Targeted bifunctional decomposition agents and methods of use thereof

Abstract

In one aspect, the present disclosure provides bifunctional compounds that can be used to promote or enhance the degradation of extracellular or cell surface proteins.In certain embodiments, the extracellular proteins mediate disease and / or disorders in a subject, and the treatment or management of the disease and / or disorders requires the degradation, removal, and / or reduction of the concentration of the proteins in the subject.In some embodiments, the disease and / or disorders are neurological diseases and / or disorders.Thus, in certain embodiments, administering the compounds of the present disclosure to a subject removes or reduces the amount of extracellular or cell surface proteins in the brain, thereby treating, ameliorating, or preventing the disease and / or disorders. TIFF2024507523000458.tif98170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 152,110, entitled "TARGETED BIFUNCTIONAL DEGRADERS," filed February 22, 2021, the entire disclosure of which is incorporated herein by reference.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under GM067543 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0003] Background of the disclosure Accumulation and aggregation of pathogenic proteins in the brain causes some neurological diseases.However, current treatment options, especially for Alzheimer's disease, aim to improve symptoms without addressing the underlying cause of pathogenic proteins or slowing the progression of the disease.For example, potential Alzheimer's disease treatment may involve regulating various pathogenic proteins located in the brain, including but not limited to inflammatory cytokines, extracellular tau, and β-amyloid.

[0004] There is a need in the art for new compounds and methods that allow for the inhibition, removal, and / or degradation of specific extracellