB, an important target in cancer, chronic anemia, and ischemia.

[0005] The von Hippel-Lindau (VHL) tumor suppressor, which is the substrate recognition subunit of the E3 ligase complex VCB and also consists of elongin B and C, Cul2, and Rbx1, is an E3 ligase with very interesting therapeutic potential. 12 The main substrate of VHL is the transcription factor hypoxia-inducible factor 1α (HIF-1α), which upregulates genes such as the angiogenesis-promoting growth factor VEGF and the erythroid-inducing cytokine erythropoietin in response to low oxygen levels. HIF-1α is constitutively expressed, but its intracellular levels are kept very low under normoxic conditions via its hydroxylation by prolyl hydroxylase domain (PHD) proteins and subsequent VHL-mediated ubiquitination (Figure 1).

[0006] Using rational design, the inventors generated the first small molecule ligand for the von Hippel-Lindau (VHL) substrate recognition subunit of the E3 ligase VCB, an important target in cancer, chronic anemia, and ischemia. 2The inventors also obtained the crystal structure of VHL along with our most potent ligand 15, and confirmed that the compound mimics the binding mode of the transcription factor HIF-1α, the major substrate of VHL.

[0007] Initial biochemical and structural analyses of hydroxylated HIF peptides bound to VHL revealed that hydroxyproline plays a crucial role in mediating this protein-protein interaction. As a result of this research, the inventors developed a hydroxylated HIF peptide:VHL fluorescence polarization (FP) binding assay, which was used to test over 120 compounds with a central hydroxyproline residue adjacent to the non-peptide moiety. In addition to this research, the inventors developed co-crystal structures of VHL compounded with seven of the top-ranking compounds. Analysis of these ligand-binding structures has driven the design and synthesis of next-generation VHL ligands linked to the protein-binding moiety for generating the bifunctional compounds of the present invention.

[0008] The primary underlying reason for this invention is the need for small molecule E3 ligase ligands for our PROTAC (Proteolytic Target-Directed Chimera) technology. This technology induces a target protein / polypeptide into an E3 ligase for ubiquitination and subsequent proteasomal degradation. In several proof-of-concept experiments, we demonstrated the usefulness of this approach using short peptide sequences from HIF that bind to VHL. To create a more "drug-like" PROTAC, we replaced the HIF peptide with a "small molecule" VHL ligand and thus provided a means of recruiting the protein into an E3 ligase for ubiquitination and degradation, leading to an endpoint that provides this proteolytically based therapy. [Overview of the project]

[0009] Purpose of the invention The object of the present invention is to provide a compound that acts to recruit endogenous proteins to E3 ubiquitin ligase for degradation.

[0010] A further object of the present invention is to provide compounds that can be used to regulate proteolysis in a patient or subject and to treat disease conditions or states regulated through the degraded proteins.

[0011] Another object of the present invention is to provide a pharmaceutical composition based on the aforementioned regulatory factors, which includes, in particular, preferably, a human patient or subject, an inhibitor for therapeutic treatment of a patient or subject.

[0012] Another objective of the present invention is to provide a method for determining the protein-binding site that binds to a protein of interest.

[0013] A further object of the present invention is to provide a method for identifying endogenous proteins that bind to the protein-binding portion of the compound of the present invention, particularly in biological systems including the human system.

[0014] A further object of the present invention is to provide a method for identifying the effect of the compounds of the present invention on the degradation of a protein of interest in a biological system.

[0015] A further aspect of the present invention is to provide a method for treating a patient in which the degradation of a target protein produces a desired therapeutic effect.

[0016] Another object of the present invention is to provide compounds and compositions that can be used in primary pharmaceutical applications.

[0017] A further aspect of the present invention is to provide compounds and / or compositions for use in treating a patient, wherein the degradation of a target protein produces a desired therapeutic effect.

[0018] [Invention 1001] Compounds with the following chemical structure: In formula TIFF0007898835000003.tif9128, L is a linker group, and TIFF0007898835000004.tif11128 is the ubiquitin ligase binding portion, where the linker group is optional. It is further connected to TIFF0007898835000005.tif10128 units. [Invention 1002] Compounds with the following chemical structures, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs: TIFF0007898835000006.tif14128In formula, TIFF0007898835000007.tif10128 is the ubiquitin ligase binding site; TIFF0007898835000008.tif10128 binds to a target protein or polypeptide that is degraded by ubiquitin ligase. TIFF0007898835000009.tif10128 is a chemical moiety (protein target moiety) that is chemically linked directly to the group or through linker moiety L, or TIFF0007898835000010.tif10128 is instead the same ubiquitin ligase binding site. This is TIFF0007898835000011.tif10128, and this is TIFF0007898835000012.tif11128 may be the same as or different from the same unit. TIFF0007898835000013.tif10128 is connected directly to the base or through the linker portion; and L may or may not exist, and if it exists, This is the linker portion that is chemically (covalently) bonded to TIFF0007898835000014.tif11128. [Invention 1003] The compound of the present invention 1002, which has the TIFF0007898835000015.tif11128 group. [Invention 1004] TIFF0007898835000016.tif10128 is the base of any of the compounds 1001 to 1003 of this invention, or any pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: TIFF0007898835000017.tif41128In formula, R 1' This may be a substituted C1-C6 alkyl group, or a substituted -(CH2) n OH may be substituted -(CH2) n SH may be substituted (CH2). n -O-(C1~C6) alkyl group, may be substituted with an epoxide moiety containing either no W or H independently (CH2). n -WCHOCHW-(C0~C6) alkyl group, may be substituted-(CH2) n COOH may be substituted -(CH2) n C(O)-(C1~C6 alkyl), may be substituted-(CH2) n NR1R2 may be substituted - (CH2) n NHC(O)-R1, may be substituted with -(CH2). n C(O)-NR1R2, may be substituted with -(CH2) n OC(O)-NR1R2, -(CH2O) n H may be substituted - (CH2) n OC(O)-(C1~C6 alkyl), may be substituted-(CH2) n C(O)-O-(C1~C6 alkyl), may be substituted-(CH2O) n COOH may be substituted - (OCH2) n O-(C1~C6 alkyl), may be substituted -(CH2O) n C(O)-(C1~C6 alkyl), may be substituted-(OCH2) n NHC(O)-R1, may be substituted with -(CH2O) n C(O)-NR1R2, -(CH2CH2O) n H may be substituted -(CH2CH2O) nCOOH may be substituted - (OCH2CH2) n O-(C1~C6 alkyl), may be substituted -(CH2CH2O) n C(O)-(C1~C6 alkyl), may be substituted-(OCH2CH2) n NHC(O)-R1, may be substituted with -(CH2CH2O) n C(O)-NR1R2, may be substituted with -SO2R S S(O)R may be substituted. S , NO2, CN, or halogen (F, Cl, Br, I, preferably F or Cl); R1 and R2 are each independently a C1-C6 alkyl group which may be substituted with H, or one or two hydroxyl groups or up to three halogen groups (preferably fluorine); R S This is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl or heterocyclic group, or -(CH2) m It has two NR1R units, X and X' are independently C=O, C=S, -S(O), and S(O)², respectively (preferably both X and X' are C=O); R 2' (CH2) may be substituted. n -(C=O) u (NR1) v (SO2) w (C1~C6) alkyl groups, R may be substituted. 1N R 2N -(CH2) n -(C=O) u (NR1) v (SO2) w NR 1N R 2N The base may be substituted - (CH2) n -(C=O) u (NR1) v (SO2) w -aryl, may be substituted-(CH2) n -(C=O) u (NR1) v (SO2)w - heteroaryl, optionally substituted -(CH2) n -(C=O) v NR1(SO2) w - heterocyclic ring, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w - C1 - C6 alkyl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -NR 1 -(CH2) n -(C=O) u (NR1) v (SO2) w - aryl, optionally substituted -NR 1 -(CH2) n -(C=O) u (NR1) v (SO2) w - heteroaryl or optionally substituted -NR 1 -(CH2) n -(C=O) v NR1(SO2) w - heterocyclic ring, optionally substituted -X R2' - C1 - C6 alkyl group; optionally substituted -X R2' - aryl group; optionally substituted -X R2' - heteroaryl group; optionally substituted -X R2' - is a heterocyclic group; optionally substituted; R 3' is optionally substituted C1 - C6 alkyl, optionally substituted -(CH2) n -C(O)u (NR1) v (SO2) w -C1~C6 alkyl, may be substituted-(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , may be substituted - (CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , may be substituted - (CH2) n -C(O) u (NR1) v (SO2) w -C(O)NR1R2, may be substituted -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, may be substituted-(CH2) n -C(O) u (NR1) v (SO2) w -Heteroaryl, may be substituted-(CH2) n -C(O) u (NR1) v (SO2) w -Hybrid algebras, may be substituted-NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -C1~C6 alkyl, may be substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N -NR may be substituted 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N-NR may be substituted 1 -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, may be substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, may be substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -Heterogeneous ring, may be substituted -O-(CH2)n-(C=O) u (NR1) v (SO2) w -C1~C6 alkyl, may be substituted -O-(CH2)n-(C=O) u (NR1) v (SO2) w -NR 1N R 2N -O-(CH2)n-(C=O) may be substituted. u (NR1) v (SO2) w -NR1C(O)R 1N -O-(CH2)n-(C=O) may be substituted. u (NR1) v (SO2) w -aryl, may be substituted -O-(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl, or possibly substituted -O-(CH2) n -(C=O) u (NR1) v (SO2) w -Hybrid algebra;-(CH2) n -(V) n' -(CH2) n -(V) n' -C1-C6 alkyl groups, may be substituted-(CH2) n -(V)n' -(CH2) n -(V) n' -Aryl group, may be substituted-(CH2) n -(V) n' -(CH2) n -(V) n' -Heteroaryl group, may be substituted-(CH2) n -(V) n' -(CH2) n -(V) n' -Heterocyclic group, may be substituted-(CH2) n -N(R 1' )(C=O) m' -(V) n' -C1-C6 alkyl groups, may be substituted-(CH2) n -N(R 1' )(C=O) m' -(V) n' -Aryl group, may be substituted-(CH2) n -N(R 1' )(C=O) m' -(V) n' -Heteroaryl group, may be substituted-(CH2) n -N(R 1' )(C=O) m' -(V) n' -Heterocyclic group, may be substituted-X R3' -C1~C6 alkyl groups; may be substituted -X R3' -Aryl group; may be substituted -X R3' -heteroaryl group; may be substituted -X R3' -It is a heterocyclic ring group; it may be substituted; Here R 1N and R 2N Each of these is independently a C1-C6 alkyl group which may be substituted with H, one or two hydroxyl groups and up to three halogen groups, or a substituted -(CH2) group. n -Aryl, -(CH2) n -heteroaryl or -(CH2) n -It is a heterocyclic ring group; V is O, S, or NR1; R1 is the same as above; R 1 and R 1' Each of these is independently H or a C1-C3 alkyl group; X R2' and X R3' Each of these can be substituted independently (-CH2) n -, -CH2) n -CH(X v )=CH(X v )-(Sys or Trans), -CH2) n -CH≡CH-, -(CH2CH2O) n -or a C3-C6 cycloalkyl group, where X v is H, halo, or an optionally substituted C1-C3 alkyl group; Each m is independently 0, 1, 2, 3, 4, 5, 6; Each m' is independently either 0 or 1; Each n is independently 0, 1, 2, 3, 4, 5, or 6; Each n' is independently either 0 or 1; Each u is independently either 0 or 1; Each v is independently either 0 or 1; Each w is independently either 0 or 1; and Here R of TIFF0007898835000018.tif10128 1' , R 2' , R 3' Any one or more of , X, and X', either directly or through the linker group TIFF0007898835000019.tif10128 is modified to covalently bond to the 8 group. [Invention 1005] TIFF0007898835000020.tif10128, and, If it exists as TIFF0007898835000021.tif10128 TIFF0007898835000022.tif10128 is the basis of any of the compounds described in items 1001 to 1004 of this invention, or any pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof, each independently being the base of the following chemical structures: TIFF0007898835000023.tif51128In formula, R 1' , R 2' , and R 3' Each of these is the same as in Invention 1004 above, and X is C=O, C=S, -S(O) group, or S(O)2 group, and Here R 1' , R 2' , and R 3' Any one or more of these are TIFF0007898835000024.tif10128 is modified to bond to a linker group that is further covalently bonded to it. [Invention 1006] A compound of the present invention 1005, wherein X is C=O. [Invention 1007] R 1' However, any of the compounds 1004 to 1006 of the present invention, wherein the compound is a hydroxyl group, or a group that can be metabolized to a hydroxyl or carboxyl group such that the compound is a prodrug of the active compound. [Invention 1008] R 1' However, -(CH2) n OH, -(CH2) n SH, (CH2) n -O-(C1~C6)alkyl, -(CH2) n COOH, -(CH2O) n H may be substituted - (CH2) n OC(O)-(C1~C6 alkyl), or possibly substituted-(CH2) n A compound of any of the present inventions 1004 to 1007, which is C(O)-O-(C1~C6 alkyl) where n is 0 or 1. [Invention 1009] R 1'However, it is a carboxylic acid group, a hydroxyl group, or an amine group, or contains one of these, and each of the hydroxyl group, carboxylic acid group, or amine group is Any compound 1004 to 1008 of the present invention can be further chemically modified to provide a covalent bond to the linker group to which the TIFF0007898835000025.tif10128 group is attached. [Invention 1010] R 2' However, it may be replaced -NR 1 -T-aryl, may be substituted with -NR 1 -T-heteroaryl group, or possibly substituted -NR 1 -T- is a complex algebra, where R 1 is H or CH3, preferably H; and T may be substituted -(CH2) n -A compound of any of the compounds 1004 to 1009 of the present invention, wherein each of the methylene groups may be substituted with one or two substituents, and n is 0, 1, 2, or 3. [Invention 1011] The aryl group is a phenyl or naphthyl group which may be substituted, where the phenyl or naphthyl group is TIFF0007898835000026.tif10128 Linker group to which a group is attached; halogen; amine; monoalkylamine or dialkylamine; OH; SH; COOH; CH3; CF3; OMe; OCF3; NO2; CN group; or A linker group bonded to a TIFF0007898835000027.tif10128 group, and a phenyl group which may be substituted with at least one of the following: F, Cl, OH, SH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group; A naphthyl group that may be substituted; Each TIFF0007898835000028.tif10128 A heteroaryl or heterocyclic compound which may be substituted with a linker group to which the linker group is bonded. Compounds of the present invention 1010, which may be substituted with [Invention 1012] The compound of the present invention 1010, wherein the aryl group is a phenyl group which may be substituted with a heteroaryl group. [Invention 1013] The heteroaryl group is an optionally substituted isoxazole, optionally substituted oxazole, optionally substituted thiazole, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted diazole, optionally substituted triazole, or optionally substituted pyridine group, where the heteroaryl group is A compound of the present invention 1010, which may be substituted with a linker group to which a TIFF0007898835000029.tif10128 group is bonded. [Invention 1014] The compound of the present invention 1013, wherein the isoxazole is a methyl-substituted isoxazole, the oxazole is a methyl-substituted oxazole, the thiazole is a methyl-substituted thiazole, the pyrrole is a methyl-substituted pyrrole, the imidazole is methylimidazole, benzylimidazole, methoxybenzylimidazole, oxiimidazole, or methyloxyimidazole, the diazole is methyldiazole, the triazole is a methyl-substituted triazole, and the pyridine group is a halo-substituted pyridine, a methyl-substituted pyridine group, or an oxapyridine group in which the pyridine group is linked to a phenyl group by oxygen. [Invention 1015] The compound of the present invention 1010, wherein the aryl group is a phenyl group which may be substituted with a heterocyclic group. [Invention 1016] The compound of the present invention 1015, wherein the heterocyclic group is substituted or otherwise tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, oxane, thian, pyrrolidine, or morpholine. [Invention 1017] The aforementioned heterocyclic group A compound of the present invention 1016, which may be substituted with a linker group to which a TIFF0007898835000030.tif10128 group is bonded. [Invention 1018] The compound of the present invention 1010, wherein the heterocycle is a substituted tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, oxane, thian, pyrrolidine, or morpholine. [Invention 1019] The aforementioned aryl group, Halogens; amines; monoalkylamines; dialkylamines; OH; SH; COOH; CH3; CF3; OMe; OCF3; NO2; or CN group; A phenyl group which may itself be substituted with at least one of the following groups: F, Cl, OH, SH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN; A naphthyl group that may be substituted; or substituted heteroaryl or heterocyclic groups A compound of the present invention 1011, wherein the phenyl group may be substituted with [another compound]. [Invention 1020] The compound of the present invention 1019, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein the optionally substituted heteroaryl is an optionally substituted isoxazole, optionally substituted oxazole, optionally substituted thiazole, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted benzimidazole, optionally substituted oxyimidazole, an optionally substituted diazole group containing a methyldiazole group, an optionally substituted triazole group containing a methyl-substituted triazole group, a halo (preferably F) or an optionally substituted pyridine group containing a methyl-substituted pyridine group or an oxapyridine group, an optionally substituted furan, an optionally substituted benzofuran, an optionally substituted dihydrobenzofuran, an optionally substituted indole, an optionally substituted indidine, an optionally substituted azaindidine, an optionally substituted quinoline, or an optionally substituted group having one of the following chemical structures: TIFF0007898835000031.tif102160, S c CHR SS , NR URE , or O; R HET This can be H, CN, NO2, a halo (preferably Cl or F), an optionally substituted C1-C6 alkyl group (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), an optionally substituted O (C1-C6 alkyl group) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylene group -C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R SSis H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE The group is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C1-C6 alkyl), where each of these groups is substituted with one or two hydroxyl groups or up to three halogens, preferably a fluorine group, or an optionally substituted phenyl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycle, preferably, for example, piperidine, morpholine, pyrrolidine, or tetrahydrofuran; R PRO is H, an optionally substituted C1-C6 alkyl group, or an optionally substituted aryl group, optionally substituted heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indidine, and azaindidine; R PRO1 and R PRO2 Each of them is independently H, an optionally substituted C1-C3 alkyl group, or together they form a keto group, and Each n is independently 0, 1, 2, 3, 4, 5, or 6. [Invention 1021] The compound of the present invention 1019, wherein the optionally substituted heterocycle is selected from the group consisting of pyrrolidine, furan, tetrahydrofuran, tetrahydrothiene, piperidine, piperazine, and morpholine. [Invention 1022] R3' may be substituted -T-aryl, substituted -T-heteroaryl, substituted -T-heterocyclic, or substituted -NR 1 -T-aryl, may be substituted with -NR 1 -T-heteroaryl, or possibly substituted -NR 1 -T is a complex algebra; and T is -(CH2) n - group, -(CH2O) n -group, -(OCH2) n - group, -(CH2CH2O) n -Base, or -(OCH2CH2) n - A compound of any of the 1001 to 1021 inventions, wherein each of these groups may be substituted with one or two substituents, and n is 0, 1, 2, or 3. [Invention 1023] The aryl group is a phenyl or naphthyl group which may be substituted, and where the phenyl or naphthyl group is TIFF0007898835000032.tif10128 Linker group to which a group is attached, or halogen group, amine, monoalkylamine or dialkylamine, OH, SH, COOH, CH3, CF3, OMe, OCF3, NO2, CN, or S(O)2R S It may be substituted with the base, where R S C1-C6 alkyl groups, -(CH2) m NR1R2 group, or optionally substituted aryl, heteroaryl, or heterocyclic group, each of which may be substituted at the ortho, meta, or para position of the phenyl ring, or the aryl group may be substituted with an optionally substituted aryl group, an optionally substituted heteroaryl, or an optionally substituted heterocyclic group, each of which is A compound of the present invention 1022, which may be substituted with a linker group to which a TIFF0007898835000033.tif10128 group is bonded. [Invention 1024] The heteroaryl is an optionally substituted isoxazole, optionally substituted oxazole, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted oxyimidazole, optionally substituted diazole, optionally substituted triazole group, optionally substituted pyridine group, or optionally substituted oxapyridine group, where the heteroaryl group is A compound of the present invention 1023, which may be substituted with a linker group to which a TIFF0007898835000034.tif10128 group is bonded. [Invention 1025] The compound of the present invention 1024, wherein the optionally substituted isoxazole is a methyl-substituted isoxazole, the optionally substituted oxazole is a methyl-substituted oxazole, the optionally substituted thiazole is a methyl-substituted thiazole, the optionally substituted isothiazole is a methyl-substituted isothiazole, the optionally substituted pyrrole is a methyl-substituted pyrrole, the optionally substituted imidazole is methylimidazole, benzylimidazole, or methoxybenzylimidazole, the optionally substituted oxyimidazole is methyloxyimidazole, the optionally substituted diazole is methyldiazole, the optionally substituted triazole group is a methyl-substituted triazole group, the optionally substituted pyridine group is halo-substituted or methyl-substituted pyridine, and the oxapyridine group is linked to a phenyl group by oxygen. [Invention 1026] The compound of the present invention 1023, wherein the heterocyclic group is substituted or otherwise tetrahydroquinoline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, pyrrolidine, morpholine, oxane, or thian. [Invention 1027] The aforementioned heterocyclic group A compound of the present invention 1026, which may be substituted with a linker group to which a TIFF0007898835000035.tif10128 group is bonded. [Invention 1028] The compound of the present invention 1022, wherein the heteroaryl group is optionally substituted quinoline, optionally substituted indole, optionally substituted isoxazole, optionally substituted benzofuran, optionally substituted thiophene, or optionally substituted pyridine. [Invention 1029] The compound of the present invention 1028, wherein the isoxazole is a methyl-substituted isoxazole. [Invention 1030] The compound of the present invention 1028, wherein the thiophene is a methyl-substituted thiophene. [Invention 1031] The compound of the present invention 1028, wherein the pyridine is methyl-substituted. [Invention 1032] The heterocyclic group is selected from the group consisting of tetrahydrofuran, tetrahydrothiophene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane, or thian, and each of these groups is A compound of the present invention 1022, which may be substituted with a linker group to which a TIFF0007898835000036.tif10128 group is bonded. [Invention 1033] The compound of the present invention 1022, wherein the heteroaryl is an optionally substituted isoxazole, an optionally substituted oxazole, an optionally substituted thiazole, an optionally substituted pyrrole, an optionally substituted imidazole, an optionally substituted oxyimidazole, an optionally substituted diazole which is methyldiazole, an optionally substituted triazole group, an optionally substituted pyridine group, or an optionally substituted oxapyridine group. [Invention 1034] The compound of the present invention 1033, wherein the optionally substituted isoxazole is a methyl-substituted isoxazole, the optionally substituted oxazole is a methyl-substituted oxazole, the optionally substituted thiazole is a methyl-substituted thiazole, the optionally substituted pyrrole is a methyl-substituted pyrrole, the optionally substituted imidazole is methylimidazole, benzylimidazole, or methoxybenzylimidazole, the optionally substituted oxyimidazole is methyloxyimidazole, the optionally substituted diazole is methyldiazole, the optionally substituted triazole group is a methyl-substituted triazole group, the optionally substituted pyridine group is halo-substituted or methyl-substituted pyridine, and the oxapyridine group is linked to a phenyl group by oxygen. [Invention 1035] The heteroaryl group may be a substituted quinoline, a substituted indole, a substituted benzimidazole, a substituted benzodiazole, a substituted benzoxofran, a substituted imidazole, a substituted isoxazole, a substituted oxazole, a substituted diazole, a substituted benzofuran, a substituted thiophene, a substituted thiazole, a substituted triazole, a triisopropylsilyl group, or a substituted -(CH2) m -O-C1~C6 alkyl group, may be substituted-(CH2) m A compound of the present invention 1022, which is a -C(O)-O-C1~C6 alkyl group, or an optionally substituted 2-, 3, or 4-pyridine, and m is 0, 1, 2, 3, 4, 5, or 6. [Invention 1036] The heteroaryl group may be a methyl-substituted oxazole or a triazole which may be substituted with a methyl group, a triisopropylsilyl group which may be substituted with -(CH2) m -O-C1~C6 alkyl groups or possibly substituted-(CH2) mThe compound of the present invention 1035, which is -C(O)-O-C1~C6 alkyl group. [Invention 1037] The compound of the present invention 1022, wherein the heterocycle is selected from the group consisting of tetrahydroquinoline, tetrahydrofuran, tetrahydrothiene, piperidine, piperazine, pyrrolidine, and morpholine, and each of these groups may be substituted. [Invention 1038] TIFF0007898835000037.tif10128, and, If it exists as TIFF0007898835000038.tif10128 TIFF0007898835000039.tif10128 is the basis of any of the compounds described in items 1001 to 1004 of this invention, or any pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof, each independently being the base of the following chemical structures: TIFF0007898835000040.tif51128In formula, R 1' It is a group that can be metabolized to OH in the patient or subject; R 2' -NR1-X may be substituted. R2' -alkyl group, may be substituted -NR1-X R2' -aryl group, may be substituted-NR1-X R2' -HET group, may be substituted -NR1-X R2' -aryl-HET group, or possibly substituted -NR1-X R2' -HET-aryl group, R1 is H or a C1-C3 alkyl group; X R2' (This may be substituted -CH2) n -, -CH2) n -CH(X v )=CH(X v )-(Sys or Trans), -CH2) n -CH≡CH-, -(CH2CH2O) n -or C3-C6 cycloalkyl groups; R 3'(CH2) may be substituted. n -(V) n' -(CH2) n -(V) n' -R S3' The base may be substituted - (CH2) n -N(R 1' )(C=O) m' -(V) n' -R S3' The base may be substituted -X R3' -Alkyl alkyl group, may be substituted -X R3' -aryl group, may be substituted-X R3' -HET group, may be substituted -X R3' -aryl-HET group, or possibly substituted-X R3' -HET-aryl group, R S3' C1~C may be substituted. 10 The alkyl group is an optionally substituted aryl group or HET group; R 1' is H or a C1-C3 alkyl group; V is O, S, or NR 1' and; X R3' (This may be substituted -CH2) n -, -CH2) n -CH(X v )=CH(X v )-(Sys or Trans), -CH2) n -CH≡CH-, -(CH2CH2O) n -or C3-C6 cycloalkyl groups; X v is a C1-C3 alkyl group which may be substituted with H, a halo, or one or two hydroxyl groups or up to three halogen groups; Alkyl may be substituted C1-C 10 It is an alkyl group; The aryl group is a substituted phenyl or naphthyl group; and HET is a substituted or substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indidine, azaindidine, quinoline, or a group with the following chemical structures: TIFF0007898835000041.tif140163In formula, S c CHR SS , NR URE , or O; R HET This is H, CN, NO2, halo, optionally substituted C1-C6 alkyl, optionally substituted O(C1-C6 alkyl), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group; R SS is H, CN, NO2, halo, optionally substituted C1-C6 alkyl, optionally substituted O-(C1-C6 alkyl), or optionally substituted -C(O)(C1-C6 alkyl); R URE is H, C1-C6 alkyl, or -C(O)(C1-C6 alkyl), and each of these groups may be substituted with one or two hydroxyl groups, up to three halogens, or a heterocycle which may be substituted, and Y C is N or CR YC And here R YC This can be H, OH, CN, NO2, halo, optionally substituted C1-C6 alkyl, optionally substituted O(C1-C6 alkyl), or optionally substituted acetylene group-C≡CR a And here R a The above is the same as; R PROis H, an optionally substituted C1-C6 alkyl group, or an optionally substituted aryl, optionally substituted heteroaryl, or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indidine, and azaindidine; R PRO1 and R PRO2 Each of them is independently either H, an optionally substituted C1-C3 alkyl group, or together forms a keto group. m' is either 0 or 1; Each n is independently 0, 1, 2, 3, 4, 5, or 6, and Each n' is independently either 0 or 1. And here the TIFF0007898835000042.tif11128 is TIFF0007898835000043.tif10128 is covalently bonded to the linker group to which it is attached. [Invention 1039] TIFF0007898835000044.tif10128, and, If it exists as TIFF0007898835000045.tif10128 TIFF0007898835000046.tif10128 is the basis of any of the compounds described in items 1001 to 1004 of this invention, or any pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof, each independently being the base of the following chemical structures: TIFF0007898835000047.tif52128In formula, R 1' It is a group that is metabolized to OH in the patient or subject; R 2' is -NH-CH2-aryl-HET; R 3' -CHR CR3'-NH-C(O)-R 3P1 base, or -CHR CR3' -R 3P2 It is the basis; Here R CR3' These are C1-C4 alkyl groups; R 3P1 This is a C1-C3 alkyl group, an optionally substituted oxetane group, and a -(CH2) group where n is 1 or 2. n The OCH3 group or CH3CH2O- group is linked to phenyl at the meta or para position. TIFF0007898835000048.tif26128 is a morpholino group, or a morpholino group linked to a carbonyl group at the 2nd or 3rd position; R 3P2 teeth TIFF0007898835000049.tif26128 units, Here, aryl is phenyl; HET is a thiazole or isothiazole that may be substituted; R HET is H or a halo group; and Here TIFF0007898835000050.tif10128 is TIFF0007898835000051.tif10128 is covalently bonded to the linker group to which it is attached. [Invention 1040] The aforementioned Compounds of the present invention 1039, or pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof, wherein the TIFF0007898835000052.tif10128 group is a group of the following chemical structure: TIFF0007898835000053.tif46169TIFF0007898835000054.tif197160TIFF0007898835000055.tif101164Here TIFF0007898835000056.tif10128 is TIFF0007898835000057.tif10128 is covalently bonded to the linker group to which it is attached. [Invention 1039] The aforementioned TIFF0007898835000058.tif10128 is one of the compounds described in Invention 1001 to 1003 below, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof: In formula TIFF0007898835000059.tif50128, X is Cl, F, C1-C3 alkyl, or an optionally substituted heterocycle; R 1 and R 2 Each of these is independently H, C1-C3 alkyl, or phenyl; and Here TIFF0007898835000060.tif10128 The group is a linker group or TIFF0007898835000061.tif10128 is replaced by a linker group to which it is optionally attached. [Invention 1040] The aforementioned TIFF0007898835000062.tif10128 The following compounds are included in any of the invention items 1001 to 1003, or any pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs thereof: In formula TIFF0007898835000063.tif51128, n is either 0 or 1; R is a linker or TIFF0007898835000064.tif10128 is a linker bonded to a base; and X is H, F, Cl, C1-C3 alkyl, or heterocycle; Here TIFF0007898835000065.tif10128 The group is a linker group or TIFF0007898835000066.tif10128 is replaced by a linker group to which it is optionally attached. [Invention 1041] The aforementioned TIFF0007898835000067.tif10128 The compound of any of the following groups, or any pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof, is described below: In the formula TIFF0007898835000068.tif51128, n is either 0 or 1; R is a linker or TIFF0007898835000069.tif10128 is a linker bonded to a group, or is a linker, or is bonded through an amide, ester, ether, or carbamate group TIFF0007898835000070.tif10128 units are linked TIFF0007898835000071.tif10128 is a linker bonded to a base; R 1 This may be a C1-C3 alkyl or -C(O)NR which may be substituted with one or two hydroxyl groups. 3 R 4 And here R 3 and R 4 Each of these is independently H, C1-C3 alkyl, or phenyl; and X is H, F, Cl, C1-C3 alkyl, or an optionally substituted heterocycle. [Invention 1042] The aforementioned Compounds of the present invention 1001 or 1002, or pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs thereof, wherein the group TIFF0007898835000072.tif10128 is as follows: In the formula TIFF0007898835000073.tif51128, n is either 0 or 1; R 1 This is via a linker, or an amide, ester, ether, carbamate, or heterocyclic group. TIFF0007898835000074.tif11128 units are linked TIFF0007898835000075.tif11128 is a linker bonded to a base; and R is a C1-C3 alkyl group that may be substituted with H, F, Cl, or one or two hydroxyl groups, -OC(O)NR 3 R 4 , or -C(O)NR 3 R 4 And here R 3 and R 4 Each of these is independently H, C1-C3 alkyl, or phenyl. [Invention 1043] The aforementioned TIFF0007898835000076.tif11128 The following compounds are included in any of the invention items 1001 to 1003, or pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs thereof: In formula TIFF0007898835000077.tif50128, n is either 0 or 1; R is a linker, or an amide, ester, ether, carbamate, or heterocyclic group. TIFF0007898835000078.tif10128 linked TIFF0007898835000079.tif10128 is a linker bonded to a base; and Each X is independently a C1-C3 alkyl, heterocyclic, or -OC(O)NR, which may be substituted with H, F, Cl, or one or two hydroxyl groups. 3 R 4 , or -C(O)NR 3 R 4 And here R 3 and R 4 Each of these is independently H, C1-C3 alkyl (preferably methyl), or phenyl. [Invention 1044] The aforementioned TIFF0007898835000080.tif10128 The group is one of the compounds 1001 to 1003 of this invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof: In the formula TIFF0007898835000081.tif51128, n is either 0 or 1; R is a linker, or an amide, ester, ether, carbamate, or heterocyclic group. TIFF0007898835000082.tif10128 linked TIFF0007898835000083.tif11128 is a linker bonded to a base; R 1 C1-C3 alkyl, -OC(O)NR which may be substituted with one or two hydroxyl groups 3 R 4 or -C(O)NR 3 R 4 And here R 3 and R 4 Each of them is independently H, C1-C3 alkyl, or phenyl; and X is independently H, F, Cl, a C1-C3 alkyl group which may be substituted with one or two hydroxyl groups, or a heterocyclic group. [Invention 1045] The aforementioned TIFF0007898835000084.tif10128 The group is one of the compounds 1001 to 1003 of this invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof: In formula TIFF0007898835000085.tif51128, n is either 0 or 1; R is a linker, or an amide, ester, ether, carbamate, or heterocyclic group. TIFF0007898835000086.tif10128 linked TIFF0007898835000087.tif10128 is a linker bonded to a base; R 1 is H, a C1-C3 alkyl group which may be substituted with one or two hydroxyl groups, -OC(O)NR 3 R 4 or -C(O)NR 3 R 4And here R 3 and R 4 Each of them is independently H, C1-C3 alkyl, or phenyl; and Each X is independently H, F, Cl, a C1-C3 alkyl group which may be substituted with one or two hydroxyl groups, or a heterocycle. [Invention 1046] A compound from any of the inventions 1001 to 1045 wherein the linker group L is one of the following groups: In formula TIFF0007898835000088.tif12128, Z is It is the base for concatenating TIFF0007898835000089.tif10128 to X; and X is based on Z This is the base linked to TIFF0007898835000090.tif11128. [Invention 1047] Z Non-existent (bond); -(CH2) i -O;-(CH2) i -S;-(CH2) i -NR; X1Y1 forms an amide group, or a urethane group, ester group, or thioester group. TIFF0007898835000091.tif11128 units; or TIFF0007898835000092.tif15128 units Each R is H, or a C1-C3 alkyl, alkanol group, or water-soluble heterocyclic group. Each Y is independently a combination, O, S, or NR. The compound of the present invention 1046, wherein each i is independently between 0 and 100. [Invention 1048] A compound of the present invention 1047, wherein i is 1 to 10. [Invention 1049] A compound of the present invention 1047, wherein i is 1 to 5. [Invention 1050] The compound of the present invention 1047, wherein the water-soluble heterocyclic group is morpholine, piperidine, or piperazine. [Invention 1051] X TIFF0007898835000093.tif17128 units, In the formula, each D is either independently combined (or does not exist), It is TIFF0007898835000094.tif58128; j is between 1 and 100; k is between 1 and 100; m' is between 1 and 100; n is between 1 and 100; X 1 is O, S, or NR; R and Y are the same as in Invention 1032; and TIFF0007898835000095.tif7128 is a bond, or a linking group that links Z to X if present in a linker group, a compound according to any of Invention 1046 to 1050. [Invention 1052] A compound of the present invention 1051, wherein j is 1 to 10; k is 1 to 10, m' is 1 to 10, and n is 1 to 10. [Invention 1053] TIFF0007898835000096.tif6128 is bonded (not present), or is a piperazinyl group, or TIFF0007898835000097.tif62128 units, In the formula, X 2 O, S, NR 4 , S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O; X 3 O, S, CHR 4 , NR 4 and R 4 The compound of the present invention 1051 or 1052, wherein is H, or a C1-C3 alkyl group which may be substituted with one or two hydroxyl groups. [Invention 1054] TIFF0007898835000098.tif7128 is A compound according to any of the invention 1051 to 1053, wherein the compound is a TIFF0007898835000099.tif15128 group, an amide group, or a piperazinyl group. [Invention 1055] The aforementioned The TIFF0007898835000100.tif10128 group is transmitted through the linker group. A compound of the present invention 1001, which is a group listed in Table 2 or Figure 15 of the affinity specifications herein, modified to be covalently bonded to the TIFF0007898835000101.tif10128 group. [Invention 1056] The aforementioned The TIFF0007898835000102.tif10128 group, through the linker group The following chemical structure is modified to have a covalent bond to the TIFF0007898835000103.tif10128 group: TIFF0007898835000104.tif125146TIFF0007898835000105.tif222153TIFF0007898835000106.tif241152TIFF0007 898835000107.tif234154TIFF0007898835000108.tif222154TIFF0007898835000109.tif216157TIFF0007898835000 Compounds of the present invention 1001, or pharmaceutically acceptable salts thereof, which are the bases of 110.tif244160TIFF0007898835000111.tif226140TIFF0007898835000112.tif231154TIFF0007898835000113.tif213153TIFF0007898835000114.tif190151TIFF0007898835000115.tif174143. [Invention 1057] The aforementioned TIFF0007898835000116.tif10128 groups, through linker groups The following chemical structure is modified to have a covalent bond to the TIFF0007898835000117.tif10128 group: The compound of Invention 1001, or a pharmaceutically acceptable salt thereof, which is the base of TIFF0007898835000118.tif73166TIFF0007898835000119.tif237170TIFF0007898835000120.tif212170TIFF0007898835000121.tif209170TIFF0007898835000122.tif231170TIFF0007898835000123.tif222170TIFF0007898835000124.tif218170TIFF0007898835000125.tif103170. [Invention 1058] In the formula, R 1PC , R 2PC , R 3PC , R 4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R 11PC , R 12PC , R 13PC , and R 14PC Any one or more of It is TIFF0007898835000126.tif12128 units, Here L is a linker group, and TIFF0007898835000127.tif10128 is the protein targeting portion. Any one of the compounds having the chemical structure shown in Figure 19 of this specification, or any pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof. [Invention 1059] R 1PC , R 2PC , R 3PC , R 4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R11PC , R 12PC , R 13PC , and R 14PC Two or fewer of the following TIFF0007898835000128.tif12128 is a group and also group R 1PC , R 2PC , R 3PC , R 4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R 11PC , R 12PC , R 13PC , and R 14PC The compound of the present invention 1058, wherein the other is independently an H or CH3 group. [Invention 1060] base R 1PC , R 2PC , R 3PC , R 4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R 11PC , R 12PC , R 13PC , and R 14PC Only one of them TIFF0007898835000129.tif12128 is a group and also group R 1PC , R 2PC , R 3PC , R 4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R 11PC , R 12PC , R 13PC , and R 14PC The compound of the present invention 1059, wherein the other is independently an H or CH3 group. [Invention 1061] The aforementioned and other base R 1PC , R 2PC , R 3PC , R4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R 11PC , R 12PC , R 13PC , and R 14PC A compound of the present invention 1060, wherein each of these is H. [Invention 1062] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000130.tif38128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000131.tif13128 is either a base or H. [Invention 1063] R 7PC or R 10PC One of the following TIFF0007898835000132.tif13128 units, and R 7PC or R 10PC A compound of the present invention 1062, wherein the other element is H. [Invention 1064] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000133.tif38128In formula, R 7PC teeth This is TIFF0007898835000134.tif13128 units. [Invention 1065] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000135.tif58128In formula, R 7PC , R 11PC R 12PC , R 13PC , and R 14PCEach is independent TIFF0007898835000136.tif13128 is either a base or H. [Invention 1066] R 7PC , R 11PC , R 12PC , R 13PC , and R 14PC One of them is A compound of the present invention 1065, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein the compound is a TIFF0007898835000137.tif12128 group and the other group is H. [Invention 1067] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000138.tif55128In formula, R 4PC , R 7PC , R 11PC R 12PC , R 13PC , and R 14PC Each is independent TIFF0007898835000139.tif12128 is either a base or H. [Invention 1068] R 4PC , R 7PC , R 11PC , R 12PC , R 13PC , and R 14PC Any one of them A compound of the present invention 1067, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein the compound is a TIFF0007898835000140.tif12128 group and the other group is H. [Invention 1069] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000141.tif54128In formula, R 3PC , R 7PC , R 11PC R 12PC , R13PC , and R 14PC Each is independent TIFF0007898835000142.tif12128 is either a base or H. [Invention 1070] R 3PC , R 7PC , R 11PC , R 12PC , R 13PC , and R 14PC One of them is A compound of the present invention 1070, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein the compound is a TIFF0007898835000143.tif13128 group and the other group is H. [Invention 1071] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000144.tif39128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000145.tif12128 is either a base or H. [Invention 1072] R 7PC and R 10PC One of them is A compound of the present invention 1071, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein the other group is H. [Invention 1073] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000147.tif38128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000148.tif13128 is either H or R 8PC It is either H or CH3. [Invention 1074] R 7PC and R 10PC One of them is TIFF0007898835000149.tif12128 is one group, and the other group is H, and R 8PC The compound of Invention 1073, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein is H. [Invention 1075] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000150.tif39128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000151.tif13128 is either H or R 8PC It is either H or CH3. [Invention 1076] R 7PC and R 10PC One of them is TIFF0007898835000152.tif12128 units, and R 7PC and R 10PC The other side is H, and R 8PC A compound of the present invention 1075, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein is H. [Invention 1077] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000153.tif38128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000154.tif12128 is either H or R 8PC It is either H or CH3. [Invention 1078] R 7PC and R 10PC One of them is TIFF0007898835000155.tif12128 is one group, and the other group is H, and R 8PC A compound of Invention 1077, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein is H. [Invention 1079] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000156.tif49128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000157.tif12128 is either a base or H. [Invention 1080] R 7PC and R 10PC One of them is A compound of the present invention 1079, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein the other group is H. [Invention 1081] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000159.tif36128In formula, R 7PC and R 9PC Each is independent TIFF0007898835000160.tif12128 is either a base or H. [Invention 1082] R 7PC and R 9PC One of them is A compound of the present invention 1081, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein the other group is H. [Invention 1083] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000162.tif46128In formula, R 7PC and R 14PC Each is independent TIFF0007898835000163.tif12128 is either H or R 12PC and R 13PC Each of them is either H or CH3. [Invention 1084] R 7PC and R 14PC One of them is TIFF0007898835000164.tif12128 units, and R 7PC and R 14PC The other side of the base is H, and R 12PC and R 13PC Each of the compounds of the present invention 1083, or pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof, wherein each of the isomers is H. [Invention 1085] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000165.tif35128In formula, R 7PC and R 9PC Each is independent TIFF0007898835000166.tif12128 is either a base or H. [Invention 1086] R 7PC and R 9PC One of them is A compound of the present invention 1085, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein the other group is H. [Invention 1087] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000168.tif36128In formula, R 7PC and R 9PC Each is independent TIFF0007898835000169.tif12128 is either a base or H. [Invention 1088] R 7PC and R 9PC One of them is A compound of the present invention 1087, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein the other group is H. [Invention 1089] The following chemical structures of the compounds of Invention 1058, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs: TIFF0007898835000171.tif39128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000172.tif12128 is either H or R 9PC It is either H or CH3. [Invention 1090] R 7PC and R 10PC One of them is TIFF0007898835000173.tif12128 is one group, and the other group is H, and R 9PC The compound of Invention 1089, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein is H. [Invention 1091] A compound according to any of the present invention 1058 to 1080, wherein the linker group is a polyethylene group containing about 2 to about 20 ethylene glycol units. [Invention 1092] The compound of the present invention 1091, wherein the polyethylene glycol group contains ethylene glycol units between approximately 2 and 8. [Invention 1093] The aforementioned TIFF0007898835000174.tif10128 units are C1~C 12 A compound according to any of invention 1001 to 1092, which is an alkylhalo group. [Invention 1094] The alkylhalo group is C2-C 10 A compound of the present invention 1093, wherein the compound is an alkylhalo group, where the halo group is Cl or Br. [Invention 1095] The compound of the present invention 1094, wherein the linker group is a polyethylene glycol group having a size range of about 2 to about 8 ethylene glycol units. [Invention 1096] The aforementioned The TIFF0007898835000175.tif10128 group is the part that binds to the target protein, and here the target protein Proteins involved in catalytic activity, aromatase activity, kinetic activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, and proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transporter activity, pathogenicity, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biodevelopmental activity, and translation regulator activity). A compound according to any of the present invention 1001 to 1092, selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, and proteins directly involved in the integrative function of cells. [Invention 1097] The aforementioned The TIFF0007898835000176.tif10128 group is the part that binds to the target protein, where the target protein is B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type 4, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, i.e., Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alpha R, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsome transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin-11, glycine receptor Selected from the group consisting of: nasal cells, norepinephrine reuptake receptors, endothelin receptors, neuropeptide Y and receptors, adenosine receptors, adenosine kinases and AMP deaminases, purine receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferases, geranylgeranyltransferases, NGF TrkA receptors, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptors, integrin receptors, Her-21 neu, telomerase inhibitors, cytosolic phospholipase A2, and EGF receptor tyrosine kinases. Further protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride ion channels, acetylcholinesterase, voltage-sensitive sodium channel proteins, calcium-releasing channels, and chloride ion channels. Further target proteins include any of the compounds 1001 to 1092 of the present invention, such as acetyl-CoA carboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, and enolpyruvirshikimic acid-phosphate synthase. [Invention 1098] The aforementioned A compound according to any of the inventions 1001 to 1092, wherein the TIFF0007898835000177.tif10128 group is an Hsp90 inhibitor, a kinase inhibitor, a phosphatase inhibitor, an MDM2 inhibitor, a compound targeting human BET bromodomain-containing protein, an HDAC inhibitor, a human lysine methyltransferase inhibitor, a compound targeting the RAF receptor, a compound targeting FKBP, an angiogenesis inhibitor, an immunosuppressant compound, a compound targeting an aryl hydrocarbon receptor, a compound targeting an androgen receptor, a compound targeting an estrogen receptor, a compound targeting a thyroid hormone receptor, a compound targeting an HIV protease, a compound targeting an HIV integrase, a compound targeting an HCV protease, or a compound targeting acyl protein thioesterase 1 and / or 2. [Invention 1099] The aforementioned A compound from any of the inventions 1001 to 1092, wherein the TIFF0007898835000178.tif10128 group is as follows: YKB N-[4-(3H-imidazo[4,5-C]pyridine-2-yl)-9H-fluoren-9-yl]-succinamide TIFF0007898835000179.tif57128 Linker part L or TIFF0007898835000180.tif6128 is derivatized by being bonded via terminal amide groups; p54 8-[(2,4-dimethylphenyl)sulfanyl]-3-penta-4-in-1-yl-3H-purine-6-amine TIFF0007898835000181.tif49128 The linker portion is derivatized so that it can be bonded via terminal acetylene groups; It has the following structure (5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(morpholine-4-ylmethyl)phenyl]isoxazole-3-carboxamide): TIFF0007898835000182.tif58128 Linker part L or TIFF0007898835000183.tif6128 is derivatized by being bonded via an amide group; Hsp90 inhibitor PU3 having the following structure: TIFF0007898835000184.tif50128 Linker part L or TIFF0007898835000185.tif6128 is derivatized by bonding via a butyl group; Derivatized Hsp90 inhibitor geldanamycin ((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1], 17-alkylamino-17-desmethoxygeldanamycin (17-AAG), or 17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin (17-DMAG), where the linker may be bonded via an amide group; Tyrosine kinase inhibitor erlotinib (derivative) TIFF0007898835000186.tif38128 Here the linker part L or TIFF0007898835000187.tif6128 The R group is bonded via an ether group; Kinase inhibitor sunitinib (derivative): TIFF0007898835000188.tif34128 Here R is the linker portion L or that is coupled to the pyrrole portion. TIFF0007898835000189.tif7128 is a base; Kinase inhibitor sorafenib (derivative) TIFF0007898835000190.tif30128 Here R is the linker portion L or bonded to the phenyl portion TIFF0007898835000191.tif7128 is a base; Kinase inhibitor dasatinib (derivative) TIFF0007898835000192.tif50128 Here R is the linker portion L or that is bound to the pyrimidine. It is TIFF0007898835000193.tif7128; Kinase inhibitor lapatinib (derivative) TIFF0007898835000194.tif62128 Here the linker part L or The TIFF0007898835000195.tif7128 group is bonded via a terminal methyl group of the sulfonylmethyl group; Kinase inhibitor U09-CX-5279 (derivative) TIFF0007898835000196.tif72128U09 CX-5279 3-(cyclopropylamino)-5-{[3-(trifluoromethyl)phenyl]amino}pyrimido[4,5-c]quinoline-8-carboxylic acid Here, linker part L or The TIFF0007898835000197.tif6128 group is bonded via an amine (aniline), carboxylic acid, or cyclopropyl group; Kinase inhibitors Y1W and Y1X (derivativeized) having the following structures: TIFF0007898835000198.tif50128YIX 1-Ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine-6-yl]sulfanyl}benzyl)urea Here, the linker part L or The TIFF0007898835000199.tif7128 group is bonded via a propyl group; TIFF0007898835000200.tif62128YIW 1-(3-tert-butyl-1-phenyl-1H-pyrazole-5-yl)-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine-6-yl]sulfanyl}benzyl)urea Linker part L or TIFF0007898835000201.tif7128 is derivatized by being bonded via a propyl or butyl group; Kinase inhibitors 6TP and OTP (derivativeized) having the following structures TIFF0007898835000202.tif451286TP 4-amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamide thienopyridine 19 Here, the linker part L or The TIFF0007898835000203.tif6128 group is bonded via a terminal methyl group attached to the amide portion; TIFF0007898835000204.tif46128OTP 4-amino-N-methyl-2-[4-(morpholine-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamide thienopyridine 8 Here, the linker part L or The TIFF0007898835000205.tif7128 group is bonded via a terminal methyl group attached to the amide portion; Kinase inhibitor 07U (derivativeized) having the following structure: TIFF0007898835000206.tif5112807U 2-Methyl-N~1~-[3-(pyridine-4-yl)-2,6-naphthyridine-1-yl]propan-1,2-diamine Here, the linker part L or The TIFF0007898835000207.tif6128 group is bonded via a secondary amine or terminal / primary amino group; The kinase inhibitor YCF (derivativeized) having the following structure: TIFF0007898835000208.tif32153 Here the linker part L or The TIFF0007898835000209.tif7128 group is bonded via one of the terminal hydroxyl groups; Kinase inhibitors XK9 and NXP (derivativeized) having the following structures: TIFF0007898835000210.tif53128XK9 N-{4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide TIFF0007898835000211.tif71128NXP N-{4-[(1E)-N-carbamimidoleethanehydrazonoyl]phenyl}-1H-indole-3-carboxamide Linker part L or TIFF0007898835000212.tif6128 is derivatized by being linked via a terminal hydroxyl group (XK9) or a hydrazone group (NXP); Kinase inhibitor afatinib (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide), Linker part L or TIFF0007898835000213.tif7128 is derivatized by being bonded via an aliphatic amine group; Kinase inhibitor hostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidine-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-1,4-oxazin-4-yl]methylphosphate disodium hexahydrate), Linker part L or TIFF0007898835000214.tif7128 is derivatized by being bonded via a methoxy group; Kinase inhibitor gefitinib (N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholine-4-ylpropoxy)quinazoline-4-amine), Linker part L or TIFF0007898835000215.tif6128 is derivatized by being bonded via a methoxy or ether group; TIFF0007898835000216.tif39128 Kinase inhibitor lenvatinib (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide), Linker part L or TIFF0007898835000217.tif7128 is derivatized by being bonded via a cyclopropyl group; Kinase inhibitor vandetanib (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidine-4-yl)methoxy]quinazoline-4-amine), Linker part L or TIFF0007898835000218.tif7128 is derivatized by being bonded via a methoxy or hydroxyl group; Kinase inhibitor vemurafenib (propan-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}amide), Linker part L or TIFF0007898835000219.tif6128 is derivatized by being bonded via a sulfonylpropyl group; Kinase inhibitor Gleevec (derivativeized): TIFF0007898835000220.tif44128 Here the linker part L or TIFF0007898835000221.tif6128 The R group is bonded via an amide group or an anilineamine group; Kinase inhibitor pazopanib (derivative) (VEGFR3 inhibitor): TIFF0007898835000222.tif50128 Here the linker part L or TIFF0007898835000223.tif6128 The R group is attached to the phenyl moiety or via an anilineamine group; Kinase inhibitor AT-9283 (derivative) Aurora kinase inhibitor TIFF0007898835000224.tif45128 Here R is the linker portion L or bonded to the phenyl portion TIFF0007898835000225.tif6128 is a base; Kinase inhibitor TAE684 (derivative) ALK inhibitor TIFF0007898835000226.tif44128 Here R is the linker portion L or bonded to the phenyl portion TIFF0007898835000227.tif7128 is a base; Kinase inhibitor nilotinib (derivative) Abl inhibitor: TIFF0007898835000228.tif51128 Here R is the phenyl moiety or the linker moiety L or that is bonded to the anilineamine group TIFF0007898835000229.tif6128 is a base; Kinase inhibitor NVP-BSK805 (derivative) JAK2 inhibitor TIFF0007898835000230.tif59128 Here R is the phenyl moiety or the linker moiety L or that is bonded to the diazole group TIFF0007898835000231.tif6128 is a base; Kinase inhibitor crizotinib (derivative) Alk inhibitor TIFF0007898835000232.tif61128 Here R is the phenyl moiety or the linker moiety L or that is bonded to the diazole group TIFF0007898835000233.tif6128 is a base; Kinase inhibitor JNJ (derivative) FMS inhibitor TIFF0007898835000234.tif52128 Here R is the linker portion L or bonded to the phenyl portion TIFF0007898835000235.tif7128 is a base; Kinase inhibitor forretinib (derivative) Met inhibitor TIFF0007898835000236.tif40128 Here R is a linker moiety L or a linker moiety bonded to a hydroxyl or ether group on the phenyl or quinoline moiety. TIFF0007898835000237.tif7128 is a base; Allosteric protein tyrosine phosphatase inhibitor PTP1B (derivative); TIFF0007898835000238.tif55128 Here linker base L or TIFF0007898835000239.tif6128 is bonded with R; Inhibitors of the SHP-2 domain of tyrosine phosphatase (derivatives): TIFF0007898835000240.tif40128 Here linker base L or TIFF0007898835000241.tif6128 is bonded with R; BRAF (BRAF V600E ) / MEK kinase inhibitors (derivatives): TIFF0007898835000242.tif38128 Here Linker L or TIFF0007898835000243.tif7128 is bonded with R; Inhibitors of tyrosine kinase ABL (derivatives) TIFF0007898835000244.tif36128 Here R is the linker base L or TIFF0007898835000245.tif7128 is a base; MDM2 inhibitors Nutriin 3, Nutriin 2, Nutriin 1, or trans-4-iodo-4'-voranyl chalcone (derivative), trans-4-iodo-4'-boranyl-chalcone, Here, the linker part L or The TIFF0007898835000246.tif6128 group is bonded via a hydroxyl group; Compounds Brd2, Brd3, and Brd4 that target human BET bromodomain-containing proteins Protein targets: Brd2, Brd3, Brd4 TIFF0007898835000247.tif182155 Here R is the linker L group or TIFF0007898835000248.tif6128 is a base; HDAC inhibitors TIFF0007898835000249.tif33128 Here R is the linker base L or TIFF0007898835000250.tif6128 is a base; Human lysine methyltransferase inhibitor BIX-01294 or UNC0244 (derivative); TIFF0007898835000251.tif36128 Here R is the linker base L or TIFF0007898835000252.tif6128 is a base; TIFF0007898835000253.tif42144 Here R is the linker base L or TIFF0007898835000254.tif7128 is a base; Azacitidine (4-amino-1-β-D-ribofuranosyl-1,3,5-triazine-2(1H)-one), Linker base L or TIFF0007898835000255.tif6128 is derivatized by being linked via a hydroxyl or amino group; and Decitabine (4-amino-1-(2-deoxy-bD-erythropentofuranosyl)-1,3,5-triazine-2(1H)-one), Linker base L or TIFF0007898835000256.tif7128 is derivatized by being bonded via either a hydroxyl group or an amino group; Angiogenic inhibitors selected from the following group: GA-1 (derivativeized); Estradiol (derivativeized); Dihydroxytestosterone (derivative); Obalicin (derivativeized), Fumagilin (derivative); Immunosuppressive compounds selected from the following group: AP21998 (derivativeized); Glucocorticoids including hydrocortisone, prednisone, prednisolone, and methylprednisolone (where the linker group L or TIFF0007898835000257.tif6128 (derivative formation is carried out in which a linker group L or TIFF0007898835000258.tif7128 is bonded; Methotrexate, Linker base L or TIFF0007898835000259.tif6128 is derivatized in which one of the terminal hydroxyls is attached; Cyclosporine, Linker base L or TIFF0007898835000260.tif6128 is derivatized by being bonded with one of the butyl groups; Tacrolimus (FK-506) and rapamycin, Linker base L or TIFF0007898835000261.tif6128 is derivatized by being bonded with one of the methoxy groups; Actinomycin, Linker base L or TIFF0007898835000262.tif7128 is derivatized by being bonded with one isopropyl group; Compounds that target aryl hydrocarbon acceptors (AHRs) selected from the group consisting of apigenin, SR1, and LGC006. Linker base L or The TIFF0007898835000263.tif7128 group is derivatized to be bound to it; Compounds that target the RAF receptor (kinase) with the following chemical structure: TIFF0007898835000264.tif47128PLX4032, Compounds targeting FKBP with the following chemical structure: TIFF0007898835000265.tif58128, where R is the linker group L or TIFF0007898835000266.tif7128 units are shown; Compounds that target androgen receptors (ARs) with the following chemical structures: TIFF0007898835000267.tif22128, where R is the linker group L or TIFF0007898835000268.tif7128 units are shown; SARM ligands of androgen receptors with the following chemical structures: TIFF0007898835000269.tif21128, where R is the linker group L or TIFF0007898835000270.tif6128 units are shown; The androgen receptor ligand DHT with the following chemical structure: TIFF0007898835000271.tif33128, where R is the linker group L or TIFF0007898835000272.tif7128 units are shown; Compounds that target estrogen receptors (ERs) with the following chemical structures: TIFF0007898835000273.tif26128 Here R is the linker base L or TIFF0007898835000274.tif6128 units are shown; Compounds that target thyroid hormone receptors (TRs) with the following chemical structures: TIFF0007898835000275.tif57128, where R is the linker group L or TIFF0007898835000276.tif7128 shows a group, and MOMO shows a methoxymethoxy group; Compounds that target HIV proteases with the following chemical structures: TIFF0007898835000277.tif63128, where R is the linker group L or TIFF0007898835000278.tif7128 units are shown; Inhibitors of HIV integrase with the following chemical structure: TIFF0007898835000279.tif45128, derivatization has been performed in which "R" indicates a site that may be a linker bond. TIFF0007898835000280.tif43128, where R is the linker group L or TIFF0007898835000281.tif6128 units are shown; Compounds that target HCV proteases with the following chemical structures: TIFF0007898835000282.tif64128, where R is the linker group L or TIFF0007898835000283.tif7128 units are shown; and Compounds that target acyl-protein thioesterase-1 and -2 (APT1 and APT2) with the following chemical structures: TIFF0007898835000284.tif51128, where R is the linker group L or This shows TIFF0007898835000285.tif7128 units. [Invention 1100] The aforementioned TIFF0007898835000286.tif10128 units A compound of any of the invention 1001 to 1092, wherein the group is TIFF0007898835000287.tif33128, where w is from 0 to 3. [Invention 1101] A compound of the present invention 1100, wherein w is 1. [Invention 1102] The following chemical structure: Compounds of TIFF0007898835000288.tif114161TIFF0007898835000289.tif205166, or pharmaceutically acceptable salts thereof. [Invention 1103] A pharmaceutical composition comprising an effective amount of any compound 1001 to 1102 of the present invention in combination with a pharmaceutically acceptable carrier, additive, or excipient, and optionally in further combination with additional bioactive agents. [Invention 1104] The composition of the present invention 1103, wherein the additional biological agent is an anticancer agent. [Invention 1105] The composition of the present invention 1103, wherein the additional biological agent is an antiviral agent. [Invention 1106] The composition of the present invention 1105, wherein the antiviral agent is an anti-HIV agent. [Invention 1107] The composition of the present invention 1105, wherein the antiviral agent is an anti-HCV agent. [Invention 1108] The aforementioned anticancer drug, Everolimus, Trabectedin, Abraxane, TLK 286, AV-299, DN-101, Pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, adhesion plaque kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, olegobomab, Lep-etu, noratexide, azd2171, batabulin, ofatumumab, zanorimumab, edotecarin, tetrandrin, lubitecan, tesmilifene, oblimersen, tisilimmumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silengitide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanton, LY317615, Neuradiab, Vitespan, Rta 744, Sdx 102, Tarampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Seliclib;PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), est Radiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258,); 3-[5-(methylsulfonylpiperazine methyl)-indolyl-quinolone, batalanib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly10] acetate (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C; 59 H 84 N 18 Oi4-(C2H4O2) xHere x=1~2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, erbitax, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib; amifostin, NVP-LAQ824, suberoyl analide hydroxamic acid(acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Calmette-Guéran bacillus (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmutin, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbest Lol, Epirubicin, Fludarabine, Fludrocortisone, Fluoxymesterone, Flutamide, Gleevec, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Imatinib, Leuprolide, Levamisole, Lomustine, Mechloretamine, Melphalan, 6-Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Niltamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Plicamycin, Porfimer, Procarbazine, Larcitrexed, Ritsu Ximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, phloxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, barrubicin, mitramycin, vinblastine, vinorelbine, Potecan, Lazoxin, Marimast, COL-3, Neovastat, BMS-275291, Squalamine, Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Doroxifene, Idoxifene, Spironolactone, Finasteride, Cymitidine, Trastuzumab, Denileukin Difutitox, Gefitinib, Bortezimib, Paclitaxel, Paclitaxel without Cremofor, Docetaxel, Epithilone BB) BMS-247550, BMS-310705, Droloxifen, 4-Hydroxytamoxifen, Pipendoxifen, ERA-923, Alzoxifen, Fulvestrant, Acorbifen, Lasofoxifen, Idoxifen, TSE-424, HMR-3339, ZK186619, Topotecan, PTK787 / ZK222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, walnutmannin, ZM336372, L-779, 450, PEG-filgrastim, da Rubepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetanTiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, paroxysmal phosphate Nosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof. A composition of the present invention 1104, selected from the group consisting of the following. [Invention 1109] The composition of the present invention 1106, wherein the anti-HIV agent is a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, a fusion inhibitor, or a mixture thereof. [Invention 1110] A method for regulating the protein activity of a target protein in a patient who requires such regulation, comprising the step of administering to the patient an effective amount of any compound from 1001 to 1092 of the present invention. [Invention 1111] The aforementioned target protein, Proteins involved in catalytic activity, aromatase activity, kinetic activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, and proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transporter activity, pathogenicity, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biodevelopmental activity, and translation regulator activity). The method of the present invention 1110, selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, and proteins directly related to the integrative function of cells. [Invention 1112] The aforementioned target proteins include B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type 4, PDE IV phosphodiesterase type 4, PDE I, PDE II, PDE III, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, i.e., Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and similar, HIV 1 protease, HIV Integrase 1, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alpha R, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neukinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsome transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, glycine receptor, noradrenaline Selected from the group consisting of ion reuptake receptors, endothelin receptors, neuropeptide Y and receptors, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinases and AMP deaminases, purine receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferases, geranylgeranyltransferases, NGF TrkA receptors, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptors, integrin receptors, Her-21 neu, telomerase inhibitors, cytosolic phospholipase A2, and EGF receptor tyrosine kinases. Further protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium-releasing channel, chloride ion channel, acetyl-CoA carboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, and enolpyruvirshikimicate-phosphate synthase, according to the method of the present invention 1110. [Invention 1113] A method for treating a disease condition or state in a patient in which dysregulation of protein activity is the cause of the disease condition or state, comprising the step of administering to the patient an effective amount of any compound 1001 to 1092 of the present invention in order to regulate the protein activity in the patient. [Invention 1114] The method of the present invention 1113, wherein the disease condition or state is asthma, multiple sclerosis, cancer, ciliary disease, cleft palate, diabetes mellitus, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, childhood steatorrhea, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemoglobinosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4(PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, or Turner syndrome. [Invention 1115] The method of the present invention 1113, wherein the disease condition or state is Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorder, 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, flu syndrome, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette's syndrome, or vasculitis. [Invention 1116] The condition or state of the aforementioned disease is: ceruloplasmin deficiency, type II achondroplasia, achondroplasia, acrocephaly, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis, ALA dehydration deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydration deficiency, alkaptonuria, Alexander disease, alkaptonuric ocronosis, alpha-1 antitrypsin deficiency, alpha-1 proteinase inhibitors, emphysema, amyotrophic lateral sclerosis, Alström's syndrome. Group, Alexander disease, enamel hypoplasia, ALA dehydrase deficiency, Anderson-Fabri disease, androgen insensitivity syndrome, anemia, diffuse angiokeratoma, retinal hemangioma (von Hippel-Lindau disease), Apert syndrome, spider finger (Marfan syndrome), Stickler syndrome, congenital polyarthralgia (Ehlers-Danlos syndrome #arthralgia type), telangiectasia ataxia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Behle-Stevenson gyruform scalp syndrome, Mediterranean fever, familial, Benjamin syndrome, Beta-Sala Seminia bilateral acoustic neurofibromatosis (Type II neurofibromatosis), Factor V Leiden thrombosis, Bloch-Salzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnewi-Ulrich syndrome (Turner syndrome), Brunneville disease (tubular sclerosis), prion disease, Birt-Hogg-Dube syndrome, osteoporosis (osteogenesis imperfecta), broad thumb-toe syndrome (Rubinstein-Taybe syndrome), bronze diabetes / bronze cirrhosis (hemochromatosis), medullary spinal muscular atrophy (Kennedy disease), Bürger-Glitz syndrome (lipoprotein lipase deficiency) (Oligopia), CGD (chronic granulomatous disease), flexor limb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat cry syndrome, CAVD (congenital absence of vas deferens), Kyler's cardiomyopathy (CBAVD), CEP (congenital erythropoiesis-porphyria), cystic fibrosis, congenital hypothyroidism, chondrodysplasia (achondroplasia), ostracogeal megaepiphysis, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, fatal osteodysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis), congenital erythropoiesis-porphyria,Congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, conotibial stem anomalous facies syndrome, Cooley's anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes' disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint malformations (Cruzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Cruschmann-Batten-Steinert syndrome (myotonic dystrophy), Behle-Stevenson gyrus-scalp syndrome, primary Hyperoxaluria, spondyloepiphysital dysplasia (Stradwick type), muscular dystrophy, Duchenne and Becker type (DBMD), degenerative neurological diseases including Usher syndrome, de Grouchy syndrome and Degerin-Sottas syndrome, developmental disorders, distal spinal muscular atrophy, type V, androgen insensitivity syndrome, diffuse globoid sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, short stature, erythrocytoproliferative protoporphyria, erythrocyte 5-aminolevulinic acid synthase deficiency, erythrocytoproliferative Porphyria, erythroproliferative protoporphyria, erythroproliferative uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, late-onset cutaneous porphyria, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), fibrocystic disease of the pancreas, fragile X syndrome, galactosemia, hereditary brain disorders, giant cell hepatitis (neonatal hemochromatosis), Grenblatt-Strandbury syndrome (pseudoxanthoma elastica), Günther's disease (congenital erythroproliferative porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, Hemophilia, myelohepatic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), androgen hyperplasia, 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 diseases including hyperoxaluria, Klinefelter syndrome, Kniist dysplasia, mottled dementia, Langer-Sardino achondroplasia,Ataxia with telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machad-Joseph disease, metabolic disorders including Kniist dysplasia, Marfan syndrome, motor disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenck syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney achondroplasia, Niemann-Pick disease, Noak syndrome (Pfeiffer syndrome), Osler-Weber-Landu disease, Peutz-Jegers syndrome, polycystic kidney disease, polyosteid fibrous dysplasia (McKune-Albright syndrome), Peutz-Jegers syndrome Garth syndrome, Prader-Lovehart-Willi syndrome, hemochromatosis, primary hyperuricemia (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary disease (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthoma elastica), Rb (retinoblastoma), neurofibromatosis type I, Recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, type 3 RFALS, Licker syndrome, Riley-Day syndrome, Lucy-Lewy syndrome, severe achondroplasia with growth retardation and acanthosis nigricans (SADDAN), Lie-Fraumeni syndrome, sarcoma, mammary gland, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis), SDAT, congenital SED (congenital spondyloepiphyseal dysplasia), Stradwick type SED (spondyloepiphyseal metaphysis dysplasia, Stradwick type), SEDc (congenital spondyloepiphyseal dysplasia) SEMD, Stradwick type (spondyloepiphyseal diaphysis). Acute dysplasia (Stradwick type), Sprinzen syndrome, cutaneous pigmentation disorder, Smith-Lemle-Oppitz syndrome, South African hereditary porphyria (atypical porphyria), infant-onset ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disorders, sausage-like neuropathy (hereditary neuropathy with a tendency toward compressive paralysis), Treacher Collins syndrome,The method of the present invention 1113 relates to Triple X syndrome, Trisomy 21 (Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease), Visual impairment and blindness (Alström syndrome), Floric disease, Waardenburg syndrome, Micro syndrome (Warburg Sjo Fledelius syndrome), Weissenbircher-Zweimüller syndrome, Wolf-Hirschhorn syndrome, Wolf's periodic disease, Weissenbircher-Zweimüller syndrome, and xeroderma pigmentosum. [Invention 1117] The method of the present invention 1113, wherein the disease is cancer. [Invention 1118] The aforementioned cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestines, breasts, cervix, colon, esophagus, head, kidneys, liver, lungs, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, and glioma. The method of the present invention 1117, which includes sarcomas such as astrocytoma, oligodendronoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and Schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. [Invention 1119] The method of the present invention 1117, wherein the cancer is T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell ALL, precursor B-cell lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML. [Invention 1120] The method of the present invention 1113, wherein the disease condition is HIV infection. [Invention 1121] The method of the present invention 1113, wherein the disease condition is HCV infection. [Invention 1122] A compound library comprising any of the compounds described in Invention 1001 to 1092. [Invention 1123] A method for screening a library of compounds according to the present invention 1122 for identifying compounds containing a target-directed moiety that recognizes a target protein related to a predetermined function of a cell, The step of incubating cells with a library of the compound; A step of monitoring a specific function of a cell; and Step 1: Identifying one or more compounds from the library that alter a predetermined function of a cell. Methods that include... [Invention 1124] The method of the present invention 1124, wherein several compounds that alter a predetermined function of a cell are identified; the cell is incubated with compounds from the group of compounds; the predetermined function of the cell is monitored; and a compound that alters the predetermined function of the cell is identified, the compound identified herein includes a target-directed moiety that recognizes the target protein related to the predetermined function. [Invention 1125] A method for degrading a target protein in a cell, comprising the step of exposing the cell to an effective amount of any of the compounds 1001 to 1092 of the present invention. [Invention 1126] A method for degrading a target protein in a patient who requires it, comprising the step of administering to the patient an effective amount of any compound from 1001 to 1092 of the present invention. [Invention 1127] The method of the present invention 1125, wherein the target protein is heat shock protein 90, kinase, phosphatase, MDM2, human BET bromodomain-containing protein, HDAC, human lysine methyltransferase, RAF receptor, FKBP, VEGF, aryl hydrocarbon receptor, androgen receptor, estrogen receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease, or acyl protein thioesterase 1 and / or 2. [Invention 1128] The method of the present invention 1126, wherein the target protein is heat shock protein 90, kinase, phosphatase, MDM2, human BET bromodomain-containing protein, HDAC, human lysine methyltransferase, RAF receptor, FKBP, VEGF, aryl hydrocarbon receptor, androgen receptor, estrogen receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease, or acyl protein thioesterase 1 and / or 2. [Invention 1129] Use of any of the compounds 1001 to 1092 of this invention in the first pharmaceutical application. [Invention 1130] Use of any compound from Invention 1001 to 1092 for regulating the protein activity of a target protein in a patient requiring such regulation, comprising the step of administering a certain amount of any compound from Invention 1001 to 1092 to the patient. [Invention 1131] The aforementioned target protein, Proteins involved in catalytic activity, aromatase activity, kinetic activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, and proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transporter activity, pathogenicity, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biodevelopmental activity, and translation regulator activity). The use of the present invention 1130 is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, and proteins directly involved in the integrative function of cells. [Invention 1132] The aforementioned target proteins include B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type 4, PDE IV phosphodiesterase type 4, PDE I, PDE II, PDE III, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, i.e., Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and similar, HIV 1 protease, HIV Integrase 1, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alpha R, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neukinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsome transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, glycine receptor, noradrenaline Selected from the group consisting of ion reuptake receptors, endothelin receptors, neuropeptide Y and receptors, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinases and AMP deaminases, purine receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferases, geranylgeranyltransferases, NGF TrkA receptors, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptors, integrin receptors, Her-21 neu, telomerase inhibitors, cytosolic phospholipase A2, and EGF receptor tyrosine kinases. Further protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium-releasing channel, chloride ion channel, acetyl-CoA carboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, and enolpyruvirshikimicate-phosphate synthase, as used in the invention 1130. [Invention 1133] Use of any compound 1001-1092 of the present invention for treating a disease condition or state in a patient in which dysregulation of protein activity is the cause of the disease condition or state. [Invention 1134] Use of Invention 1133, wherein the disease condition or state is asthma, multiple sclerosis, cancer, ciliary disorders, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, childhood steatorrhea, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromocysplasia, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease (PKD1) or PKD4 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, or Turner syndrome. [Invention 1135] Use of Invention 1133, wherein the disease condition or state is Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorder, 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, flu, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette's syndrome, or vasculitis. [Invention 1136] The condition or state of the aforementioned disease is: ceruloplasmin deficiency, type II achondroplasia, achondroplasia, acrocephaly, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis, ALA dehydration deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydration deficiency, alkaptonuria, Alexander disease, alkaptonuric ocronosis, alpha-1 antitrypsin deficiency, alpha-1 proteinase inhibitors, emphysema, amyotrophic lateral sclerosis, Alström's syndrome. Group, Alexander disease, enamel hypoplasia, ALA dehydrase deficiency, Anderson-Fabri disease, androgen insensitivity syndrome, anemia, diffuse angiokeratoma, retinal hemangioma (von Hippel-Lindau disease), Apert syndrome, spider finger (Marfan syndrome), Stickler syndrome, congenital polyarthralgia (Ehlers-Danlos syndrome #arthralgia type), telangiectasia ataxia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Behle-Stevenson gyruform scalp syndrome, Mediterranean fever, familial, Benjamin syndrome, Beta-Sala Seminia bilateral acoustic neurofibromatosis (Type II neurofibromatosis), Factor V Leiden thrombosis, Bloch-Salzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnewi-Ulrich syndrome (Turner syndrome), Brunneville disease (tubular sclerosis), prion disease, Birt-Hogg-Dube syndrome, osteoporosis (osteogenesis imperfecta), broad thumb-toe syndrome (Rubinstein-Taybe syndrome), bronze diabetes / bronze cirrhosis (hemochromatosis), medullary spinal muscular atrophy (Kennedy disease), Bürger-Glitz syndrome (lipoprotein lipase deficiency) (Oligopia), CGD (chronic granulomatous disease), flexor limb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat cry syndrome, CAVD (congenital absence of vas deferens), Kyler's cardiomyopathy (CBAVD), CEP (congenital erythropoiesis-porphyria), cystic fibrosis, congenital hypothyroidism, chondrodysplasia (achondroplasia), ostracogeal megaepiphysis, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, fatal osteodysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis), congenital erythropoiesis-porphyria,Congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, conotibial stem anomalous facies syndrome, Cooley's anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes' disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint malformations (Cruzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Cruschmann-Batten-Steinert syndrome (myotonic dystrophy), Behle-Stevenson gyrus-scalp syndrome, primary Hyperoxaluria, spondyloepiphysital dysplasia (Stradwick type), muscular dystrophy, Duchenne and Becker type (DBMD), degenerative neurological diseases including Usher syndrome, de Grouchy syndrome and Degerin-Sottas syndrome, developmental disorders, distal spinal muscular atrophy, type V, androgen insensitivity syndrome, diffuse globoid sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, short stature, erythrocytoproliferative protoporphyria, erythrocyte 5-aminolevulinic acid synthase deficiency, erythrocytoproliferative Porphyria, erythroproliferative protoporphyria, erythroproliferative uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, late-onset cutaneous porphyria, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), fibrocystic disease of the pancreas, fragile X syndrome, galactosemia, hereditary brain disorders, giant cell hepatitis (neonatal hemochromatosis), Grenblatt-Strandbury syndrome (pseudoxanthoma elastica), Günther's disease (congenital erythroproliferative porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, Hemophilia, myelohepatic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), androgen hyperplasia, 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 diseases including hyperoxaluria, Klinefelter syndrome, Kniist dysplasia, mottled dementia, Langer-Sardino achondroplasia,Ataxia with telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machad-Joseph disease, metabolic disorders including Kniist dysplasia, Marfan syndrome, motor disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenck syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney achondroplasia, Niemann-Pick disease, Noak syndrome (Pfeiffer syndrome), Osler-Weber-Landu disease, Peutz-Jegers syndrome, polycystic kidney disease, polyosteid fibrous dysplasia (McKune-Albright syndrome), Peutz-Jegers syndrome Garth syndrome, Prader-Lovehart-Willi syndrome, hemochromatosis, primary hyperuricemia (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary disease (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthoma elastica), Rb (retinoblastoma), neurofibromatosis type I, Recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, type 3 RFALS, Licker syndrome, Riley-Day syndrome, Lucy-Lewy syndrome, severe achondroplasia with growth retardation and acanthosis nigricans (SADDAN), Lie-Fraumeni syndrome, sarcoma, mammary gland, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis), SDAT, congenital SED (congenital spondyloepiphyseal dysplasia), Stradwick type SED (spondyloepiphyseal metaphysis dysplasia, Stradwick type), SEDc (congenital spondyloepiphyseal dysplasia) SEMD, Stradwick type (spondyloepiphyseal diaphysis). Acute dysplasia (Stradwick type), Sprinzen syndrome, cutaneous pigmentation disorder, Smith-Lemle-Oppitz syndrome, South African hereditary porphyria (atypical porphyria), infant-onset ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disorders, sausage-like neuropathy (hereditary neuropathy with a tendency toward compressive paralysis), Treacher Collins syndrome,Uses of Invention 1133 include Triple X syndrome, Trisomy 21 (Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease), Visual impairment and blindness (Alström syndrome), Floric disease, Waardenburg syndrome, Micro syndrome (Warburg Sjo Fledelius syndrome), Weissenbircher-Zweimüller syndrome, Wolf-Hirschhorn syndrome, Wolf's periodic disease, Weissenbircher-Zweimüller syndrome, and xeroderma pigmentosum. [Invention 1137] Use of the present invention 1133, wherein the disease is cancer. [Invention 1138] The aforementioned cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestines, breasts, cervix, colon, esophagus, head, kidneys, liver, lungs, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, and glioma. Uses of Invention 1137 include sarcomas such as astrocytoma, oligodendronoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. [Invention 1139] Use of Invention 1137, wherein the cancer is T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell ALL, precursor B-cell lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML. [Invention 1140] Use of the present invention 1133, wherein the disease condition is HIV infection. [Invention 1141] Use of the present invention 1133, wherein the disease condition is HCV infection. [Invention 1142] Use of any of the compounds 1001 to 1092 of this invention in a compound library. [Invention 1143] Use of any compound 1001 to 1092 of the present invention for degrading a target protein in a cell. [Invention 1144] The use of any compound 1001 to 1092 of the present invention for degrading a target protein in a patient who requires it. [Invention 1145] Use of Invention 1143 or 1144, wherein the target protein is heat shock protein 90, kinase, phosphatase, MDM2, human BET bromodomain-containing protein, HDAC, human lysine methyltransferase, RAF receptor, FKBP, VEGF, aryl hydrocarbon receptor, androgen receptor, estrogen receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease, or acyl protein thioesterase 1 and / or 2. Any one or more of these and / or other purposes of the present invention can be readily gathered from a routine scrutiny of the present invention described below. [Brief explanation of the drawing]

[0019] [Figure 1] (A) This shows that HIF-1α accumulation leads to transcriptional upregulation of genes involved in the hypoxic response, such as erythropoietin and VEGF. (B) Under normal oxygen conditions, HIF-1α is hydroxylated, recognized by VHL, ubiquitinated, and degraded by the proteasome, preventing transcriptional upregulation. [Figure 2] WaterLOGSY NMR spectroscopy shows that 3 binds to VHL, while L-Hyp or NAc-Hyp-NMe do not. [Figure 3]This image displays the key interaction between 15 and VHL. [Figure 4] The co-crystal structure at 2.9 Å of carbon 15 (the lightest gray carbon) bound to VHL indicates that this bond mimics that of the HIF-1α peptide (light gray carbon, pdb 1LM817). [Figure 5] The crystal structure of the complex (B) of V54BC apo (A) and 15 is shown. The Hyp-binding site residues (bars, yellow carbon) and conserved water molecules (red dots), as well as the superimposed electron density (2Fo-Fc) around 15 (bars, blue-green carbon) are shown in blue, with outlines at 1.2σ. The protein surface is shown in green with 50% transparency. [Figure 6] A and B show the activity of the individual compounds of the present invention in the VHL polarization / substitution test described. The compounds of the present invention are indicated by numbers at the top of each graph. A control compound is shown in Figure 15B and is provided as minimum polarization (maximum substitution) for comparison. The percentage of inhibition shown was determined by normalizing for maximum and minimum polarization and graphed against log[VL]. IC50 values ​​were determined for each overlapping measurement (n=9) using Prism 5 and then averaged to obtain the mean IC50 and the mean standard error (SEM). [Figure 7] A and B show the activity of the individual compounds of the present invention in the VHL polarization / substitution test described. The compounds of the present invention are indicated by numbers at the top of each graph. A control compound is shown in Figure 15B and is provided as minimum polarization (maximum substitution) for comparison. The percentage of inhibition shown was determined by normalizing for maximum and minimum polarization and graphed against log[VL]. IC50 values ​​were determined for each overlapping measurement (n=9) using Prism 5 and then averaged to obtain the mean IC50 and the mean standard error (SEM). [Figure 8]A and B show the activity of the individual compounds of the present invention in the VHL polarization / substitution test described. The compounds of the present invention are indicated by numbers at the top of each graph. A control compound is shown in Figure 15B and is provided as minimum polarization (maximum substitution) for comparison. The percentage of inhibition shown was determined by normalizing for maximum and minimum polarization and graphed against log[VL]. IC50 values ​​were determined for each overlapping measurement (n=9) using Prism 5 and then averaged to obtain the mean IC50 and the mean standard error (SEM). [Figure 9] A and B show the activity of the individual compounds of the present invention in the VHL polarization / substitution test described. The compounds of the present invention are indicated by numbers at the top of each graph. A control compound is shown in Figure 15B and is provided as minimum polarization (maximum substitution) for comparison. The percentage of inhibition shown was determined by normalizing for maximum and minimum polarization and graphed against log[VL]. IC50 values ​​were determined for each overlapping measurement (n=9) using Prism 5 and then averaged to obtain the mean IC50 and the mean standard error (SEM). [Figure 9A] A and B show the activity of the individual compounds of the present invention in the VHL polarization / substitution test described. The compounds of the present invention are indicated by numbers at the top of each graph. A control compound is shown in Figure 15B and is provided as minimum polarization (maximum substitution) for comparison. The percentage of inhibition shown was determined by normalizing for maximum and minimum polarization and graphed against log[VL]. IC50 values ​​were determined for each overlapping measurement (n=9) using Prism 5 and then averaged to obtain the mean IC50 and the mean standard error (SEM). [Figure 10]A and B show the activity of the individual compounds of the present invention in the VHL polarization / substitution test described. The compounds of the present invention are indicated by numbers at the top of each graph. A control compound is shown in Figure 15B and is provided as minimum polarization (maximum substitution) for comparison. The percentage of inhibition shown was determined by normalizing for maximum and minimum polarization and graphed against log[VL]. IC50 values ​​were determined for each overlapping measurement (n=9) using Prism 5 and then averaged to obtain the mean IC50 and the mean standard error (SEM). [Figure 11] A and B show the activity of the individual compounds of the present invention in the VHL polarization / substitution test described. The compounds of the present invention are indicated by numbers at the top of each graph. A control compound is shown in Figure 15B and is provided as minimum polarization (maximum substitution) for comparison. The percentage of inhibition shown was determined by normalizing for maximum and minimum polarization and graphed against log[VL]. IC50 values ​​were determined for each overlapping measurement (n=9) using Prism 5 and then averaged to obtain the mean IC50 and the mean standard error (SEM). [Figure 12] A and B show the activity of the individual compounds of the present invention in the VHL polarization / substitution test described. The compounds of the present invention are indicated by numbers at the top of each graph. A control compound is shown in Figure 15B and is provided as minimum polarization (maximum substitution) for comparison. The percentage of inhibition shown was determined by normalizing for maximum and minimum polarization and graphed against log[VL]. IC50 values ​​were determined for each overlapping measurement (n=9) using Prism 5 and then averaged to obtain the mean IC50 and the mean standard error (SEM). [Figure 13-1] (Table 2 - along with affinity tables) shows many exemplary compounds of the present invention. [Figure 13-2] Figure 13-2 is a continuation of Figure 13-1. [Figure 13-3] Figure 13-3 is a continuation of Figure 13-2. [Figure 13-4] Figure 13-4 is a continuation of Figure 13-3. [Figure 14-1] Many preferred compounds from Table 2 of the present invention are shown. [Figure 14-2] Figure 14-2 is a continuation of Figure 14-1. [Figure 14-3] Figure 14-3 is a continuation of Figure 14-2. [Figure 14-4] Figure 14-4 is a continuation of Figure 14-3. [Figure 14-5] Figure 14-5 is a continuation of Figure 14-4. [Figure 14-6] Figure 14-6 is a continuation of Figure 14-5. [Figure 14-7] Figure 14-7 is a continuation of Figure 14-6. [Figure 14-8] Figure 14-8 is a continuation of Figure 14-7. [Figure 14-9] Figure 14-9 is a continuation of Figure 14-8. [Figure 14-10] Figure 14-10 is a continuation of Figure 14-9. [Figure 14-11] Figure 14-11 is a continuation of Figure 14-10. [Figure 15-1] Further compounds of the present invention and their activities are shown. Most compounds are active at concentrations of less than 100 μM. [Figure 15-2] Figure 15-2 is a continuation of Figure 15-1. [Figure 15-3] Figure 15-3 is a continuation of Figure 15-2. [Figure 15-4] Figure 15-4 is a continuation of Figure 15-3. [Figure 15-5] Figure 15-5 is a continuation of Figure 15-4. [Figure 15-6] Figure 15-6 is a continuation of Figure 15-5. [Figure 15-7] Figure 15-7 is a continuation of Figure 15-6. [Figure 15-8] Figure 15-8 is a continuation of Figure 15-7. [Figure 15-9] Figure 15-9 is a continuation of Figure 15-8. [Figure 15-10] Figure 15-10 is a continuation of Figure 15-9. [Figure 15-11] Figure 15-11 is a continuation of Figure 15-10. [Figure 15-12] Figure 15-12 is a continuation of Figure 15-11. [Figure 15-13] Figure 15-13 is a continuation of Figure 15-12. [Figure 15-14] Figure 15-14 is a continuation of Figure 15-13. [Figure 15-15] Figure 15-15 is a continuation of Figure 15-14. [Figure 15-16] Figure 15-16 is a continuation of Figure 15-15. [Figure 15-17] Figure 15-17 is a continuation of Figure 15-16. [Figure 15-18] Figure 15-18 is a continuation of Figure 15-17. [Figure 15-19] Figure 15-19 is a continuation of Figure 15-18. [Figure 15-20] Figure 15-20 is a continuation of Figure 15-19. [Figure 15-21] Figure 15-21 is a continuation of Figure 15-20. [Figure 15-22] Figure 15-22 is a continuation of Figure 15-21. [Figure 15-23] Figure 15-23 is a continuation of Figure 15-22. [Figure 15-24] Figure 15-24 is a continuation of Figure 15-23. [Figure 15-25] Figure 15-25 is a continuation of Figure 15-24. [Figure 15-26] Figure 15-26 is a continuation of Figure 15-25. [Figure 15-27] Figure 15-27 is a continuation of Figure 15-26. [Figure 15-28] Figure 15-28 is a continuation of Figure 15-27. [Figure 15-29] Figure 15-29 is a continuation of Figure 15-28. [Figure 15-30] Figure 15-30 is a continuation of Figure 15-29. [Figure 15-31] Figure 15-31 is a continuation of Figure 15-30. [Figure 15-32] Figure 15-32 is a continuation of Figure 15-31. [Figure 15-33] Figure 15-33 is a continuation of Figure 15-32. [Figure 15-34] Figure 15-34 is a continuation of Figure 15-33. [Figure 15-35] Figure 15-35 is a continuation of Figure 15-34. [Figure 15-36] Figure 15-36 is a continuation of Figure 15-35. [Figure 15-37] Figure 15-37 is a continuation of Figure 15-36. [Figure 15-38] Figure 15-38 is a continuation of Figure 15-37. [Figure 15-39] Figure 15-39 is a continuation of Figure 15-38. [Figure 15-40] Figure 15-40 is a continuation of Figure 15-39. [Figure 15-41] Figure 15-41 is a continuation of Figure 15-40. [Figure 15-42] Figure 15-42 is a continuation of Figure 15-41. [Figure 15-43] Figure 15-43 is a continuation of Figure 15-42. [Figure 15-44] Figure 15-44 is a continuation of Figure 15-43. [Figure 15-45] Figure 15-45 is a continuation of Figure 15-44. [Figure 15-46] Figure 15-46 is a continuation of Figure 15-45. [Figure 15-47] Figure 15-47 is a continuation of Figure 15-46. [Figure 15-48] Figure 15-48 is a continuation of Figure 15-47. [Figure 15-49] Figure 15-49 is a continuation of Figure 15-48. [Figure 15-50] Figure 15-50 is a continuation of Figure 15-49. [Figure 15-51] Figure 15-51 is a continuation of Figure 15-50. [Figure 15-52] Figure 15-52 is a continuation of Figure 15-51. [Figure 15-53] Figure 15-53 is a continuation of Figure 15-52. [Figure 15-54] Figure 15-54 is a continuation of Figure 15-53. [Figure 15-55] Figure 15-55 is a continuation of Figure 15-54. [Figure 15-56] Figure 15-56 is a continuation of Figure 15-55. [Figure 15-57] Figure 15-57 is a continuation of Figure 15-56. [Figure 15-58] Figure 15-58 is a continuation of Figure 15-57. [Figure 15-59] Figure 15-59 is a continuation of Figure 15-58. [Figure 15-60] Figure 15-60 is a continuation of Figure 15-59. [Figure 15-61] Figure 15-61 is a continuation of Figure 15-60. [Figure 15-62] Figure 15-62 is a continuation of Figure 15-61. [Figure 16-1] The present invention shows many preferred compounds from Figure 15. [Figure 16-2] Figure 16-2 is a continuation of Figure 16-1. [Figure 16-3] Figure 16-3 is a continuation of Figure 16-2. [Figure 16-4] Figure 16-4 is a continuation of Figure 16-3. [Figure 16-5] Figure 16-5 is a continuation of Figure 16-4. [Figure 16-6] Figure 16-6 is a continuation of Figure 16-5. [Figure 16-7] Figure 16-7 is a continuation of Figure 16-6. [Figure 16-8] Figure 16-8 is a continuation of Figure 16-7. [Figure 17-1] The present invention is shown in Figure 15, which contains eight particularly preferred compounds. [Figure 17-2] Figure 17-2 is a continuation of Figure 17-1. [Figure 18-1] The present invention presents six preferred compounds, each containing an estrogen-binding protein targeting moiety linked to a preferred ubiquitin ligand-binding moiety. [Figure 18-2] Figure 18-2 is a continuation of Figure 18-1. [Figure 19-1] The following are preferred compounds of the present invention. [Figure 19-2] Figure 19-2 is a continuation of Figure 19-1. [Figure 19-3] Figure 19-3 is a continuation of Figure 19-2. [Figure 19-4] Figure 19-4 is a continuation of Figure 19-3. [Modes for carrying out the invention]

[0020] Summary of the Invention This invention is based on the discovery that once a ubiquitin pathway protein and a target protein are positioned in close proximity, the ubiquitin pathway protein ubiquitinates any target protein by forming a chimeric construct that binds the ubiquitin pathway protein and the target protein. Therefore, this invention provides compositions that result in the ubiquitination of a selected target protein. This invention also provides a library of compositions and their use.

[0021] In one embodiment, the present invention provides a composition useful for regulating protein activity. The composition comprises a ubiquitin pathway protein-binding moiety of a defined chemical structure (preferably for an E3 ubiquitin ligase alone or in a complex with an E2 ubiquitin-conjugating enzyme responsible for the transfer of ubiquitin to a target protein) and a protein target-directing moiety linked together, preferably via a linker, where the ubiquitin pathway protein-binding moiety recognizes a ubiquitin pathway protein, the target-directing moiety recognizes a target protein, and the ubiquitin pathway protein-binding moiety is bound to the target-directing moiety.

[0022] In another embodiment, the present invention provides a library of compounds comprising a plurality of compounds, each composition having the formula A, B, where A is a ubiquitin pathway protein-binding moiety (preferably an E3 ubiquitin ligase moiety as otherwise disclosed herein), and B is a protein-binding member of the molecular library, where A is bound to B (preferably through a linker moiety), and where the ubiquitin pathway protein-binding moiety recognizes ubiquitin pathway proteins, particularly E3 ubiquitin ligase. In a particular embodiment, the library comprises a VHL-specific ubiquitination-recognizing peptide for E3 ubiquitin ligase (a ubiquitin pathway protein-binding moiety as otherwise disclosed herein), together with a random target protein-binding element (e.g., a chemical compound library). Thus, the target protein is not predetermined, and the method can be used to determine the activity of the putative protein-binding element and its pharmacological value as a target after degradation by ubiquitin ligase.

[0023] In yet another embodiment, the present invention provides a method for screening a library of the present invention to identify compounds comprising a target-directed moiety that recognizes a target protein related to a predetermined function of a cell. The method comprises the steps of: incubating cells with a pool of entities from the library; monitoring a predetermined function of the cells; identifying a pool of entities that alter the predetermined function of the cells; incubating cells with compositions from the identified pool of entities; monitoring a predetermined function of the cells; and identifying compositions that alter the predetermined function of the cells, wherein the identified compositions comprise a target-directed moiety that recognizes a target protein related to the predetermined function.

[0024] In another embodiment, the present invention provides a method for screening a library of the present invention to identify compositions comprising a target-directed moiety that recognizes a target protein related to a predetermined function of a cell. The method comprises the steps of: incubating cells with each composition from the library; monitoring a predetermined function of the cell; and identifying compositions that alter the predetermined function of the cell; and the compositions identified herein comprising a target-directed moiety that recognizes a target protein related to the predetermined function.

[0025] In yet another embodiment, the present invention provides a method for identifying target proteins associated with a particular function of a cell. The method comprises the steps of: incubating cells with compositions from the library of the present invention; monitoring a particular function of the cell; identifying compositions that alter a particular function of the cell; and identifying target proteins that bind to the identified compositions, where the target proteins are associated with a particular function of the cell.

[0026] In yet another embodiment, the present invention provides a method for identifying a target protein associated with a predetermined function of a cell. The method comprises the steps of: incubating a cell with a pool of entities from the library of the present invention; monitoring a predetermined function of the cell; identifying a pool of entities that alter the predetermined function of the cell; incubating the cell with a composition from the identified pool of entities; monitoring a predetermined function of the cell; identifying a composition that alters the predetermined function of the cell; and identifying a target protein that binds to the identified composition, wherein the target protein is associated with a predetermined function of the cell.

[0027] In yet another embodiment, the present invention provides a method for ubiquitinating / degrading a target protein in cells. The method comprises the step of administering a bifunctional composition comprising a ubiquitin pathway protein-binding moiety and a target-directing moiety, preferably linked via a linker moiety, as otherwise described herein, wherein the ubiquitin pathway protein-binding moiety is bound to the target-directing moiety, such that when the target protein is positioned in close proximity to a ubiquitin ligase, degradation of the target protein occurs, thus resulting in degradation / inhibition of its effects and control of protein levels, where the ubiquitin pathway protein-binding moiety recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably E3 ubiquitin ligase) and the target-directing moiety recognizes the target protein. The control of protein levels according to the present invention provides treatment for a disease situation or condition regulated through a target protein by lowering its level in the patient's cells.

[0028] In another embodiment, the present invention aims to provide a method for treating a patient in need of a disease condition or state regulated through a protein, wherein the degradation of the protein produces a therapeutic effect in the patient, the method comprising the step of administering an effective amount of the compound of the present invention to the patient in need, optionally in combination with another bioactive agent. The disease condition or state may be a disease caused by a microbial factor or other exogenous factor, such as a virus, bacteria, fungus, protozoan or other microorganism, or a disease condition caused by the overexpression of a protein that leads to the disease condition and / or state.

[0029] In one aspect, the present invention aims to provide compounds having the following structure: In formula TIFF0007898835000290.tif10128, L is a linker group, and TIFF0007898835000291.tif10128 is the ubiquitin ligase binding portion, where the linker group is optional. It is further connected to TIFF0007898835000292.tif10128 units.

[0030] In another embodiment, the present invention has the following general structure The purpose is to obtain compounds containing the TIFF0007898835000293.tif10128 group, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs thereof: TIFF0007898835000294.tif15128In formula, TIFF0007898835000295.tif10128 is a ligand that binds to a ubiquitin ligase, preferably a ubiquitin ligase, preferably an E3 ubiquitin ligase; TIFF0007898835000296.tif10128 binds to a target protein or polypeptide that is ubiquitinated by a ubiquitin ligase. TIFF0007898835000297.tif10128 is a chemical moiety (protein target-directed moiety) that is chemically linked to the base directly or through linker moiety L, or TIFF0007898835000298.tif11128 is instead the same ubiquitin ligase binding site. This is TIFF0007898835000299.tif10128, and this is TIFF0007898835000300.tif10128 may be the same as or different from the same unit. TIFF0007898835000301.tif10128 is connected directly to the base or through the linker portion; and L may or may not exist. This is the linker portion that is chemically (covalently) bonded to TIFF0007898835000302.tif11128.

[0031] TIFF0007898835000303.tif10128 is In a particular aspect of the present invention, the compound is a TIFF0007898835000304.tif10128 group, and the compound is similar to a dimer compound in which both ends of the compound contain ubiquitin ligase binding sites as otherwise described herein.

[0032] In a preferred aspect of the present invention, TIFF0007898835000305.tif10128 and, if present TIFF0007898835000306.tif10128 is independently one of the following chemical structures, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: TIFF0007898835000307.tif41128In formula, R 1' C1-C6 alkyl groups may be substituted, and -(CH2) may be substituted. n OH may be substituted -(CH2) n SH may be substituted (CH2). n-O-(C1~C6) alkyl group, containing an epoxide moiety WCOCW in which each W is independently either H or a C1~C3 alkyl group, which may be substituted (CH2) n -WCOCW-(C0~C6) alkyl group, may be substituted-(CH2) n COOH may be substituted -(CH2) n C(O)-(C1~C6 alkyl), may be substituted-(CH2) n NHC(O)-R1, may be substituted with -(CH2). n C(O)-NR1R2, may be substituted with -(CH2) n OC(O)-NR1R2, -(CH2O) n H may be substituted - (CH2) n OC(O)-(C1~C6 alkyl), may be substituted-(CH2) n C(O)-O-(C1~C6 alkyl), may be substituted-(CH2O) n COOH may be substituted - (OCH2) n O-(C1~C6 alkyl), may be substituted -(CH2O) n C(O)-(C1~C6 alkyl), may be substituted-(OCH2) n NHC(O)-R1, may be substituted with -(CH2O) n C(O)-NR1R2, -(CH2CH2O) n H may be substituted -(CH2CH2O) n COOH may be substituted - (OCH2CH2) n O-(C1~C6 alkyl), may be substituted -(CH2CH2O) n C(O)-(C1~C6 alkyl), may be substituted-(OCH2CH2) n NHC(O)-R1, may be substituted with -(CH2CH2O) n C(O)-NR1R2, may be substituted with -SO2R S S(O)R may be substituted. S , NO2, CN, or halogen (F, Cl, Br, I, preferably F or Cl); R1 and R2 are each independently C1-C6 alkyl groups which may be substituted with H, one or two hydroxyl groups, or up to three halogen groups (preferably fluorine); R S C1-C6 alkyl groups, optionally substituted aryl, heteroaryl or heterocyclic groups, or -(CH2) m It has two NR1R units, X and X' are independently C=O, C=S, -S(O), and S(O)2, respectively (preferably both X and X' are C=O); R 2' (CH2) may be substituted. n -(C=O) u (NR1) v (SO2) w Alkyl group, may be substituted - (CH2) n -(C=O) u (NR1) v (SO2) w NR 1N R 2N The base may be substituted - (CH2) n -(C=O) u (NR1) v (SO2) w -aryl, may be substituted-(CH2) n -(C=O) u (NR1) v (SO2) w -Heteroaryl, may be substituted-(CH2) n -(C=O) v NR1(SO2) w -Hybrid algebras, may be substituted-NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, may be substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N -NR may be substituted1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N -NR may be substituted 1 -(CH2) n -(C=O) u (NR1) v (SO2) w -aryl, may be substituted -NR 1 -(CH2) n -(C=O) u (NR1) v (SO2) w - Heteroaryl or possibly substituted - NR 1 -(CH2) n -(C=O) v NR1(SO2) w -Hybrid algebra, may be permuted -X R2' -alkyl group; may be substituted -X R2' -Aryl group; may be substituted -X R2' -heteroaryl group; may be substituted -X R2' -It is a heterocyclic ring group; it may be substituted; R 3' is an optionally substituted alkyl group, or optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -Alkyl, may be substituted-(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , may be substituted - (CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , may be substituted - (CH2) n -C(O) u (NR1) v (SO2) w-C(O)NR1R2, may be substituted -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, may be substituted-(CH2) n -C(O) u (NR1) v (SO2) w -Heteroaryl, may be substituted-(CH2) n -C(O) u (NR1) v (SO2) w -Hybrid algebras, may be substituted-NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, may be substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N -NR may be substituted 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N -NR may be substituted 1 -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, may be substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, may be substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -Heterogeneous ring, may be substituted -O-(CH2)n-(C=O) u (NR1)v (SO2) w -alkyl, may be substituted -O-(CH2)n-(C=O) u (NR1) v (SO2) w -NR 1N R 2N -O-(CH2)n-(C=O) may be substituted. u (NR1) v (SO2) w -NR1C(O)R 1N -O-(CH2)n-(C=O) may be substituted. u (NR1) v (SO2) w -aryl, may be substituted -O-(CH2) n -(C=O) u (NR1) v (SO2) w -Heteroaryl or possibly substituted-O-(CH2) n -(C=O) u (NR1) v (SO2) w -Hybrid algebra;-(CH2) n -(V) n' -(CH2) n -(V) n' -Alkyl alkyl group, may be substituted-(CH2) n -(V) n' -(CH2) n -(V) n' -Aryl group, may be substituted-(CH2) n -(V) n' -(CH2) n -(V) n' -Heteroaryl group, may be substituted-(CH2) n -(V) n' -(CH2) n -(V) n' -Heterocyclic group, may be substituted-(CH2) n -N(R 1' )(C=O) m' -(V) n' -Alkyl alkyl group, may be substituted-(CH2) n -N(R 1' )(C=O)m' -(V) n' -Aryl group, may be substituted-(CH2) n -N(R 1' )(C=O) m' -(V) n' -Heteroaryl group, may be substituted-(CH2) n -N(R 1' )(C=O) m' -(V) n' -Heterocyclic group, may be substituted-X R3' -alkyl group; may be substituted -X R3' -Aryl group; may be substituted -X R3' -heteroaryl group; may be substituted -X R3' -It is a heterocyclic ring group; it may be substituted; Here R 1N and R 2N Each of these is independently a C1-C6 alkyl group which may be substituted with H, one or two hydroxyl groups and up to three halogen groups, or a substituted -(CH2) group. n -Aryl, -(CH2) n -heteroaryl or -(CH2) n -It is a heterocyclic ring group; V is O, S, or NR1; R1 is the same as above; R 1 and R 1' Each of these is independently either H or a C1-C3 alkyl group; X R2' and X R3' These may each be substituted independently (-CH2) n -, -CH2) n -CH(X v )=CH(X v )-(Sys or Trans), -CH2) n -CH≡CH-, -(CH2CH2O) n -or a C3-C6 cycloalkyl group, where X v is H, halo, or an optionally substituted C1-C3 alkyl group; Each m is independently 0, 1, 2, 3, 4, 5, 6; Each m' is independently either 0 or 1; Each n is independently 0, 1, 2, 3, 4, 5, or 6; Each n' is independently either 0 or 1; Each u is independently either 0 or 1; Each v is independently either 0 or 1; Each w is independently either 0 or 1; and Here If it is not TIFF0007898835000308.tif11128, R of TIFF0007898835000309.tif11128 1' , R 2' , R 3' Any one or more of X and X' are transmitted through the linker group. TIFF0007898835000310.tif10128 Modified to covalently bond to a group, or When it is TIFF0007898835000311.tif11128, Each R of TIFF0007898835000312.tif13128 1' , R 2' , R 3' Any one or more of X and X' are modified to be covalently bonded to each other directly or through linker groups.

[0033] In another aspect of the present invention, TIFF0007898835000313.tif10128 and, if present TIFF0007898835000314.tif10128 is independently a base of the following chemical structures, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof: TIFF0007898835000315.tif51128In formula, R 1' , R 2' and R 3' Each of them is the same as above, and X is C=O, C=S, -S(O) group or S(O)2 group, more preferably C=O group, and Here If it is not TIFF0007898835000316.tif12128, R 1' , R 2' and R 3' Any one or more of these are TIFF0007898835000317.tif10128 is modified to bond to a linker group that is further covalently bonded to the group, or When it is TIFF0007898835000318.tif11128, Each R of TIFF0007898835000319.tif12128 1' , R 2' , R 3' Any one or more of these are modified to be covalently bonded to each other directly or through linker groups.

[0034] In a more preferred aspect of the present invention, TIFF0007898835000320.tif10128 and, if present TIFF0007898835000321.tif10128 is independently one of the following chemical structures, or their pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs: TIFF0007898835000322.tif51128 expression If it is not TIFF0007898835000323.tif12128, R 1' , R 2' and R 3' Any one or more of these are TIFF0007898835000324.tif10128 is modified to bond to a linker group that is further covalently bonded to the group, or When it is TIFF0007898835000325.tif12128, Each R of TIFF0007898835000326.tif11128 1' , R 2' , R 3' Any one or more of these are modified to be covalently bonded to each other directly or through linker groups.

[0035] In a more preferred aspect of the present invention, R 1' Preferably, is a hydroxyl group or a group that can be metabolized to a hydroxyl or carboxyl group such that the compound is a prodrug of the active compound. Exemplary preferred R 1' The base is, for example, -(CH2) n OH, (CH2) n -O-(C1~C6) alkyl group, -(CH2) n COOH, -(CH2O) n H may be substituted - (CH2) n OC(O)-(C1~C6 alkyl), or possibly substituted-(CH2) n It contains C(O)-O-(C1~C6 alkyl), where n is 0 or 1. 1' If is a carboxylic acid group, a hydroxyl group, or an amine group, or contains one of these, the hydroxyl group, carboxylic acid group, or amine (each of which may be substituted) TIFF0007898835000327.tif10128 groups ( Further chemical modifications may be made to provide a covalent bond to the linker group to which the TIFF0007898835000328.tif10128 group is bonded.

[0036] X and, if present, X' are preferably C=O, C=S, -S(O) group or S(O)2 group, more preferably C=O group.

[0037] R 2' -NR may preferably be substituted. 1 -T-aryl, may be substituted with -NR 1 -T-heteroaryl group or possibly substituted -NR 1 -T- is a complex algebra, where R 1 is H or CH3, preferably H, and T may be substituted -(CH2) n- is a group, where each methylene group may be substituted with one or two substituents, preferably selected from halogens, amino acid side chains as otherwise described herein, or optionally substituted C1-C3 alkyl groups, preferably one or two methyl groups; and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1. Or, T is -(CH2O) n -group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n -These may be groups, and all of them may be substituted.

[0038] R 2' The preferred aryl group for this purpose includes a substituted phenyl or naphthyl group, preferably a phenyl group, where the phenyl group is TIFF0007898835000329.tif11128 groups ( Linker group to which a TIFF0007898835000330.tif10128 group is attached, halogen (preferably F or Cl), amine, monoalkyl- or dialkylamine (preferably dimethylamine), F, Cl, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN group (each of which may be substituted at the ortho, meta and / or para, preferably para, position of the phenyl ring), optionally substituted phenyl group (the phenyl group itself is preferably Includes TIFF0007898835000331.tif10128 units TIFF0007898835000332.tif10128 Linker group bonded to the group and / or at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (substituted at the ortho, meta, and / or para, preferably para, position of the phenyl ring), naphthyl group, which may be substituted, or a substituted heteroaryl, preferably a substituted isoxazole including a methyl-substituted isoxazole, a substituted oxazole including a methyl-substituted oxazole, a substituted thiazole including a methyl-substituted thiazole, a substituted isothiazole including a methyl-substituted isothiazole, a substituted pyrrole including a methyl-substituted pyrrole, methylimidazole, or a substituted benzimidazole Alternatively, methoxybenzylimidazole, optionally substituted imidazoles including optionally substituted oximidazole or methyloximidazole, optionally substituted diazole groups including a methyldiazole group, optionally substituted triazole groups including a methyl-substituted triazole group, optionally substituted pyridine groups including a halo (preferably F) or a methyl-substituted pyridine group or oxapyridine group (where the pyridine group is oxygen-linked to the phenyl group), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indidine or azaindridine (2, 3, or 4-azandridine), optionally substituted quinoline, optionally substituted groups of the following chemical structures: TIFF0007898835000333.tif102161In formula, S c is CHR SS , NR URE , or O; R HETThe group is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE The group is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), and each of these groups is substituted with one or two hydroxyl groups or up to three halogens, preferably a fluorine group, or an optionally substituted phenyl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycle, preferably, for example, piperidine, morpholine, pyrrolidine, or tetrahydrofuran. R PROThe group is H, a substituted C1-C6 alkyl group or an substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of H, an optionally substituted C1-C6 alkyl group, or an oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably with a methyl or halo group, preferably with F or Cl), benzofuran, indole, indidine, and azaindidine; R PRO1 and R PRO2 Each is independently H, an optionally substituted C1-C3 alkyl group, or together forms a keto group; and Each n is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), or The heterocycle may be substituted, preferably with tetrahydrofuran, tetrahydrothiene, piperidine, piperazine or morpholine (each of these groups, if substituted, preferably with methyl or halo(F,Br,Cl)), Each of those bases TIFF0007898835000334.tif10128 groups ( It may be substituted with a linker group to which a TIFF0007898835000335.tif10128 group is bonded.

[0039] In certain favorable situations, TIFF0007898835000336.tif41128 is It is TIFF0007898835000337.tif31128 units, R in the formula PRO And n is the same as above.

[0040] R 2'Preferred heteroaryl groups for this include optionally substituted quinoline (which may be bonded to a pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole, optionally substituted indolinidine, optionally substituted azaindolinidine, optionally substituted benzofuran, optionally substituted isoxazole, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted thiophene, optionally substituted pyridine (2-, 3-, or 4-pyridine), optionally substituted imidazole, optionally substituted pyrrole, optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted oxyimidazole, or groups with the following chemical structures: TIFF0007898835000338.tif92142, S c is CHR SS , NR URE , or O; R HET The group is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R SSis H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), and each of these groups may be substituted with one or two hydroxyl groups or up to three halogens, preferably a fluorine group, or a substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, or piperazine, and each of these may be substituted, and Y C is N or CR YC And here R YC The group is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group), Each of those bases TIFF0007898835000339.tif10128 groups ( It may be substituted with a linker group to which a TIFF0007898835000340.tif10128 group is bonded;

[0041] R 2'Preferred heterocyclic groups for this include tetrahydrofuran, tetrahydrothien, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane, or thian, each of which may be substituted, or a group of the following chemical structure: TIFF0007898835000341.tif40128 Preferably, TIFF0007898835000342.tif27128 units are included, In the formula, R PRO is H, an optionally substituted C1-C6 alkyl or optionally substituted aryl, heteroaryl or heterocyclic group; R PRO1 and R PRO2 Each is independently H, an optionally substituted C1-C3 alkyl group, or together they form a keto group, Each n is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1), and each of those bases is TIFF0007898835000343.tif10128 groups ( It may be substituted with a linker group to which a TIFF0007898835000344.tif10128 group is bonded.

[0042] Preferred R for use in the present invention 2' The substituents include R found in particular (and not limited to the specific compounds disclosed herein) the identified compounds disclosed herein (including the specific compounds disclosed herein and in the accompanying drawings) 2' This also includes substituents. These R 2' Each substituent is also any number of R as disclosed herein. 3' It may be used with substituents.

[0043] R 3' Preferably, -T-aryl, -T-heteroaryl, -T-heterocyclic, or -NR 1 -T-aryl, may be substituted with -NR1 -T-heteroaryl or optionally substituted -NR 1 -T-is a heterocyclic ring, where R 1 is H or a C1-C3 alkyl group, preferably H or CH3, and T is an optionally substituted -(CH2) n -group, where each of the methylene groups is preferably substituted with one or two substituents selected from halogen, an optionally substituted C1-C3 alkyl group or the side chain of an amino acid described separately herein, preferably methyl; and n is from 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1. Alternatively, T is -(CH2O) n -group, -(OCH2) n -group, -(CH2CH2O) n -group, -(OCH2CH2) n -group, and each of those groups may be substituted.

[0044] R 3' Preferred aryl groups for include an optionally substituted phenyl or naphthyl group, preferably a phenyl group, where the phenyl or naphthyl group is TIFF0007898835000345.tif10128 groups ( TIFF0007898835000346.tif10128 groups included), a linker group to which they are attached, and / or halogen (preferably F or Cl), amine, monoalkyl- or dialkylamine (preferably, dimethylamine), amide group (preferably -(CH2) m -NR1C(O)R2 group, where m, R1 and R2 are the same as above), halo (often F or Cl), OH, CH3, CF3, OMe, OCF3, NO2, CN or S(O)2R S group (R S is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl or heterocyclic group or -(CH2) mThe substituted phenyl group is an NR1R2 group, each of which may be substituted at the ortho, meta, and / or para position of the phenyl ring, preferably at the para position), or may be substituted with an aryl (preferably phenyl), heteroaryl, or heterocyclic group. Preferably, the substituted phenyl group is an optional phenyl group (i.e., the substituted phenyl group itself is preferably F, Cl, OH, SH, COOH, CH3, CF3, OMe, OCF3, NO2, CN or TIFF0007898835000347.tif10128 groups ( TIFF0007898835000348.tif10128 (including the group) is substituted at least one linker group to which it is bonded, where the substitution occurs at the ortho, meta and / or para positions of the phenyl ring, preferably at the para position), naphthyl group, which may be substituted, including the aforementioned, and may be substituted heteroaryl (preferably methyl-substituted isoxazole, methyl-substituted oxazole, methyl-substituted thiazole, methyl-substituted pyrrole, methyl-substituted pyrrole, methylimidazole) Zole, benzimidazole or methoxybenzylimidazole, oxyimidazole or methyloxyimidazole, optionally substituted diazole groups including a methyldiazole group, optionally substituted triazole groups including a methyl-substituted triazole group, pyridine groups including a halo (preferably F) or methyl-substituted pyridine group or oxapyridine group (where the pyridine group is linked to the phenyl group by oxygen), or optionally substituted heterocyclic groups (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane, or thian). Each of the aryl, heteroaryl, or heterocyclic groups is TIFF0007898835000349.tif10128 groups ( It may be substituted with a linker group to which a TIFF0007898835000350.tif10128 group is bonded.

[0045] R 3' Preferred heteroaryl groups for this include optionally substituted quinoline (which may be bonded to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indidine, optionally substituted azaindidine (2,3 or 4-azindidine), optionally substituted benzimidazole, benzodiazole, benzoxofran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl-substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or thiol-substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl group, triisopropylsilyl group, optionally substituted -(CH2) m -O-C1~C6 alkyl groups or possibly substituted-(CH2) m It contains a group of -C(O)-O-C1~C6 alkyl group substituted with 1,2,3-triazole, optionally substituted pyridine (2-, 3-, or 4-pyridine), or the following chemical structures: TIFF0007898835000351.tif91141In formula, S c is CHR SS , NR URE , or O; R HET The group is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R ais H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), and each of these groups may be substituted with one or two hydroxyl groups or up to three halogens, preferably a fluorine group, or a substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, or piperazine, and each of these may be substituted, and Y C is N or CR YC And here R YC The group is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). Each of the heteroaryl groups is TIFF0007898835000352.tif10128 groups ( It may be substituted with a linker group to which a TIFF0007898835000353.tif10128 group is bonded.

[0046] R 3' Preferred heterocyclic groups for this include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane, and thian, each of which may be substituted or have the following chemical structures: TIFF0007898835000354.tif42128 Preferably, TIFF0007898835000355.tif26128 units are included, In the formula, R PRO The group is H, a substituted C1-C6 alkyl group or an substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of H, an optionally substituted C1-C6 alkyl group, or an oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably with a methyl or halo group, preferably with F or Cl), benzofuran, indole, indidine, and azaindidine; R PRO1 and R PRO2 Each is independently H, an optionally substituted C1-C3 alkyl group, or together they form a keto group, Each n is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), where each of the heterocyclic groups is TIFF0007898835000356.tif10128 groups ( It may be substituted with a linker group to which a TIFF0007898835000357.tif10128 group is bonded.

[0047] Preferred R for use in the present invention 3'The substituents include R found in particular (and not limited to the specific compounds disclosed herein) the identified compounds disclosed herein (including the specific compounds disclosed herein and in the accompanying drawings) 3' This also includes substituents. These R 3' Each substituent is also any number of R as disclosed herein. 2' It may be used with substituents.

[0048] In a particular alternative embodiment, R 2' -NR1-X may be substituted. R2' -alkyl group, -NR1-X R2' -Aryl group; may be substituted -NR1-X R2' -HET, may be substituted with -NR1-X R2' -aryl-HET or possibly substituted-NR1-X R2' -HET-aryl, Here, R1 is H or a C1-C3 alkyl group (preferably H); X R2' (May be substituted -CH2) n -, -CH2) n -CH(X v )=CH(X v )-(Sys or Trans), -CH2) n -CH≡CH-, -(CH2CH2O) n -or C3-C6 cycloalkyl groups; Here X v is a C1-C3 alkyl group which may be substituted with H, a halo, one or two hydroxyl groups, or up to three halogen groups; Alkyl may be substituted C1-C 10 The group is an alkyl (preferably C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is terminally capped with a halo group, often Cl or Br); The aryl is a substituted phenyl or naphthyl group (preferably a phenyl group); and HET is a substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indridine, azaindridine, quinoline (if substituted, each is preferably substituted with a C1-C3 alkyl group, preferably with a methyl or halo group, preferably with F or Cl) or a group with the following chemical structure: TIFF0007898835000358.tif138163In formula, S c is CHR SS , NR URE , or O; R HET The group is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), and each of these groups may be substituted with one or two hydroxyl groups or up to three halogens, preferably a fluorine group, or a substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, or piperazine, and each of these may be substituted, and Y C is N or CR YC And here R YC The group is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R PRO The group is H, a substituted C1-C6 alkyl group or an substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of H, an optionally substituted C1-C6 alkyl group, or an oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably with a methyl or halo group, preferably with F or Cl), benzofuran, indole, indidine, and azaindidine; R PRO1 and R PRO2 Each is independently H, an optionally substituted C1-C3 alkyl group, or together forms a keto group; and Each n is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1). Each of the aforementioned groups is TIFF0007898835000359.tif10128 groups ( TIFF0007898835000360.tif10128 groups included) may be substituted with a linker group that is bonded.

[0049] In another specific preferred embodiment of the present invention, R 3' may be substituted -(CH2) n -(V) n' -(CH2) n -(V) n' -R S3' group, may be substituted -(CH2) n -N(R 1' )(C=O) m' -(V) n' -R S3' group, may be substituted -X R3' -alkyl group, may be substituted -X R3' -aryl group; may be substituted -X R3' ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​-CH≡CH- or C3-C6 cycloalkyl groups, which may be fully substituted; Here X v is a C1-C3 alkyl group which may be substituted with H, a halo, one or two hydroxyl groups, or up to three halogen groups; Alkyl may be substituted C1-C 10 The group is an alkyl (preferably C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is terminally capped with a halo group, often Cl or Br); The aryl is a substituted phenyl or naphthyl group (preferably a phenyl group); and HET may be a substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indidine, azaindidine, quinoline (if substituted, each preferably substituted with a C1-C3 alkyl group, preferably a methyl or halo group, preferably F or Cl), or a group with the following chemical structure: TIFF0007898835000361.tif135161In formula, S c is CHR SS , NR URE , or O; R HET The group is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R SSis H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C0-C6 alkyl), and each of these groups may be substituted with one or two hydroxyl groups or up to three halogens, preferably a fluorine group, or a substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, or piperazine, and each of these may be substituted, and Y C is N or CR YC And here R YC The group is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R PROThe group is H, a substituted C1-C6 alkyl group or an substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of H, an optionally substituted C1-C6 alkyl group, or an oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably with a methyl or halo group, preferably with F or Cl), benzofuran, indole, indidine, and azaindidine; R PRO1 and R PRO2 Each is independently H, an optionally substituted C1-C3 alkyl group, or together forms a keto group; and Each n is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); Each m' is either 0 or 1; and Each n' is either 0 or 1, Here, each of the compounds preferably has an alkyl, aryl, or Het group. TIFF0007898835000362.tif10128 groups ( It is substituted with a linker group to which a TIFF0007898835000363.tif10128 group is attached.

[0050] In another embodiment, R 3 ' is - (CH2) n -aryl, -(CH2CH2O) n -Aryl, -(CH2) n -HET or -(CH2CH2O) n -HET; Here, the aryl is a phenyl which may be substituted with one or two substituents, where the substituent is preferably -(CH2) n OH, which itself is CN, halo (up to 3 halo groups), C1-C6 alkyl, -(CH2) which may be further substituted with OH nSelected from O(C1-C6) alkyl, amine, mono- or di-(C1-C6 alkyl)amine, in which the alkyl group on the amine may be substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, or the aryl group is -(CH2) n OH, -(CH2) n -O-(C1~C6)alkyl, -(CH2) n -O-(CH2) n -(C1~C6) alkyl, -(CH2) n -C(O)(C0~C6)alkyl, -(CH2) n -C(O)O(C0~C6)alkyl, -(CH2) n -OC(O)(C0~C6)alkyl, amine, mono- or di-(C1~C6alkyl)amine, CN, NO2, optionally substituted-(CH2) n -(V) m' -CH2) n -(V) m' -(C1~C6) alkyl groups, -(V) m' -(CH2CH2O) n -R PEG It is substituted with a base, where V is O, S, or NR 1' And R 1' is H or a C1-C3 alkyl group (preferably H), and R PEGThe aryl group may be H or an optionally substituted C1-C6 alkyl group (including being substituted with a carboxyl group), or the aryl group may be substituted with a heterocyclic heteroaryl group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indidine, azaindidine (where substituted, each is preferably substituted with a C1-C3 alkyl group, preferably with a methyl or halo group, preferably with F or Cl), or a group with the following chemical structures: TIFF0007898835000364.tif136161In formula, S c is CHR SS , NR URE , or O; R HET The group is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C0-C6 alkyl), and each of these groups may be substituted with one or two hydroxyl groups or up to three halogens, preferably a fluorine group, or a substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, or piperazine, and each of these may be substituted, and Y C is N or CR YC And here R YC The group is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R PRO The group is H, a substituted C1-C6 alkyl group or an substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of H, an optionally substituted C1-C6 alkyl group, or an oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably with a methyl or halo group, preferably with F or Cl), benzofuran, indole, indidine, and azaindidine; R PRO1 and R PRO2 Each is independently a H, an optionally substituted C1-C3 alkyl group, or together forms a keto group; HET is preferably an oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably with a methyl or halo group, preferably with F or Cl), benzofuran, indole, indidine, azaindidine, or a group with the following chemical structures: TIFF0007898835000365.tif134161In formula, S c is CHR SS , NR URE , or O; R HET The group is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C0-C6 alkyl), and each of these groups may be substituted with one or two hydroxyl groups or up to three halogens, preferably a fluorine group, or a substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, or piperazine, and each of these may be substituted, and Y C is N or CR YC And here R YC The group is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And here R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R PRO is H, an optionally substituted C1-C6 alkyl or optionally substituted aryl, heteroaryl or heterocyclic group; R PRO1 and R PRO2 Each is independently a H, an optionally substituted C1-C3 alkyl group, or together forms a keto group; Each m' is independently either 0 or 1; and Each n is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); Here, each of the compounds preferably has the aryl or HET group TIFF0007898835000366.tif10128 groups ( It is substituted with a linker group to which a TIFF0007898835000367.tif10128 group is attached.

[0051] In further embodiments, preferred compounds, or pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof, include those with the following chemical structures: TIFF0007898835000368.tif51128In formula, R 1' It is a group that is metabolized to OH in the patient or subject; R 2' is -NH-CH2-aryl-HET (preferably a phenyl directly linked to a methyl-substituted thiazole); R 3' ha-CHR CR3' -NH-C(O)-R 3P1 base or -CHR CR3' -R 3P2 It is the basis; Here R CR3' The alkyl group is a C1-C4 alkyl group, preferably methyl, isopropyl, or tert-butyl; R 3P1 -(CH2) is a C1-C3 alkyl group (preferably methyl), or an optionally substituted oxetane group (preferably methyl-substituted, n is 1 or 2 (preferably 2)). n OCH3 group, or TIFF0007898835000369.tif27128 group (ethyl ether group preferably meta-substituted with phenyl moiety), morpholino group (linked to carbonyl at position 2 or 3); R 3P2 teeth TIFF0007898835000370.tif25128 units, Here, aryl is phenyl; HET is a thiazole or isothiazole that may be substituted; and R HET is H or a halo group (preferably H), Here, each of the compounds is TIFF0007898835000371.tif10128 groups ( It is substituted with a linker group to which a TIFF0007898835000372.tif10128 group is attached.

[0052] In another embodiment, the compounds of the present invention, or their pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs, are contained within them. The TIFF0007898835000373.tif10128 unit includes the following: In formula TIFF0007898835000374.tif50128, X is Cl, F, C1-C3 alkyl (preferably methyl) or heterocyclic (preferably R) 3' A complex algebra that may be permuted, including those defined above; R 1 and R 2 Each is independently H, C1-C3 alkyl (preferably methyl), or phenyl, and each of the compounds is linked by a linker group or TIFF0007898835000375.tif10128 is substituted with a linker group to which it is bonded.

[0053] Further preferred compounds of the present invention, or their pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs, are included in the present invention. The TIFF0007898835000376.tif10128 unit includes the following: In formula TIFF0007898835000377.tif51128, n is either 0 or 1; R is a linker or TIFF0007898835000378.tif10128 is a linker bonded to a base. X is H, F, Cl, C1-C3 alkyl (preferably methyl) or heterocyclic (preferably R 3' This includes the elements defined above, particularly water-soluble heterocycles such as morpholino groups, and may be substituted heterocycles.

[0054] Further preferred compounds of the present invention, or their pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs, are included in the present invention. The TIFF0007898835000379.tif10128 base includes, for example, the following: In formula TIFF0007898835000380.tif50128, n is either 0 or 1; R is a linker or TIFF0007898835000381.tif10128 is a linker bonded to a group, or is a linker, or is bonded to an amide, ester, ether or carbamate group TIFF0007898835000382.tif10128 linked TIFF0007898835000383.tif10128 is a linker bonded to a base; R 1 C1-C3 alkyl (may be substituted with one or two hydroxyl groups) or -C(O)NR 3 R 4 And here R 3 and R 4 Each of these is independently H, C1-C3 alkyl (preferably methyl), phenyl, or heterocycle (including heterocycles such as morpholino, piperazine, or other groups that enhance water solubility), X is H, F, Cl, C1-C3 alkyl (preferably methyl) or heterocyclic (preferably R 3' This includes the soluble heterocycles defined above, and may be substituted.

[0055] Further preferred compounds of the present invention, or their pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs, are included in the present invention. The TIFF0007898835000384.tif10128 base includes, for example, the following: In the formula TIFF0007898835000385.tif51128, n is either 0 or 1; R 1 is a linker or amide, ester, ether, carbamate or heterocyclic group (preferably R 3' Through the complex ring (which may be substituted) including those defined above TIFF0007898835000386.tif10128 linked TIFF0007898835000387.tif10128 is a linker bonded to a base; R is H, F, Cl, C1-C3 alkyl (which may be substituted with one or two hydroxyl groups, preferably methyl), -OC(O)NR 3 R 4 or -C(O)NR 3 R 4 And here R 3 and R 4 Each of these is independently a heterocycle containing H, a C1-C3 alkyl group (preferably methyl), a phenyl group, or a water-soluble heterocycle.

[0056] Further preferred compounds of the present invention, or their pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs, are included in the present invention. The TIFF0007898835000388.tif11128 entity includes, for example, the following: In formula TIFF0007898835000389.tif50128, n is either 0 or 1; R is a linker or an amide, ester, ether, carbamate, or heterocyclic group. TIFF0007898835000390.tif10128 units are linked TIFF0007898835000391.tif10128 is a linker bonded to a base; Each X is independently H, F, Cl, C1-C3 alkyl (which may be substituted with one or two hydroxyl groups, preferably methyl), heterocyclic (preferably a water-soluble heterocyclic, and / or R) 3' The complex rings (including those defined above, even if substituted), -OC(O)NR 3 R 4 or -C(O)NR 3 R 4 And here R 3 and R 4Each of these is independently H, C1-C3 alkyl (preferably methyl), or phenyl.

[0057] Further preferred compounds of the present invention, or their pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs, are included in the present invention. The TIFF0007898835000392.tif10128 base includes, for example, the following: In formula TIFF0007898835000393.tif50128, n is either 0 or 1; R is a linker or an amide, ester, ether, carbamate, or heterocyclic group. TIFF0007898835000394.tif10128 linked TIFF0007898835000395.tif10128 is a linker bonded to a base; R 1 C1-C3 alkyl, -OC(O)NR which may be substituted with one or two hydroxyl groups 3 R 4 or -C(O)NR 3 R 4 And here R 3 and R 4 Each of them is independently H, C1-C3 alkyl (preferably methyl), or phenyl; and X is independently H, F, Cl, C1-C3 alkyl (which may be substituted with one or two hydroxyl groups, preferably methyl), or heterocyclic (preferably a water-soluble heterocyclic, and / or R) 3' It is a complex algebra (which may be permuted) that includes the one defined above.

[0058] Further preferred compounds of the present invention, or their pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs, are included in the present invention. The TIFF0007898835000396.tif10128 entity includes, for example, the following: In formula TIFF0007898835000397.tif51128, n is either 0 or 1; R is a linker or an amide, ester, ether, carbamate, or heterocyclic group. TIFF0007898835000398.tif10128 linked TIFF0007898835000399.tif10128 is a linker bonded to a base; R 1 C1-C3 alkyl, -OC(O)NR, which may be substituted with H, one or two hydroxyl groups. 3 R 4 or -C(O)NR 3 R 4 And here R 3 and R 4 Each of them is independently H, C1-C3 alkyl (preferably methyl), or phenyl; and Each X is independently H, F, Cl, C1-C3 alkyl (which may be substituted with one or two hydroxyl groups, preferably methyl), or heterocyclic (preferably containing a water-soluble heterocyclic and / or R 3' It is a complex algebra (which may be permuted) that includes the one defined above.

[0059] In further embodiments, particularly preferred compounds of the present invention, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs, may be identified according to any one or more of the chemical structures shown in Figure 19 herein: In the formula, R 1PC , R 2PC , R 3PC , R 4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R 11PC , R 12PC , R 13PC and R 14PC Any one or more of It is TIFF0007898835000400.tif13128 units, Here L is a linker group, and TIFF0007898835000401.tif10128 is the protein targeting portion.

[0060] In a preferred embodiment, R 1PC , R 2PC , R 3PC , R 4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R 11PC , R 12PC , R 13PC and R 14PC Two or fewer of the following are TIFF0007898835000402.tif12128 is a group and also group R 1PC , R 2PC , R 3PC , R 4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R 11PC , R 12PC , R 13PC and R 14PC The other components are independently H or CH3 groups, most often H.

[0061] Certain preferred embodiments aim to provide compounds having the following chemical structures, or pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof: TIFF0007898835000403.tif38128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000404.tif12128 is a group or H. Preferably, R 7PC or R 10PC One of them TIFF0007898835000405.tif12128 is a unit, and other R 7PC or R 10PCH is H.

[0062] In another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000406.tif38128In formula, R 7PC teeth This is TIFF0007898835000407.tif13128 units.

[0063] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000408.tif58128In formula, R 7PC , R 11PC R 12PC , R 13PC and R 14PC Each is independent TIFF0007898835000409.tif13128 is a group or H. Preferably, R 7PC , R 11PC , R 12PC , R 13PC and R 14PC One of them is TIFF0007898835000410.tif12128 is a group, and the other groups are H, or These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0064] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000411.tif56128In formula, R 4PC , R 7PC , R 11PC R 12PC , R 13PC and R 14PC Each is independent TIFF0007898835000412.tif12128 is a group or H. Preferably, R 4PC , R 7PC Either of the above, or R 11PC , R 12PC , R 13PC and R 14PC One of them is TIFF0007898835000413.tif12128 is a group, and the other groups are H, or These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0065] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000414.tif54128In formula, R 3PC , R 7PC , R 11PC R 12PC , R 13PC and R 14PC Each is independent TIFF0007898835000415.tif12128 is a group or H. Preferably, R 3PC , R 7PC , R 11PC , R 12PC , R 13PC and R 14PC One of them is TIFF0007898835000416.tif12128 is a group, and the other groups are H, or These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0066] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000417.tif39128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000418.tif12128 is a group or H. Preferably, R 7PC and R 10PC One of them is TIFF0007898835000419.tif12128 is a group, and the other groups are H, or These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0067] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000420.tif39128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000421.tif12128 is either H or R 8PC is H or CH3. Preferably, R 7PC and R 10PC One of them is TIFF0007898835000422.tif12128 is a group, and the other groups are H and R 8PC is H, or These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0068] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000423.tif40128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000424.tif12128 is either H or R 8PC is H or CH3. Preferably, R 7PC and R 10PC One of them is TIFF0007898835000425.tif12128 is a group, and the other groups are H and R8PC is H, or These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0069] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000426.tif38128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000427.tif12128 is either H or R 8PC is H or CH3. Preferably, R 7PC and R 10PC One of them is TIFF0007898835000428.tif12128 is a group, and the other groups are H and R 8PC is H, or These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0070] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000429.tif49128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000430.tif12128 is a group or H. Preferably, R 7PC and R 10PC One of them is TIFF0007898835000431.tif12128 is a group, and the other groups are H, or These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0071] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000432.tif35128In formula, R 7PC and R 9PC Each is independent TIFF0007898835000433.tif13128 is a group or H. Preferably, R 7PC and R 9PC One of them is TIFF0007898835000434.tif12128 is a group, and the other groups are H, or These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0072] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000435.tif47128 formula, R 7PC and R 14PC Each is independent TIFF0007898835000436.tif12128 is either H or R 12PC and R 13PC Each of them is either H or CH3. Preferably, R 7PC and R 14PC One of them is TIFF0007898835000437.tif12128 units, and R 7PC and R 14PC The other side of the base is H, and R 12PC and R 13PC Each of them is H, These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0073] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000438.tif35128In formula, R 7PC and R 9PC Each is independent TIFF0007898835000439.tif12128 is a group or H. Preferably, R 7PC and R 9PC One of them is TIFF0007898835000440.tif12128 is a group, and the other groups are H, or These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0074] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000441.tif36128 formula, R 7PC and R 9PC Each is independent TIFF0007898835000442.tif12128 is a group or H. Preferably, R 7PC and R 9PC One of them is TIFF0007898835000443.tif12128 is a group, and the other groups are H, or These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0075] In yet another preferred embodiment, the compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, or polymorph, has the following chemical structure: TIFF0007898835000444.tif40128In formula, R 7PC and R 10PC Each is independent TIFF0007898835000445.tif12128 is either H or R 9PC is H or CH3. Preferably, R 7PC and R 10PC One of them is TIFF0007898835000446.tif12128 is a group, and the other groups are H and R 9PC is H, or These are pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0076] In the embodiments described above, the linker group may be any linker group described herein, preferably polyethylene glycol groups having a size in the range of ethylene glycol units of about 1 to about 12, ethylene glycol units between 1 and about 10, ethylene glycol units of about 2 and about 6, ethylene glycol units between about 2 and 5, and ethylene glycol units between about 2 and 4.

[0077] In a preferred embodiment, the linker group L is the following group: In formula TIFF0007898835000447.tif11128, Z is It is the base for concatenating TIFF0007898835000448.tif10128 to X; and X is based on Z TIFF0007898835000449.tif10128( This is a group linked to TIFF0007898835000450.tif10128.

[0078] In a preferred embodiment, Z is absent (bond), -(CH2) i -O, -(CH2) i -S, -(CH2) i -NR, X1Y1 forms an amide group, or a urethane group, ester, or thioester group. TIFF0007898835000451.tif10128 units, or TIFF0007898835000452.tif15128 units Each R is H, or a C1-C3 alkyl, alkanol group, or heterocycle (to promote the water solubility of the linker group, a water-soluble heterocycle, preferably a morpholino, piperidine, or piperazine group); Each Y is independently bonded, O, S, or NR; And each i is independently 0-100, 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5;

[0079] In a favorable situation, X TIFF0007898835000453.tif18128 units In the formula, each D is either independently combined (or does not exist), It is TIFF0007898835000454.tif51128; j is 1-100, 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5; k is 1-100, 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5; preferably k is 1, 2, 3, 4, or 5; m' is 1-100, 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5; n is 1-100, 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5; X 1 is O, S, or NR, preferably O; Y is the same as above; and TIFF0007898835000455.tif7128, when present in a linker group, is a linking group (or bond) that connects Z to X.

[0080] In favorable situations, TIFF0007898835000456.tif7128 is either a bond (not present), a heterocycle containing a water-soluble heterocycle such as piperazinyl or another group, or TIFF0007898835000457.tif62128 group, or its pharmaceutically acceptable salts, enantiomers, or stereoisomers, In the formula, X 2 O, S, NR 4 , S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O; X 3 O, S, CHR 4 , NR 4 and R 4 is a C1-C3 alkyl group which may be substituted with H or one or two hydroxyl groups.

[0081] In another preferred aspect, the linker group is a (poly)ethylene glycol having ethylene glycol units between 1 and about 100, ethylene glycol units between about 1 and about 50, ethylene glycol units between 1 and about 25, ethylene glycol units between about 1 and 10, ethylene glycol units between 1 and about 8, and ethylene glycol units between 1 and 6 and ethylene glycol units between 2 and 4.

[0082] In another favorable scenario, TIFF0007898835000458.tif7128 is TIFF0007898835000459.tif15128 is either an amide group or a septum group.

[0083] TIFF0007898835000460.tif10128 units and TIFF0007898835000461.tif10128 groups ( The linker group (including TIFF0007898835000462.tif10128) may be linked to the linker group through any group that is appropriate and stable to the chemical structure of the linker, but in a preferred aspect of the present invention, the linker is independently TIFF0007898835000463.tif10128 units and TIFF0007898835000464.tif10128 groups ( TIFF0007898835000465.tif10128 contains a covalent bond to a group, preferably via an amide, ester, thioester, keto group, carbamate (urethane), or ether, and each of these groups is TIFF0007898835000466.tif10128 units and TIFF0007898835000467.tif10128 groups ( Inserted at any location on TIFF0007898835000468.tif10128 (including the group) onto ubiquitin ligase TIFF0007898835000469.tif10128 groups and on the target protein to be degraded TIFF0007898835000470.tif10128 may provide the maximum number of bonds. TIFF0007898835000471.tif11128 units It should be noted that in certain aspects, the target protein for degradation may be the ubiquitin ligase itself. In certain preferred aspects, the linker TIFF0007898835000473.tif11128 The group may be linked to an alkyl, alkylene, alkene or alkyne group, aryl group or heterocyclic group that may be substituted.

[0084] In a preferred aspect of the present invention, The TIFF0007898835000474.tif10128 group is a group that binds to the target protein. The targets of TIFF0007898835000475.tif10128 are diverse, and at least a portion of the sequence has been found in cells. A protein is selected from intracellularly expressed proteins that can bind to the TIFF0007898835000476.tif11128 group. The term "protein" is used in this invention. The TIFF0007898835000477.tif10128 contains oligopeptide and polypeptide sequences of sufficient length to bind to a group. Any protein in a eukaryotic system or a microbial system including viruses, bacteria or fungi, as otherwise described herein, is a target for ubiquitination mediated by the compounds of the present invention. Preferably, the target protein is a eukaryotic protein. In a particular aspect, the protein binding moiety contains a haloalkane (preferably at least one halo group, preferably the distal end of an alkyl group (i.e., a linker or TIFF0007898835000478.tif10128 is a C1-C10 alkyl group substituted with a halo group (away from the group), which can covalently bind to the dehalogenase enzyme in patients or subjects, or in diagnostic tests.

[0085] This invention The TIFF0007898835000479.tif10128 group includes, for example, any moiety that specifically binds to a protein (bounds to a target protein), and includes non-limiting examples of small molecule target protein moieties, particularly Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting aryl hydrocarbon receptors (AHRs). The compositions described below exemplify some members of these nine types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that may target proteins of interest. To present the target protein (to which the protein target moiety binds) in close proximity to a ubiquitin ligase for ubiquitination and degradation, these binding moieties are linked to a ubiquitin ligase binding moiety, preferably via a linker.

[0086] Protein target region or Any protein that can bind to the TIFF0007898835000480.tif10128 group and acts on or is degraded by a ubiquitin ligase is a target protein of the present invention. Generally, target proteins may include, for example, structural proteins, receptors, enzymes, cell surface proteins, and proteins directly related to cellular integration functions, including proteins involved in catalytic activity, aromatase activity, motility, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory activity, signal transducer activity, structural molecular activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, proteins involved in response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, and proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transporter activity, pathogenicity, chaperone regulatory activity, nucleic acid binding activity, transcription regulatory activity, extracellular organization and biodevelopmental activity, and translation regulatory activity). Proteins of interest may include, in particular, proteins from eukaryotes and prokaryotes, including humans, other animals including livestock, microorganisms and plants for targeting of antibiotics and other antimicrobial substances, and viruses.

[0087] In another embodiment, The TIFF0007898835000481.tif10128 group is a haloalkyl group, where the alkyl group is generally in the size range of about 1 or 2 carbons to about 12 carbons in length, often about 2 to 10 carbons in length, often about 3 to about 8 carbons in length, and more often about 4 to about 6 carbons in length. The haloalkyl group is generally a linear alkyl group (branched alkyl groups can also be used) and is terminally capped with at least one halogen group, preferably a single halogen group, often a single chloride group. Haloalkyl group for use in the present invention TIFF0007898835000482.tif10128 The group preferably has the chemical structure -(CH2) v - Represented by a halo, where v is any integer between 2 and approximately 12, often between approximately 3 and approximately 8, and more often between approximately 4 and approximately 6. The halo can be any halogen, but preferably Cl or Br, more often Cl.

[0088] In another embodiment, TIFF0007898835000483.tif10128 is The group is TIFF0007898835000484.tif34128, where w is 0 to 3, preferably 1 or 2. This group selectively binds to estrogen receptors and is useful for treating diseases regulated through estrogen receptors, particularly cancers such as breast cancer, endometrial cancer, ovarian cancer, and uterine cancer.

[0089] The present invention can be used to treat several disease conditions and / or conditions, including any disease conditions and / or conditions in which proteins are dysregulated and the patient would benefit from protein breakdown.

[0090] In another aspect, the present invention relates to a pharmaceutical composition comprising an effective amount of the compounds described herein in combination with a pharmaceutically acceptable carrier, additive or excipient, and optionally an additional bioactive agent.

[0091] In another aspect, the present invention relates to a method for treating a disease condition by degrading a protein or polypeptide through which the disease condition or state is modulated, the method comprising administering to the patient or subject an effective amount of at least one compound described herein, optionally in combination with additional bioactive agents. The method of the present invention can be used to treat many disease conditions or states, including cancer, by administering an effective amount of at least one compound described herein.

[0092] Detailed description of the invention The following terms are used to describe the present invention. Unless otherwise defined herein, a term is given the meaning that is recognized in the art by those skilled in the art who are applying the term in the context in which it is used to describe the present invention.

[0093] Where a range of values ​​is given, it is understood that the values ​​between the upper and lower limits of that range, up to one-tenth of the lower limit unit, unless the context clearly indicates otherwise (for example, in the case of a group containing several carbon atoms, in which case the number of each carbon atom that falls within the range is given), and any other specified values ​​within that specified range, or values ​​between them, are included within the scope of the invention. Assuming any particularly excluded limits within the specified range, the upper and lower limits of these smaller ranges are independently included in the smaller range and are also included within the scope of the invention. If the specified range includes one or both of the limits, the range excluding either / both of the limits that they include is also included within the invention.

[0094] As used herein, the term “compound” means any specific chemical compound disclosed herein unless otherwise specified, including tautomers, positional isomers, geometric isomers, and, where applicable, stereoisomers including their optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as, where applicable in context, their pharmaceutically acceptable salts and derivatives (including prodrugs). Within the scope of its use in context, the term “compound” generally means a single compound, but may also include other compounds such as stereoisomers, positional isomers, and / or optical isomers (including racemic mixtures) of the disclosed compound, as well as specific enantiomers or enantiomerically concentrated mixtures. In context, the term also means prodrug forms of the compound modified to facilitate administration and delivery to the active site of the compound. It should be noted that many substituents and variables, particularly those related thereto, are described in the description of the compound. Those skilled in the art will understand that the molecules described herein are stable compounds, as generally described below. Bonding When TIFF0007898835000485.tif12128 is shown, both double and single bonds are shown within the context of the compound being shown.

[0095] The terms “patient” or “subject” are used throughout this specification to describe animals, preferably humans or livestock, to which treatment, including preventive treatment, is provided by the compositions of the present invention. For the treatment of infectious diseases, conditions or disease situations specific to a particular animal, such as a human patient, the term patient means that particular animal, including livestock such as dogs or cats, or farm animals such as horses, cattle, or sheep. In general, in the present invention, the term patient means a human patient unless otherwise specified or indicated by the context of use of the term.

[0096] The term "effective" is used to describe the amount of a compound, composition, or component that produces the intended result when used within the context of its intended use. The term "effective" encompasses all other terms of effective quantity or effective concentration as otherwise described or used in this application.

[0097] The terms "VCB E3 ubiquitin ligase," "Hippel-Lindau E3 ubiquitin ligase," or "ubiquitin ligase" are used to describe the target enzyme binding site of the ubiquitin ligase moiety in the bifunctional (chimeric) compounds of the present invention. VCB E3 is a protein that, in combination with E2 ubiquitin-conjugating enzyme, causes ubiquitin to bind to lysine on target proteins; E3 ubiquitin ligases target specific protein substrates for proteasome degradation. Thus, E3 ubiquitin ligases, either alone or in combination with E2 ubiquitin-conjugating enzyme, are responsible for the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin binds to the first, a third to the second, and so on. Polyubiquitination marks proteins for proteasome degradation. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin molecule is added to the substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted by the proteasome for degradation, but instead their location or function on the cell can be altered, for example, through the binding of other proteins that have ubiquitin-binding domains. To further complicate matters, different lysines on ubiquitin can be targeted by E3 to form chains. The most common lysine is Lys48 on the ubiquitin chain, which is used to create polyubiquitin that is recognized by the proteasome.

[0098] The term “protein targeting moiety” or PTM is used to describe small molecules that bind to a target protein or another protein or polypeptide of interest, positioning / presenting the protein or polypeptide in close proximity to a ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase may occur. Non-limiting examples of small molecule targeting protein binding moieties include, in particular, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting aryl hydrocarbon receptors (AHRs). Some members of these nine types of small molecule targeting proteins are illustrated below.

[0099] The protein targeting moieties of the present invention include, for example, haloalkanehalogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting aryl hydrocarbon receptors (AHRs). The compositions described below exemplify some members of these types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest. References cited below herein are incorporated herein by reference in their entirety.

[0100] I. Heat shock protein 90 (HSP90) inhibitors : The HSP90 inhibitors used herein include, but are not limited to, the following: 1. HSP90 inhibitors identified in Vallee, et al., "Tricyclic Series of Heat Shock Protein 90 (HSP90) inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the HSP90 Molecular Chaperone (2011) J.Med.Chem. 54: 7206," including the following: YKB N-[4-(3H-imidazo[4,5-C]pyridine-2-yl)-9H-fluoren-9-yl]-succinamide TIFF0007898835000486.tif57128 Linker base L or Derivatization was performed in which the TIFF0007898835000487.tif18128 group was bonded via a terminal amide group; 2. HSP90 inhibitor p54 (modified): p54 8-[(2,4-dimethylphenyl)sulfanyl]-3-penta-4-in-1-yl-3H-purine-6-amine TIFF0007898835000488.tif49128 Here linker base L or The TIFF0007898835000489.tif18128 group is bonded via terminal acetylene groups; 3. HSP90 inhibitors identified in Broough, et al., ''4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer'', J.MED.CHEM. vol: 51, pag:196 (2008), including compound 2GJ having the following structure (5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(morpholine-4-ylmethyl)phenyl]isoxazole-3-carboxamide) (modified): TIFF0007898835000490.tif58128 Linker base L or TIFF0007898835000491.tif17128 was derivatized by being bonded via an amide group (amine or alkyl group on an amine); 4. Wright, et al., Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms, containing the HSP90 inhibitor PU3 having the following structure. Chem Biol. HSP90 inhibitors identified in 2004 Jun;11(6):775-85 (modified): TIFF0007898835000492.tif50128 Here linker base L or TIFF0007898835000493.tif17128 The group is bonded via a butyl group; and 5. HSP90 inhibitor geldanamycin ((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1] (derivativeized) or any derivative thereof (e.g., 17-alkylamino-17-desmethoxygeldanamycin ("17-AAG") or 17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin ("17-DMAG")) (Linker base L or TIFF0007898835000494.tif17128 (Derivatization was performed, in which the group is bonded via an amide group).

[0101] II. Kinase and phosphatase inhibitors : Kinase inhibitors used herein include, but are not limited to, the following: 1. Erlotinib derivative tyrosine kinase inhibitors TIFF0007898835000495.tif38128 Here R is a linker group L or bonded via an ether group This is TIFF0007898835000496.tif17128; 2. Kinase inhibitor sunitinib (derivative): TIFF0007898835000497.tif35128(R is a linker group L or bonded to the pyrrole portion) The TIFF0007898835000498.tif17128 group was derivatized. 3. Kinase inhibitor sorafenib (derivative) TIFF0007898835000499.tif31128(R is a linker group L or bonded to the phenyl portion) The TIFF0007898835000500.tif18128 group was derivatized); 4. Kinase inhibitor dasatinib (derivative) TIFF0007898835000501.tif48128(R is a linker group L or that is bonded to a pyrimidine) The file is TIFF0007898835000502.tif17128, which has been derivatized. 5. Kinase inhibitor lapatinib (derivative) TIFF0007898835000503.tif74128 Linker base L or Derivatization was performed in which the TIFF0007898835000504.tif17128 group was bonded via the terminal methyl group of the sulfonylmethyl group; 6. Kinase inhibitor U09-CX-5279 (derivative) 7. TIFF0007898835000505.tif73128U09 CX-5279 3-(cyclopropylamino)-5-{[3-(trifluoromethyl)phenyl]amino}pyrimido[4,5-c]quinoline-8-carboxylic acid Linker base L or TIFF0007898835000506.tif17128 was derivatized by bonding the amine (aniline), carboxylic acid, or cyclopropyl group via an alpha-amine or cyclopropyl group; 7. Kinase inhibitors identified in Millan, et al., Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease, J.MED.CHEM. vol:54, pag:7797 (2011), including kinase inhibitors Y1W and Y1X (derivativeized) having the following structures: TIFF0007898835000507.tif50128YIX 1-Ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine-6-yl]sulfanyl}benzyl)urea Linker base L or Derivatization was performed in which the TIFF0007898835000508.tif18128 group is preferably bonded via a propyl group; TIFF0007898835000509.tif62128YIW 1-(3-tert-butyl-1-phenyl-1H-pyrazole-5-yl)-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine-6-yl]sulfanyl}benzyl)urea Linker base L or Derivatization was performed in which the TIFF0007898835000510.tif18128 group is preferably bonded via either a propyl group or a butyl group; 8. Kinase inhibitors identified in Schenkel, et al., Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors J. Med. Chem., 2011, 54(24), pp 8440-8450, including compounds 6TP and 0TP (derivative) having the following structures: TIFF0007898835000511.tif451286TP 4-amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamide thienopyridine 19 Linker base L or Derivatization was performed in which the TIFF0007898835000512.tif18128 group is preferably bonded via a terminal methyl group attached to the amide portion; TIFF0007898835000513.tif461280TP 4-amino-N-methyl-2-[4-(morpholine-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamide thienopyridine 8 Linker base L or Derivatization was performed in which the TIFF0007898835000514.tif18128 group is preferably bonded via a terminal methyl group attached to the amide moiety; 9. Kinase inhibitors identified in Van Eis, et al., ''2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes'', Biorg. Med. Chem. Lett. 2011 Dec 15;21(24):7367-72, including kinase inhibitor 07U having the following structure: TIFF0007898835000515.tif5012807U 2-Methyl-N~1~-[3-(pyridine-4-yl)-2,6-naphthyridine-1-yl]propan-1,2-diamine Linker base L or Derivatization was performed in which the TIFF0007898835000516.tif17128 group is preferably bonded via a secondary amine or terminal amino group; 10. Kinase inhibitors identified in Lountos, et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy", J.STRUCT.BIOL. vol:176, pag:292 (2011), including the kinase inhibitor YCF having the following structure: TIFF0007898835000517.tif31152 Linker base L or Derivatization was performed in which the TIFF0007898835000518.tif17128 group is preferably bonded via one of the terminal hydroxyl groups; 11. Kinase inhibitors identified in Lountos, et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy", J.STRUCT.BIOL. vol:176, pag:292 (2011), including kinase inhibitors XK9 and NXP (derivativeized) having the following structures: TIFF0007898835000519.tif52128XK9 N-{4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide TIFF0007898835000520.tif71128NXP N-{4-[(1E)-N-carbamimidoleethanehydrazonoyl]phenyl}-1H-indole-3-carboxamide Linker base L or Derivatization was performed in which the TIFF0007898835000521.tif17128 group is preferably bonded via a terminal hydroxyl group (XK9) or a hydrazone group (NXP); 12. Kinase inhibitor afatinib (derivative) (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide) (linker group L or Derivatization was performed in which the TIFF0007898835000522.tif17128 group is preferably bonded via an aliphatic amine group. 13. Kinase inhibitor hostamatinib (derivative) ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidine-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-1,4-oxazine-4-yl]methylphosphate disodium hexahydrate) (linker group L or Derivatization was performed in which the TIFF0007898835000523.tif17128 group is preferably bonded via a methoxy group); 14. Kinase inhibitor gefitinib (derivative) (N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholine-4-ylpropoxy)quinazoline-4-amine) (linker group L or TIFF0007898835000524.tif17128 The group is preferably bonded via a methoxy or ether group, and derivatization is performed. TIFF0007898835000525.tif3912815. Kinase inhibitor lenvatinib (derivative) (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide) (linker group L or Derivatization was performed in which the TIFF0007898835000526.tif17128 group is preferably bonded via a cyclopropyl group. 16. Kinase inhibitor vandetanib (derivative) (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidine-4-yl)methoxy]quinazoline-4-amine) (linker group L or TIFF0007898835000527.tif17128 is derivatized, preferably via a methoxy or hydroxyl group); and 17. Kinase inhibitor vemurafenib (derivative) (propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}amide) (linker group L or Derivatization was performed in which the TIFF0007898835000528.tif17128 group is preferably bonded via a sulfonylpropyl group). 18. Kinase inhibitor Gleevec (derivative): TIFF0007898835000529.tif44128(linker base L or Derivatization was performed in which R, as the group, is preferably bonded via an amide group or an anilineamine group. 19. Kinase inhibitor pazopanib (derivative) (VEGFR3 inhibitor): TIFF0007898835000531.tif49128(R is preferably linked to the phenyl moiety, or to a linker group L or linked via an anilineamine group) The TIFF0007898835000532.tif17128 group was derivatized); 20. Kinase inhibitor AT-9283 (derivative) Aurora kinase inhibitor TIFF0007898835000533.tif45128 (where R is preferably a linker group L or bonded to the phenyl portion) TIFF0007898835000534.tif17128 units); 21. Kinase inhibitor TAE684 (derivative) ALK inhibitor TIFF0007898835000535.tif45128 (where R is preferably a linker group L or bonded to the phenyl portion) TIFF0007898835000536.tif17128 units); 22. Kinase inhibitor nilotinib (derivative) Abl inhibitor: TIFF0007898835000537.tif51128(R is preferably a linker group L or bonded to a phenyl moiety or anilineamine group) The TIFF0007898835000538.tif17128 group was derivatized); 27. Kinase inhibitor NVP-BSK805 (derivative) JAK2 inhibitor TIFF0007898835000539.tif58128(R is a linker group L or bonded to a phenyl moiety or diazole group) The TIFF0007898835000540.tif17128 group was derivatized); 28. Kinase inhibitors: Crizotinib derivatized Alk inhibitors TIFF0007898835000541.tif61128(R is a linker group L or bonded to a phenyl moiety or diazole group) The TIFF0007898835000542.tif17128 group was derivatized); 29. Kinase inhibitors JNJ FMS (derivative) inhibitors TIFF0007898835000543.tif52128(R is preferably a linker group L or bonded to the phenyl portion) The TIFF0007898835000544.tif17128 group was derivatized); 30. Kinase inhibitor forretinib (derivative) Met inhibitor TIFF0007898835000545.tif41128(R is a linker group L or bonded to a hydroxyl or ether group on the phenyl or quinoline moiety) The TIFF0007898835000546.tif17128 group was derivatized); 31. Allosteric protein tyrosine phosphatase inhibitor PTP1B (derivative); TIFF0007898835000547.tif55128 Linker base L or Derivatization was performed in which the TIFF0007898835000548.tif18128 group is preferably bonded with R, as shown. 32. Inhibitors of the SHP-2 domain of tyrosine phosphatase (derivatives): TIFF0007898835000549.tif40128 Linker base L or Derivatization was performed in which the TIFF0007898835000550.tif17128 group is preferably bonded with R. 33. BRAF (BRAF V600E ) / MEK inhibitors (derivativeization): TIFF0007898835000551.tif37128 Linker base L or Derivatization was performed in which the TIFF0007898835000552.tif17128 group is preferably bonded with R. 34. Inhibitors of tyrosine kinase ABL (derivatives) TIFF0007898835000553.tif36128("R" is the linker group L on the piperazine portion or TIFF0007898835000554.tif17128 (showing the binding site of 8 groups, after derivatization).

[0102] III. MDM2 inhibitors : The MDM2 inhibitors used herein include, but are not limited to, the following: 1. MDM2 inhibitors identified in Vassilev, et al., In vivo activation of the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol:303, pag:844-848 (2004), and Schneekloth, et al., Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908, including (or in addition to) the compounds Nutrin 3, Nutrin 2, and Nutrin 1 (derivative), and all their derivatives and analogues: TIFF0007898835000555.tif57128(linker base L or TIFF0007898835000556.tif18128 (Derivatization performed, where the group is preferably bonded as a methoxy group or a hydroxyl group) TIFF0007898835000557.tif52128(linker base L or TIFF0007898835000558.tif18128 The group is preferably bonded with a methoxy group or a hydroxyl group, and derivatization is performed. TIFF0007898835000559.tif67128(linker base L or TIFF0007898835000560.tif17128 Derivatization was performed in which the group is preferably bonded via a methoxy group or as a hydroxyl group); and 2. Trans-4-iodo-4'-boranyl-chalcone TIFF0007898835000561.tif32128(linker base L or TIFF0007898835000562.tif18128 was derivatized by bonding via a hydroxyl group.

[0103] IV. Compounds that target human BET bromodomain-containing proteins : Compounds that target human BET bromodomain-containing proteins include, but are not limited to, the target-related compounds listed below, where "R" represents the linker group L or TIFF0007898835000563.tif17128 indicates the site for group binding: 1. Protein targets: Brd2, Brd3, Brd4 TIFF0007898835000564.tif248156(where R is the linker base L or in each case) TIFF0007898835000565.tif17128 (shows the binding sites for 8 groups).

[0104] V. HDAC inhibitors : HDAC inhibitors (derivatives) include, but are not limited to, the following: 1. TIFF0007898835000566.tif46152("R" is linker base L or TIFF0007898835000567.tif17128 shows the site for binding of the group, and derivatization was performed); and 2. Compounds defined by formula (I) of PCT WO0222577 ("DEACETYLASE INHIBITORS") (linker group L or TIFF0007898835000568.tif17128 was derivatized by bonding via a hydroxyl group.

[0105] VI. Human lysine methyltransferase inhibitors : Human lysine methyltransferase inhibitors include, but are not limited to, the following: 1. TIFF0007898835000569.tif46144("R" is linker base L or TIFF0007898835000570.tif17128 (Derivatization performed, showing the binding sites for the 8 groups). 2. TIFF0007898835000571.tif60150("R" is linker base L or TIFF0007898835000572.tif17128 (This shows the possible sites for the binding of 8 groups, after derivatization). 3. Azacitidine (derivative) (4-amino-1-β-D-ribofuranosyl-1,3,5-triazine-2(1H)-one) (linker group L or TIFF0007898835000573.tif17128 is derivatized by linking a hydroxyl or amino group); and 4. Decitabine (derivative) (4-amino-1-(2-deoxy-bD-erythropentofuranosyl)-1,3,5-triazine-2(1H)-one) (linker group L or TIFF0007898835000574.tif18128 (Derivatization was performed, in which the group is bonded via either a hydroxyl group or an amino group).

[0106] VII. Angiogenesis inhibitors : Angiogenesis inhibitors include, but are not limited to, the following: 1. GA-1 (derivativeized) and its derivatives and analogs having the structure and linker binding described in Sakamoto, et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, Mol Cell Proteomics 2003 Dec;2(12):1350-8: 2. As generally described in Rodriguez-Gonzalez, et al., Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer, Oncogene (2008) 27, 7201-7211, linker group L or Estradiol (derivativeized), which can be bound to the TIFF0007898835000575.tif17128 group; 3. The structure and linker group L or as generally described in Sakamoto, et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, Mol Cell Proteomics 2003 Dec; 2(12):1350-8. estradiol, testosterone (derivativeized), and related derivatives, including but not limited to DHT and its derivatives and analogues having a bond to the TIFF0007898835000576.tif18128 group; and 4. Sakamoto, et al., Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation Proc Natl Acad Sci USA. 2001 Jul 17;98(15):8554-9 and the structure and linker group L or as commonly described in U.S. Patent No. 7,208,157. Obalicin, fumaginine (derivative), and their derivatives and analogs, having a bond to the TIFF0007898835000577.tif17128 group.

[0107] VIII. immunosuppressive compounds : Immunosuppressive compounds include, but are not limited to, the following: 1. The structure and linker group L or as generally described in Schneekloth, et al., Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation, J. AM. CHEM. SOC. 2004, 126, 3748-3754. AP21998 (derivativeized), having a bond to the TIFF0007898835000578.tif17128 group; 2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, and methylprednisolone) (linker group L or TIFF0007898835000579.tif17128 (derivativeized, for example, with the linker group L or hydroxyl group attached) and beclomethasone dipropionate (linker group L or TIFF0007898835000580.tif17128 was derivatized, for example, by being bound to a propionic acid ester. 3. Methotrexate (linker group L or The TIFF0007898835000581.tif17128 group was derivatized in which it could be attached to, for example, one of the terminal hydroxyls); 4. Cyclosporine (linker group L or The TIFF0007898835000582.tif17128 group was derivatized, for example, by being bonded with any of the butyl groups. 5. Tacrolimus (FK-506) and rapamycin (linker group L or TIFF0007898835000583.tif17128 The group was derivatized, for example, by being bonded with one of the methoxy groups); and 6. Actinomycin (linker group L or The TIFF0007898835000584.tif17128 group was derivatized, for example, by being bonded with one isopropyl group.

[0108] IX. Compounds that target aryl hydrocarbon acceptors (AHRs) : Compounds that target aryl hydrocarbon acceptors (AHRs) include, but are not limited to, the following: 1. Apigenin (Lee, et al., Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem Volume 8, Issue 17, As generally shown on pages 2058-2062, November 23, 2007, linker group L or Derivatized in a manner that binds to the TIFF0007898835000585.tif17128 group); and 2. Boitano, et al., Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells, Science 10 September 2010: Vol. 329 no. 5997 pp. 1345-1348 describes SR1 and LGC006 (linker group L or (Derivatized so that TIFF0007898835000586.tif17128 is bound.)

[0109] X. Compounds that target the RAF receptor (kinase) : TIFF0007898835000587.tif47128("R" is linker base L or TIFF0007898835000588.tif18128 (Derivatization performed, showing the site for group binding).

[0110] XI. Compounds that target FKBP TIFF0007898835000589.tif59128("R" is linker base L or TIFF0007898835000590.tif17128 (Derivatization performed, showing the site for group binding).

[0111] XII. Compounds that target androgen receptors (ARs) 1. Androgen receptor RU59063 ligand (derivative) TIFF0007898835000591.tif22128("R" is linker base L or TIFF0007898835000592.tif18128 (Derivatization performed, showing the site for group binding). 2. SARM ligands for androgen receptors (derivatives) TIFF0007898835000593.tif21128("R" is linker base L or TIFF0007898835000594.tif18128 (Derivatization performed, showing the site for group binding). 3. Androgen receptor ligand DHT (derivative) TIFF0007898835000595.tif33128("R" is linker base L or TIFF0007898835000596.tif17128 (Derivatization performed, showing the site for group binding).

[0112] XIII. Compound ICI-182780 that targets the estrogen receptor (ER) 1. Estrogen receptor ligand TIFF0007898835000597.tif26128("R" is linker base L or TIFF0007898835000598.tif18128 (Derivatization performed, showing the site for group binding).

[0113] XIV. Compounds that target thyroid hormone receptors (TRs) 1. Thyroid hormone receptor ligand (derivative) TIFF0007898835000599.tif57128("R" is linker base L or TIFF0007898835000600.tif17128 (Derivatization was performed, showing the site for group bonding, and MOMO representing a methoxymethoxy group).

[0114] XV. Compounds that target HIV protease 1. HIV protease inhibitors (derivatives) TIFF0007898835000601.tif22128("R" is linker base L or TIFF0007898835000602.tif17128 (shows the site for group binding, derivatization performed). See J. Med. Chem. 2010, 53, 521-538. 2. HIV protease inhibitors TIFF0007898835000603.tif31128("R" is linker base L or TIFF0007898835000604.tif17128 (Derivatization performed, showing possible sites for group binding). See J. Med. Chem. 2010, 53, 521-538.

[0115] XVI. Compounds that target HIV integrase 1. HIV integrase inhibitors (derivatives) TIFF0007898835000605.tif45128("R" is linker base L or TIFF0007898835000606.tif17128 (showing the site for group binding, after derivatization). See J. Med. Chem. 2010, 53, 6466. 2. HIV integrase inhibitors (derivatives) TIFF0007898835000607.tif42128("R" is linker base L or TIFF0007898835000608.tif18128 (shows the site for group binding, derivatization performed). See J. Med. Chem. 2010, 53, 6466.

[0116] XVII. Compounds targeting HCV proteases 1. HCV protease inhibitors (derivatives) TIFF0007898835000609.tif71128("R" is linker base L or TIFF0007898835000610.tif17128 (Derivatization performed, showing the site for group binding).

[0117] XVIII. Compounds targeting acyl-protein thioesterase-1 and -2 (APT1 and APT2) 1. Inhibitors of APT1 and APT2 (derivatives) TIFF0007898835000611.tif53128("R" is linker base L or TIFF0007898835000612.tif17128 shows the site for group bonding (derivativeized). See Angew. Chem. Int. Ed. 2011, 50, 9838-9842, where L is a linker group as otherwise described herein. TIFF0007898835000613.tif16128 is as described separately herein, therefore TIFF0007898835000614.tif17128 is TIFF0007898835000615.tif17128 is described separately in this specification. It binds to the TIFF0007898835000616.tif16128 base.

[0118] The term "target protein" is used to describe the protein or polypeptide that is targeted for binding to the compounds of the present invention and for degradation by the ubiquitin ligase described below. Such small molecule target protein binding sites include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that may target the protein of interest. These binding sites TIFF0007898835000617.tif16128 is linked to the linker group L.

[0119] Target proteins that can be degraded by ligases to which the ubiquitin ligase binding portion is bound include those involved in catalytic activity, aromatase activity, motility, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory factor activity, signal transducer activity, structural molecular activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, etc. Proteins of interest include structural proteins, receptors, enzymes, cell surface proteins, and proteins directly involved in cellular integration functions, including proteins involved in cell communication, regulation of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, and proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transporter activity, pathogenicity, chaperone regulatory activity, nucleic acid binding activity, transcription regulatory activity, extracellular organization and biodevelopmental activity, and translation regulatory activity). Proteins of interest may include, in particular, proteins from eukaryotes and prokaryotes, including microorganisms, viruses, fungi and parasites, especially humans, microorganisms, viruses, fungi and parasites, other animals including livestock, for targeting of antibiotics and other antimicrobial substances, and viruses.

[0120] More specifically, some drug targets for human therapeutics are protein targets to which a protein targeting moiety can be bound and incorporated into the compounds of the present invention. These include, for example, B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type 4, PDE IV phosphodiesterase type 4, PDE I, PDE II, PDE III, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, i.e., Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and similar, HIV 1 protease, HIV Integrase 1, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alpha R, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsome transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, glycine receptor, noradrenaline The target proteins include many proteins that can be used to restore function in polygenic diseases, such as ion reuptake receptors, endothelin receptors, neuropeptide Y and receptors, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinases and AMP deaminases, purine receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferases, geranylgeranyltransferases, TrkA receptors for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptors, integrin receptors, Her-21 neu, telomerase inhibitors, cytosolic phospholipase A2, and EGF receptor tyrosine kinases. Further protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride ion channels, acetylcholinesterases, voltage-sensitive sodium channel proteins, calcium release channels, and chloride ion channels. Further target proteins include acetyl-CoA carboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, and enolpyruvirshikimicate-phosphate synthase.

[0121] Haloalkane dehalogenase enzymes are another target of the specific compounds of the present invention. Chloroalkane peptide bond moieties (C1-C 12 In many cases, approximately C2~C 10Compounds of the present invention containing an alkylhalo group can be used to inhibit and / or degrade haloalkane dehalogenase enzymes used in fusion proteins or related diagnostic proteins, as described in PCT / US 2012 / 063401, filed on 6 December 2011 and published on 14 June 2012 as WO 2012 / 0786559, the contents of the aforementioned patent are incorporated herein by reference.

[0122] These various protein targets may be used in a screen to identify compound moieties that bind to proteins, and by incorporating these moieties into the compounds of the present invention, the level of protein activity may be modified for the final therapeutic outcome.

[0123] The term “disease condition or state” is used to describe any disease condition or state in which protein dysregulation occurs (i.e., increased levels of protein expression in a patient) and the breakdown of one or more proteins in the patient may provide beneficial treatment or symptom relief to a patient in need. In certain cases, the disease condition or state may be curable.

[0124] Diseases that can be treated with the compounds of the present invention include, for example, autoimmune diseases such as asthma and multiple sclerosis, various cancers, ciliary disorders, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, childhood steatorrhea, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemoglobinosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease (PKD1) or PKD4 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, and Turner syndrome.

[0125] Further disease conditions or states that can be treated with 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, flu, metabolic syndromes, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette's syndrome, and vasculitis.

[0126] Further disease conditions or states that can be treated with the compounds of the present invention include, in particular, ceruloplasmin deficiency, type II achondroplasia, achondroplasia, acrocephaly, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polycolon polyps, ALA dehydration deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydration deficiency, alkaptonuria, Alexander disease, alkaptonuric ocronosis, alpha-1 antitrypsin deficiency, and alpha-1 proteinase inhibitors. , emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, enamel hypoplasia, ALA dehydrase deficiency, Anderson-Fabri disease, androgen insensitivity syndrome, anemia, diffuse angiokeratoma of the body, retinal hemangioma (von Hippel-Lindau disease), Apert syndrome, spider finger (Marfan syndrome), Stickler syndrome, congenital polyarthralgia (Ehlers-Danlos syndrome #arthralgia type), telangiectasia ataxia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Behle-Stevenson gyroscal syndrome, Mediterranean fever, familial, Benjamin syndrome, beta-thalassemia bilateral acoustic neurofibromatosis (type II neurofibromatosis), factor V Leiden thrombosis, Bloch-Salzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnewi-Ulrich syndrome (Turner syndrome), Brunneville disease (tubular sclerosis), prion disease, Birt-Hogg-Dubé syndrome, osteoporosis (osteogenesis imperfecta), broad thumb-toe syndrome (Rubinstein-Taybe syndrome), bronze-colored diabetes / bronze-colored cirrhosis (hemochromatosis), medullary spinal muscular atrophy (Kennedy disease), Bürger-Glitz syndrome (lipoprotein lipase deficiency), CGD (chronic granulomatous disease), flexor limb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat cry syndrome, CAVD (congenital absence of vas deferens), Kyler's cardiomyopathy (CBAVD), CEP (congenital erythropoiesis-porphyria), cystic fibrosis, congenital hypothyroidism, chondrodysplasia (achondroplasia), ostracogeal megaepiphysis, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, fatal osteodysplasia, Coffin-Lowry syndrome, Cockayne syndrome,Familial adenomatous polyposis, congenital erythropoiesis-porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, conotibial stump anomalous facies syndrome, Cooley's anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes' disease), hereditary coproporphyria, Cowden syndrome, craniofacial malformations (Cruzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Kruschmann-Batten-Steinert syndrome (myotonic dystrophy) ), Behle-Stevenson gyriform scalp syndrome, primary hyperoxaluria, spondyloepiphysital dysplasia (Stradwick type), muscular dystrophy, Duchenne and Becker type (DBMD), degenerative neurological diseases including Usher syndrome, de Grouchy syndrome and Degerin-Sottas syndrome, developmental disorders, distal spinal muscular atrophy, type V, androgen insensitivity syndrome, diffuse globoid sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, short stature, erythrocytoproliferative protoporphyria, erythrocyte 5 - Aminolevulinic acid synthase deficiency, erythroproliferative porphyria, erythroproliferative protoporphyria, erythroproliferative uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, late-onset cutaneous porphyria, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), fibrocystic disease of the pancreas, fragile X syndrome, galactosemia, hereditary brain disorders, giant cell hepatitis (neonatal hemochromatosis), Glenblatt-Strandbury syndrome (pseudoxanthoma elasticum), Günther's disease (congenital erythroproliferative porphyria), hemochromatosis Cis, Hargren's syndrome, sickle cell anemia, hemophilia, myelohepatic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), androgen hyperplasia, 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 diseases including hyperoxaluria, Klinefelter syndrome, Kniist dysplasia, mottled dementia,Langer-Sardino achondroplasia, telangiectasia ataxia, Lynch syndrome, lysyl hydroxylase deficiency, Machad-Joseph disease, metabolic disorders including Kniist dysplasia, Marfan syndrome, motor disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenck syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney achondroplasia, Niemann-Pick disease, Noak syndrome (Pfeiffer syndrome), Osler-Weber-Landu disease, Peutz-Jegers syndrome, polycystic kidney disease, polyosteid fibrous dysplasia (McKune-O Lulbright syndrome, Peutz-Jeghers syndrome, Prader-Lovehart-Willi syndrome, hemochromatosis, primary hyperuricemia (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary disease (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthoma elastica), Rb (retinoblastoma), neurofibromatosis. Hausen's disease (neurofibromatosis type 1), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Licker syndrome, Riley-Day syndrome, Lucy-Lewy syndrome, severe achondroplasia with growth retardation and acanthosis nigricans (SADDAN), Lie-Fraumeni syndrome, sarcoma, mammary gland, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis), SDAT, congenital SED (congenital spondyloepiphyseal dysplasia), Stradwick type SED (spondyloepiphyseal metaphysical dysplasia, Stradwick type), SEDc (congenital spondyloepiphyseal dysplasia), SEMD, S Stradwick type (spine epiphyseal metaphysical dysplasia, Stradwick type), Sprinzen syndrome, cutaneous pigmentation disorder, Smith-Lemle-Oppitz syndrome, South African hereditary porphyria (atypical porphyria), infant-onset ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disorders, sausage-like neuropathy (hereditary neuropathy with a tendency toward compressive paralysis),This includes Treacher Collins syndrome, Triple X syndrome, Trisomy 21 (Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Floric disease, Waardenburg syndrome, Micro syndrome (Warburg Sjo Fledelius syndrome), Weissenbürcher-Zweimüller syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disorder, Weissenbürcher-Zweimüller syndrome, and xeroderma pigmentosum.

[0127] The terms “neoplasia” or “cancer” are used throughout this specification to mean cancerous or malignant neoplasms, that is, pathological processes resulting from cell proliferation that often grow more rapidly than normal and continue to grow even after the initial stimulus for new growth has ceased. Malignant neoplasms partially or completely lack structural order and functional coordination with normal tissue, most invade surrounding tissues, metastasize to several sites, recur after attempted removal, and can lead to patient death if not adequately treated. As used herein, the term neoplasm is used to describe the state of all cancerous diseases and includes or encompasses pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that can be treated either 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 carcinoma, and renal cell carcinoma; cancers of the bladder, intestines, breasts, cervix, colon, esophagus, head, kidneys, liver, lungs, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's positivity. Sarcomas including sarcomas, liposarcomas, myosarcomas, peripheral neuroepitheliomas, synovial sarcomas, gliomas, astrocytomas, oligodendronomas, ependymomas, glioblastomas, neuroblastomas, gangliocytomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, and schwannomas; sarcomas including colon cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytomas, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcomas, Hodgkin's disease, Wilms' tumor, and teratomas. Further cancers that can be treated with the compounds of the present invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell ALL, precursor B-cell lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0128] The term "bioactive agent" is used to describe agents other than the compounds of the present invention that are used in combination with the compounds of the present invention as agents having biological activity that helps to perform the intended therapy, inhibition and / or prevention / prevention using the compounds of the present invention. Preferred bioactive agents for use herein include agents having pharmacological activity similar to that which uses or administers the compounds of the present invention for that purpose, and include, for example, anticancer agents, antiviral agents including anti-HIV and anti-HCV agents, antibacterial agents, antifungal agents, and the like.

[0129] The term "further anticancer agents" is used to describe anticancer agents that can be combined with the compounds of the present invention to treat cancer. These drugs include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, and EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, adhesion plaque kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, olegobomab, Lep-etu, noratexide, azd2171, batabulin, ofatumumab, zanorimumab, edotecarin, tetrandrin, lubitecan, tesmilifene, oblimersen, tisilimmumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silengitide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanton, LY317615, Neuradiab, Vitespan, Rta 744, Sdx 102, Tarampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Seliclib;PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), es Estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperazine methyl)-indolyl-quinolone, batalanib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly10] acetate (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C; 59 H 84 N 18 Oi4-(C2H4O2) xHere x=1~2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, erbitax, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib; amifostin, NVP-LAQ824, suberoyl analide hydroxamic acid(acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Calmette-Guéran bacillus (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmutin, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilvestrom Epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechloretamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, larcitrexed, rituximab Simab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, phloxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, barrubicin, mitramycin, vinblastine, vinorelbine, to Potecan, Lazoxin, Marimast, COL-3, Neovastat, BMS-275291, Squalamine, Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Doroxifene, Idoxifene, Spironolactone, Finasteride, Cymitidine, Trastuzumab, Denileukin Difutitox, Gefitinib, Bortezimib, Paclitaxel, Paclitaxel without Cremofor, Docetaxel, Epithilone BB) BMS-247550, BMS-310705, Droloxifen, 4-Hydroxytamoxifen, Pipendoxifen, ERA-923, Alzoxifen, Fulvestrant, Acorbifen, Lasofoxifen, Idoxifen, TSE-424, HMR-3339, ZK186619, Topotecan, PTK787 / ZK222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, walnutmannin, ZM336372, L-779, 450, PEG-filgrastim, da Rubepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetanTiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonose This includes thorone, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0130] The terms “anti-HIV agents” or “further anti-HIV agents” include, for example, nucleoside reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., those not typical of the present invention), protease inhibitors, and fusion inhibitors, the exemplary compounds of which include, for example, 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), and D-D4FC (Reverse Set (Reverse This may include mixtures thereof, including t), D4T (stabuzin), Lacivir, L-FddC, L-FD4C, NVP (nevirapine), DLV (delavirdine), EFV (efavirenz), SQVM (saquinavir mesylate), RTV (ritonavir), IDV (indinavir), SQV (saquinavir), NFV (nelfinavir), APV (amprenavir), LPV (lopinavir), fusion inhibitors such as T20, Fuseon, and anti-HIV compounds currently in clinical trials or under development.

[0131] Other anti-HIV agents that can be used in co-administration with the compounds of the present invention include, for example, other NNRTIs (i.e., NNRTIs other than those of the present invention), particularly nevirapine (BI-R6-587), delavirdin (U-90152S / T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl3-francarbotiamide), etravirine (TMC125), trovirdin (Ly300046.HCl), MKC-442 (emivirin, coactinon), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, and HBY. 097, DMP266, Baicalin (TJN-151) ADAM-II (3',3'-dichloro-4',4''-dimethoxy-5',5''-bis(methoxycarbonyl)-6,6-Diphenylhexanoate methyl), 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hepta-1-enyl)-2-methoxybenzoate methyl (alkenyldiarylmethane analog, Adam analog), 5Cl3PhS-2IndolCONH2 (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), caplavillin (AG-1549, S-1153), atevirdin (U-87201E), orintricarboxylic acid (SD-095345), 1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine (Pyridinyl) Piperazine (1-pyridine 4-indolyl derivative), 1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine (piperazine 1-pyridine 5-indolyl derivative), 1-[3-(ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine, 1-[(6-formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[[5-(methylsulfonyloxy)-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, U88204E, bis(2-nitrophenyl)sulfone (NSC 633001), Caranolid A (NSC675451), Caranolid B, 6-benzyl-5-methyl-2-(cyclohexyloxy)pyrimidine-4-one (DABO-546), DPC 961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (Foscavir), HEPT (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M (1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine), HEPT-S (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine), Inofilm P, L-737,126, Mikelamin A (NSC650898), Mikelamin B (NSC649324), Mikelamin F, 6-(3,5-Dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-Dimethylbenzyl)-1-(ethioxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC 648400), Ortiplasm (4-methyl-5-(pyradinyl)-3H-1,2-dithiol-3-thion), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (PETT Cl, F derivative), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)] thiourea (PETT derivative), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-methylpyridyl)] thiourea (PETT pyridyl derivative), N-[2-(3-fluorofuranyl)ethyl]-N'-[2-(5-chloropyridyl)] thiourea, N-[2-(2-fluoro-6-ethoxyphenethyl)]-N'-[2-(5-bromopyridyl)] thiourea, N-(2-phenethyl)-N'-(2-thiazolyl) thiourea (LY-73497), L-697,639 L-697,593, L-697,661, 3-[2-(4,7-difluorobenzoxazole-2-yl)ethyl]-5-ethyl-6-methyl(pyridinone-2(1H)-thion (2-pyridinone derivative), 3-[[(2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pyridinone-2(1H)-thion (2-pyridinone-3pyrido-3MeNH derivative), R82150, R82913, R87232, R88703, R89439 (Roviride), R90385, S-2720, Suramin sodium, TBZ (thiazolobenzimidazole, NSC 625487), thiazoloisoindole-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindole-5(9bH)-one, tibirapine (R86183), UC-38 and UC-84 may be selected from this group.

[0132] The term “pharmaceutically acceptable salt” is used throughout this specification to describe one or more salt forms of the compounds described herein that are presented to enhance the solubility of the compounds in gastric juice of a patient’s gastrointestinal tract, where applicable, in order to promote the dissolution and bioavailability of the compounds. Pharmaceutically acceptable salts include, where applicable, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, and ammonium salts, among many other acids and bases known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralized salts of the phosphates of the present invention.

[0133] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (such as esters, amides, or other prodrug groups) that directly or indirectly provide the compound of the present invention or an active metabolite of the compound of the present invention after administration to a patient.

[0134] The term "independently" is used herein to indicate that the variables applied independently vary independently from application to application.

[0135] The term "hydrocarbyl" refers to compounds that contain carbon and hydrogen and can be fully saturated, partially unsaturated, or aromatic, including aryl, alkyl, alkenyl, and alkynyl groups.

[0136] The term "alkyl" in this context refers to a linear, branched, or cyclic fully saturated hydrocarbon group or alkyl group, preferably C1-C11. 10, more preferably C1-C6, or C1-C3 alkyl groups, which may be substituted. Examples of alkyl groups include, in particular, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl. Compounds of the present invention that can be used to covalently bond to dehalogenase enzymes in certain preferred embodiments. These compounds generally include a side chain (often linked via polyethylene glycol groups) having an alkyl group at its distal end with a halogen substituent (often chlorine or bromine), thereby allowing the compound containing such a moiety to covalently bond to a protein. The term "alkenyl" refers to a linear, branched, or cyclic C2-C3 chain containing at least one C=C bond. 10 (Preferably C2-C6) hydrocarbon group. The term "alkynyl" refers to a linear, branched, or cyclic C2-C bond containing at least one C≡C bond. 10 (Preferably C2-C6) refers to a hydrocarbon group. When the term "alkylene" is used, this refers to -(CH2) n- means a group (where n is generally an integer from 0 to 6) and may be substituted. If substituted, the alkylene group is preferably substituted with a C1-C6 alkyl group (including a cyclopropyl group or a t-butyl group), more preferably a methyl group, at one or more methylene groups, but may be substituted with one or more halo groups, preferably one to three halo groups or one or two hydroxyl groups, an O-(C1-C6 alkyl) group or an amino acid side chain as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a urethane or alkoxy group (or other group), which is further substituted with a polyethylene glycol chain (1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units), which is substituted with an alkyl chain substituted with one halogen group, preferably a chlorine group (preferably at the distal end of the polyethylene glycol chain, but not limited thereto). In yet another embodiment, the alkylene (often methylene) group may be substituted with an amino acid side chain, such as alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine.

[0137] The term "unsubstituted" means that substitution is only with hydrogen atoms. The range of carbon atoms including C0 means that there is no carbon and it is replaced by H. Therefore, the range of carbon atoms C0-C6 includes 1, 2, 3, 4, 5 and 6 carbon atoms, and for C0, H is in place of carbon. The terms "substituted" or "may be substituted" independently (i.e., if multiple substituents appear, each substituent is independent of the other substituents) mean one or more substituents on carbon (or nitrogen) at any position on the molecule within the context (independently, up to 5 substituents in a part of the compound of the present invention, preferably up to 3 substituents, often 1 or 2 substituents, which themselves may be further substituted), and substituents include hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO2), halogen (preferably, trifluoromethyl, especially alkyl, especially 1, 2 or 3 halogens on the methyl group), alkyl (preferably C1-C) 10More preferably C1-C6), aryl (particularly phenyl and substituted phenyl, e.g., benzyl or benzoyl), alkoxy group (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), alkylene ester (the bond is on an alkylene group rather than an ester functional group, which is preferably substituted with a C1-C6 alkyl or aryl group), preferably ester or thioester containing a C1-C6 alkyl or aryl (preferably C1-C6 alkyl or aryl), halogen (preferably F or Cl), amine (including 5 or 6-membered cyclic alkyleneamine, C1-C6 The present invention further comprises alkylamines or C1-C6 dialkylamines, wherein the alkyl group may be substituted with one or two hydroxyl groups) or substituted -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) groups (which may be substituted with polyethylene glycol chains, which are further bonded to alkyl groups containing one halogen, preferably a chlorine substituent), hydrazines, amides preferably substituted with one or two C1-C6 alkyl groups (including carboxamides which may be substituted with one or two C1-C6 alkyl groups), alkanols (preferably C1-C6 alkyl or aryl), or alkanoic acids (preferably C1-C6 alkyl or aryl). Substituents of the present invention include, for example, the -SiR1R2R3 group, where R1 and R2 are as separately described herein, and R3 is H or a C1-C6 alkyl group, preferably R1, R2, and R3 in this context are C1-C3 alkyl groups (including isopropyl or t-butyl groups). Each of the aforementioned groups may be directly bonded to the substituted moiety, or the substituent may be substituted on the substituted moiety (preferably an aryl or heteroaryl moiety) - (CH2) m -or may be substituted-(OCH2) m -,-(OCH2CH2) m -or-(CH2CH2O) m-The group may be linked through a substituent, which may be substituted with any one or more of the substituents mentioned above. Alkylene group-(CH2) m -or-(CH2) n - The group or other chains, such as the ethylene glycol chain specified above, may be substituted at any point on the chain. Preferred substituents on the alkylene group include halogens or C1-C6 (preferably C1-C3) alkyl groups, which may be substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or amino acid side chains as otherwise described herein, and optionally substituted amides (preferably carboxamides substituted as described above) or urethane groups (often having one or two C0-C6 alkyl substituents, the groups of which may be further substituted). In certain embodiments, the alkylene group (often one methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl groups, or amino acid side chains as otherwise described herein. In the present invention, the intramolecular portion may be substituted with up to five substituents, preferably up to three substituents. In most cases, the substituted portion in the present invention is substituted with one or two substituents.

[0138] The term "substituted" (where each substituent is independent of any other substituent) also, within the context of its use, means C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carboxamide, sulfone including sulfonamide, keto, carboxy, C1-C6 ester (oxyester or carbonyl ester), C1-C6 keto, urethane-OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano and amine (in particular C1-C6 alkylene-NR1R2, mono- or di-C1-C6 alkylsubstituted amines, which may be substituted with one or two hydroxyl groups). Each of these groups, within the context, contains between 1 and 6 carbon atoms unless otherwise specified. In certain embodiments, preferred substituents include, depending on the context of the substituent's use, e.g., -NH-, -NHC(O)-, -O-, =O, -(CH2) m -(where m and n are 1, 2, 3, 4, 5, or 6 in the context), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1~C6 alkyl), -(CH2) n C(O)-(C1~C6 alkyl), -(CH2) n OC(O)-(C1~C6 alkyl),-(CH2) n C(O)O-(C1~C6 alkyl),-(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2, -(OCH2) n OH, -(CH2O) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1~C6 alkyl), -(CH2O) n C(O)-(C1~C6 alkyl), -(OCH2) n NHC(O)-R1, -(CH2O) n C(O)-NR1R2, -S(O)2-R S ,-S(O)-R S (RS C1-C6 alkyl or -(CH2) m The alkylene group is preferably a C1-C6 alkyl group (which is an NR1R2 group), NO2, CN, or a halogen (F, Cl, Br, I, preferably F or Cl). R1 ​​and R2 are, in the context of this specification, H or a C1-C6 alkyl group (which may be substituted with one or two hydroxyl groups or up to three halogen groups, preferably substituted with fluorine). The term "substituted" also means, in the context of the chemical context of the defining compound and the substituents used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as otherwise disclosed herein. The alkylene group is preferably an optionally substituted C1-C6 alkyl group (which may be methyl, ethyl, or hydroxymethyl or hydroxyethyl, thus providing a chiral center), a side chain of an amino acid group as otherwise described herein, an amide group as otherwise disclosed herein, or a urethane group OC(O)-NR1R2 group where R1 and R2 are as otherwise described herein, which may be substituted as otherwise disclosed herein, but many other groups can also be used as substituents. Various substituted portions may be substituted with three or more substituents, preferably three or fewer substituents, preferably one or two substituents. It should be noted that in a compound, substitution is required at a specific position of the molecule (primarily for valence reasons), but if the substitution is not shown, that substituent is interpreted or understood to be H unless the context of the substitution suggests otherwise.

[0139] The terms “aryl” or “aromatic” in context mean a substituted (as otherwise described herein) or unsubstituted monovalent aromatic group having a monocyclic (e.g., benzene, phenyl, benzyl) or fused ring (e.g., naphthyl, anthracenyl, phenantrenyl, etc.) structure, which can be attached to the compounds of the present invention at any possible stable position on the ring or as shown in the chemical structures presented separately. Other examples of aryl groups may include, in context, heterocyclic aromatic ring “heteroaryl” groups having one or more nitrogen, oxygen, or sulfur atoms in a ring (monocyclic) or fused ring system such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, etc., which may be substituted as described above.Among the heteroaryl groups that can be mentioned, in particular, are pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indidine, azaindidine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinoridine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, perimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, and py This includes nitrogen-containing heteroaryl groups such as lolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, thiadiazole, isothiazosol, benzoxazole, benzothiadiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, phlopyrrole, pyridoxazine, phlopyridine, phlopyrimidine, thienofyrimidine and oxazole, all of which may be substituted.

[0140] The term "heterocyclic" refers to a cyclic group that contains at least one heteroatom, i.e., O, N, or S, and may be aromatic (heteroaryl) or non-aromatic. Therefore, heteroaryl moieties are included under the definition of heterocyclic, depending on the context of their use. Exemplary heteroaryl groups are described herein. Exemplary non-aromatic heterocyclic groups for use in the present invention include, for example, pyrrolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl, pyridone, 2-pyrrolidone, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, phthalimide, and succinimide.

[0141] As used herein, terms such as “to treat,” “to treat,” and “treatment” mean any action that benefits a patient to whom the compounds of the present invention can be administered, including treatment of any disease situation or condition regulated through the protein to which the compounds of the present invention are bound. Disease situations or conditions, including cancer, that can be treated with the compounds of the present invention are described herein prior to this.

[0142] The terms “concurrent administration” or “combination therapy” mean administering at least two compounds or compositions to a patient simultaneously such that effective amounts or concentrations of each compound are recognized in the patient at a given time. The compounds of the present invention may be administered concurrently to a patient at the same time, but the term includes both administration of two or more drugs at the same or different time points, provided that effective concentrations of all concurrently administered compounds or compositions are recognized in the subject at a given time. In a particular preferred aspect of the present invention, one or more of the aforementioned compounds of the present invention are administered concurrently in combination with at least one additional bioactive agent, particularly including an anticancer agent. In a particularly preferred aspect of the present invention, the concurrent administration of compounds results in a synergistic therapy, including anticancer therapy.

[0143] A further aspect of the present invention is a pharmaceutical composition comprising, in combination with a pharmaceutically effective amount of at least one bifunctional compound of the present invention and one or more combinations of compounds otherwise described herein in all effective amounts, a pharmaceutically effective amount of a carrier, additive or excipient.

[0144] The present invention includes, where applicable, compositions comprising pharmaceutically acceptable salts of the compounds of the present invention, particularly acid or base addition salts. Acids used to prepare pharmaceutically acceptable acid addition salts of the aforementioned basic compounds useful in the present invention are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, particularly hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, phosphates, acidic phosphates, acetates, lactates, citrates, acidic citrates, tartrates, hydrogen tartrates, succinates, maleates, fumarates, glucons, sugarates, benzoates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates [i.e., 1,1'-methylene-bis-(2-hydroxy-3 naphthoate)].

[0145] Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives of the present invention. Chemical bases that can be used as reagents for preparing pharmaceutically acceptable basic salts of the compounds of the present invention, which are inherently acidic, are those that form non-toxic basic salts with such compounds. Such non-toxic basic salts include, but are not limited to, those derived from pharmaceutically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine) and lower alkanolammonium, and other basic salts of pharmaceutically acceptable organic amines.

[0146] The compounds of the present invention may be administered orally, parenterally, or topically in single or divided doses, according to the present invention. Administration of the active compound may range from continuous (intravenous infusion) to several oral doses per day (e.g., four times per day), and other routes of administration may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (may contain penetration enhancers), oral, sublingual, and suppository administration. Enteric-coated oral tablets may also be used to enhance the bioavailability of the compound from the oral administration route. The most effective dosage form will depend on the pharmacokinetics of the chosen specific drug and the severity of the patient's disease. The compounds of the present invention may also be administered as sprays, mists, or aerosols for intranasal, intratracheal, or pulmonary administration. Therefore, the present invention also aims at pharmaceutical compositions containing an effective amount of the compounds of the present invention in combination with optionally pharmaceutically acceptable carriers, additives, or excipients. The compounds of the present invention may be administered in immediate-release, intermediate-release, sustained-release, or controlled-release dosage forms. Sustained-release or controlled-release formulations are preferably administered orally, but can also be administered as suppositories and transdermal or other topical formulations. Intramuscular injection in liposomal form may also be used to control or sustain the release of the compound at the injection site.

[0147] The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, or administered as controlled-release formulations. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, electrolyte salts such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block copolymer, polyethylene glycol, and lanolin.

[0148] The compositions of the present invention may be administered orally, parenterally, or as inhalation sprays, topically, rectally, nasally, orally, vaginally, or via implanted reservoirs. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrabursal, intrasternal, subarachnoid, intrahepatic, intrafocal, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0149] The sterile injection formulations of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art, using appropriate dispersants or wetting agents and suspending agents. The sterile injection formulations may also be sterile injection solutions or suspensions, such as solutions in 1,3-butanediol, in non-toxic, parenterally acceptable diluents or solvents. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solutions. In addition, sterile fixative oils are conventionally used as solvents or suspensions. For this purpose, any non-irritating fixative oil containing synthetic mono- or di-glycerides may be used. Fatty acids, such as oleic acid and its glyceride derivatives, as well as naturally pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions, are useful in the preparation of injections. These oily solutions or suspensions may also include long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0150] The pharmaceutical composition of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or liquids. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension is required for oral use, the active ingredient is mixed with an emulsifier and a suspending agent. Specific sweeteners, flavorings, or colorings may be added as desired.

[0151] Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0152] The pharmaceutical compositions of the present invention may be administered topically. Suitable topical formulations can be readily prepared for each of these sites and organs. Topical application for the lower intestine can be done with rectal suppositories (see above) or suitable enema formulations. Topically acceptable transdermal patches may also be used.

[0153] For topical application, the pharmaceutical composition may be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. In certain preferred aspects of the present invention, the compounds may be coated onto a stent surgically implanted in a patient to inhibit or reduce the likelihood of occlusion occurring in the stent within the patient's body.

[0154] Alternatively, the pharmaceutical composition may be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0155] For ophthalmic use, the pharmaceutical composition may be formulated as a microsuspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment such as petrolatum.

[0156] The pharmaceutical compositions of the present invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the field of pharmaceutical formulations, and may be prepared as a solution in saline solution using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0157] The amount of compound in the pharmaceutical composition of the present invention, which can be combined with a carrier material to produce a single dosage form, will vary depending on the host and disease being treated and the specific mode of administration. Preferably, the composition should be formulated to contain about 0.05 milligrams to about 750 milligrams or more, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams of the active ingredient, either alone or in combination with at least one other compound of the present invention.

[0158] The specific dosage and administration method for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, timing of administration, elimination rate, drug combinations, and the judgment of the treating physician and the severity of the specific disease or condition during treatment.

[0159] Patients or subjects requiring treatment with the compounds of the present invention can be treated by administering an effective amount thereof, either alone or in combination with other known erythropoiesis-stimulating agents as otherwise specified herein, containing a pharmaceutically acceptable salt, solvate, or polymorph of the compound of the present invention in an optionally pharmaceutically acceptable carrier or diluent.

[0160] These compounds can be administered via any suitable route, such as orally, parenterally, intravenously, intradermally, subcutaneously, or topically, including transdermally, in liquid, cream, gel, or solid dosage form, or in aerosol dosage form.

[0161] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose for the desired indication to the patient without causing serious toxic effects in the patient being treated. Preferred doses of the active compound for all conditions referred to herein range from about 10 ng / kg to 300 mg / kg per day, preferably 0.1 to 100 mg / kg, and more generally from 0.5 to about 25 mg per kilogram of recipient / patient body weight per day. Typical topical doses range from 0.01 to 5% by weight in a suitable carrier.

[0162] The compound may contain, but is not limited to, a unit dosage form containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of the active ingredient, and can be conveniently administered in any suitable unit dosage form. An oral dose of approximately 25 to 250 mg is often convenient.

[0163] The active ingredient is administered to achieve a peak plasma concentration of the active compound, preferably about 0.00001 to 30 mM, more preferably about 0.1 to 30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient in saline or an aqueous medium, or by administration as a bolus of the active ingredient. Oral administration is also suitable for producing effective plasma concentrations of the active drug.

[0164] The concentration of the active compound in the drug composition will depend on the drug's absorption, distribution, inactivation, and elimination rates, as well as other factors known to those skilled in the art. It should be noted that the dose value will also vary depending on the severity of the condition to be alleviated. It should be further understood that for any particular subject, a specific dosage regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges shown herein are illustrative and not intended to limit the scope or implementation of the claimed composition. The active ingredient may be administered in a single dose or divided into several smaller doses administered at various intervals.

[0165] Oral compositions generally contain an inert diluent or food carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For therapeutic oral administration purposes, the active compound or its prodrug derivative can be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Pharmaceutically compatible binders and / or auxiliary materials may be included as part of the composition.

[0166] Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring. If the dose unit dosage form is a capsule, in addition to the types of materials described above, it may also contain a liquid carrier such as fatty oil. In addition, the dose unit dosage form may also contain various other materials that modify the physical form of the dose unit, such as a coating of sugar, shellac, or enteric solvent.

[0167] The active compound or a pharmaceutically acceptable salt thereof can be administered as an ingredient in elixirs, suspensions, syrups, wafers, chewing gums, and the like. In addition to the active compound, the syrup may contain sucrose as a sweetener, certain preservatives, colorants, and flavorings.

[0168] The active compound or a pharmaceutically acceptable salt thereof may also be mixed with other active materials that do not impair the desired effect, or with materials that supplement the desired effect, such as erythropoietin stimulants, particularly those containing EPO and darbepoetin alfa. In certain preferred aspects of the present invention, one or more compounds of the present invention are administered co-administered with another bioactive agent, such as an erythropoietin stimulant or wound healing agent, including an antibiotic, as otherwise described herein.

[0169] Liquids or suspensions used for parenteral, intradermal, subcutaneous, or topical application may contain the following components: sterile diluents such as water for injection, saline solution, fixative oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and actionants for adjusting tonicity such as sodium chloride or dextrose. Parenteral formulations may be sealed in glass or plastic ampoules, disposable syringes, or multi-dose vials.

[0170] When administered intravenously, the preferred carrier is physiological saline or phosphate-buffered saline (PBS).

[0171] In one embodiment, the active compound is prepared with a carrier that protects the compound from rapid elimination from the body, such as a controlled-release formulation, which includes an implant and a microencapsulation delivery system. Biodeg...

Claims

1. Compounds with the following chemical structures, or their pharmaceutically acceptable salts, enantiomers, or diastereomers: ULM-L-PTM During the ceremony i) ULM has the following structure: It is a small molecule that binds to von Hippel-Lindau E3 ubiquitin ligase (VHL), and in the formula... R 1' is OH; R 2' -NR 1 -CH 2 -phenyl-oxazole or -NR 1 -CH 2 -phenyl-thiazole, and here, R 2' The phenyl inside is CH 3 Alternatively, it may be substituted with OH; R 2' The oxazole and thiazole in it may be independently substituted with at least one substituent selected from the group consisting of C 1 to C 3 alkyl and halogen; R 1 Each occurrence of H or C is independent of H or C 1 ~C 3 It is alkyl; R 3' is, -(CH 2 ) n -(V) n' -(CH 2 ) n -(V) n' -R S3' group, -(CH 2 ) n -N(R 1' )(C=O) m' -(V) n' -R S3' group, -X R3' -alkyl group, -X R3' -Aryl group; -X R3' -HET base, -X R3' -aryl-HET group, or -X R3' -HET-aryl group, where R 3' inside (i) Each occurrence of n is independently 0, 1, 2, 3, 4, 5, or 6; (ii) n' is either 0 or 1; (iii) m' is either 0 or 1; (iv) Each -(CH2)n- group may be independently substituted with a C1-C3 alkyl group; R S3' C 1 ~C 6 It is an alkyl group, an aryl group, or an HET group; R 3' and R S3' The HETs defined within are selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, imidazolidine-2-one, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, pyridone, piperidine, piperazine, morpholine, benzofuran, indole, isoindrone, indoridine, azaindridine, and quinoline, each of which is C 1 ~C 3 It may be substituted with at least one substituent selected from the group consisting of alkyl, O(C1-C6 alkyl), and halo; R 3' and R S3’ The aryls defined within are F, Cl, Br, OH, OMe, OEt, and NH. 2 CH 3 phenyl, hydroxyl-substituted phenyl, CH 2 A phenyl molecule that may be substituted with at least one substituent selected from the group consisting of CN, -(CH2)nO(C1-C6) alkyl, and CN, where n is 0, 1, 2, 3, 4, 5, or 6; R 1' H or C 1 ~C 3 It is alkyl; Each occurrence of V is independently O, S, or NR 1' And; X R3' is, -(CH 2 ) n -, or F, Cl, Br, OH, OMe, OEt, NH 2 CH 3 phenyl, hydroxyl-substituted phenyl, CH 2 (CH) may be substituted with at least one substituent selected from the group consisting of CN and CN. 2 CH 2 O) n -and; Each occurrence of n is independently 0, 1, 2, 3, 4, 5, or 6; ii) PTM is as follows: (Here R is (It is the basis), and (Here R is It is a small protein targeting moiety that binds to a target protein selected from the group consisting of (the base); iii) L is a chemical linker moiety that covalently bonds ULM and PTM, and the chemical linker moiety is R of ULM. 2’ or R 3’ It is connected and Lは、-(CH 2 ) i -AND 2 -CH 2 -O) i -、-(CH 2 ) i -NR-,-(CH 2 ) i -X 1 Y 1 -、 , and at least one member selected from the group consisting of combinations thereof, -(CH2)i-NR- group: R is H, C 1 ~C 3 It is an alkyl, alkanol, morpholino, piperidinyl, or piperazinyl group; X 1 Y 1 It forms an amide group, urethane group, ester group, or thioester group; Each occurrence of D is independent, combined (not present), And; Y is independently a combination, O, S, or NR. Each R in the NR group is independently either H or C1-C3 alkyl. Each occurrence of i is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; m' is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; X 1 Each occurrence of is independently O, S, or NR; CON is a bond (non-existent), a piperazinyl group, an optionally substituted alkylene, a heterocycle, And, however, At least one D or CON inside is not a bond (it does not exist); However, L is -(CH 2 -CH 2 -O) i -If i is not 0; X 2 は、O、S、NR 4 、S(O)、S(O) 2 ,-ONLY) 2 O、-OS(O) 2 、またはOS(O) 2 Oであり; X 3 Each occurrence of O, S, and CHR is independent of the others. 4 , or NR 4 and R 4 Each occurrence of 1 is independently H or a C 3 -C alkyl group which may be substituted with one or two hydroxyl groups.

2. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable excipient.

3. ULM is as follows: A compound according to claim 1, selected from the group consisting of the following.

4. ULM is as follows: A compound according to claim 1, selected from the group consisting of the following.

5. ULM is as follows: A compound according to claim 1, selected from the group consisting of the following.

6. ULM is as follows: The compound according to claim 1, which is a member selected from the group consisting of the following.

7. A compound having the following chemical structure, or a pharmaceutically acceptable salt thereof, enantiomer, or diastereomer: ULM-L-PTM During the ceremony ULM has the following structure: The ULM is a small molecule that binds to von Hippel-Lindau E3 ubiquitin ligase (VHL), and the ULM is selected from the group consisting of: wherein, R 1PC R 2PC R 8PC R 9PC R 10PC R 11PC R 12PC R 13PC and R 14PC each independently is H, C 1 to C 3 alkyl, or And; R 3PC , R 4PC , R 5PC , and R 6PC Each of these is independently H or CH 3 and; R 7PC H or And; ii) PTM is as follows: (Here R is (It is the basis), and (Here R is It is a small protein targeting moiety that binds to a target protein selected from the group consisting of (the base); iii) L is a chemical linker moiety that covalently bonds ULM and PTM, and the chemical linker moiety is bonded to R 2' or R 3' of ULM, and L is -(CH 2 ) i -O-, -(CH 2 -CH 2 -O) i -, -(CH 2 ) i -NR-, -(CH 2 ) i -X 1 Y 1 -, , and at least one member selected from the group consisting of combinations thereof, The R in the -(CH2)i-NR- group is H, C1-C3 alkyl, alkanol group, morpholino, piperidinyl, or piperadinyl group; X 1 Y 1 forms an amide group, a urethane group, an ester group, or a thioester group; Each occurrence of D is independent, combined (not present), And; Y is independently a combination, O, S, or NR. Each R in the NR group is independently either H or C1-C3 alkyl. Each occurrence of i is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; m' is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of X 1 is independently O, S, or NR; CON is a bond (non-existent), a piperazinyl group, an optionally substituted alkylene, a heterocycle, And, however, At least one D or CON inside is not a bond (it does not exist); However, if L is -(CH₂-CH₂-O)i-, then i is not 0; X2 is O, S, NR4, S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O; Each occurrence of X 3 is independently O, S, CHR 4, or NR 4; and Each occurrence of R4 is independently a C1-C3 alkyl group which may be substituted with H or one or two hydroxyl groups.

8. ULM has the following chemical structure: It has R 10PC but , C 1 ~C 3 The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl or H.

9. ULM has the following structure: It has R 7PC、 R 8PC、 R 9PC , and R 10PC Each of them is independently H or The compound according to claim 7.

10. A compound having the following chemical structure, or a pharmaceutically acceptable salt thereof, enantiomer, or diastereomer: ULM-L-PTM During the ceremony ULM has the following structure: The ULM is a small molecule that binds to von Hippel-Lindau E3 ubiquitin ligase (VHL), and the ULM is selected from the group consisting of the following: ii) PTM is as follows: (Here R is (It is the basis), and (Here R is It is a small protein targeting moiety that binds to a target protein selected from the group consisting of (the base); iii) L is a chemical linker moiety that covalently bonds ULM and PTM, and the chemical linker moiety is bonded to R 2' or R 3' of ULM, and L is -(CH 2 ) i -O-, -(CH 2 -CH 2 -O) i -, -(CH 2 ) i -NR-, -(CH 2 ) i -X 1 Y 1 -, , and at least one member selected from the group consisting of combinations thereof, The R in the -(CH2)i-NR- group is H, C1-C3 alkyl, alkanol group, morpholino, piperidinyl, or piperadinyl group; X 1 Y 1 forms an amide group, a urethane group, an ester group, or a thioester group; Each occurrence of D is independent, combined (not present), And; Y is independently a combination, O, S, or NR. Each R in the NR group is independently either H or C1-C3 alkyl. Each occurrence of i is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; m' is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of X 1 is independently O, S, or NR; CON is a bond (non-existent), a piperazinyl group, an optionally substituted alkylene, a heterocycle, And, however, At least one D or CON inside is not a bond (it does not exist); However, if L is -(CH₂-CH₂-O)i-, then i is not 0; X2 is O, S, NR4, S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O; Each occurrence of X 3 is independently O, S, CHR 4, or NR 4; and Each occurrence of R4 is independently a C1-C3 alkyl group which may be substituted with H or one or two hydroxyl groups.

11. A pharmaceutical composition for treating or preventing a disease or disorder in a subject requiring such treatment, comprising an effective amount of the compound according to any one of claims 1, 7, and 10, wherein the disease or disorder is breast cancer or prostate cancer.

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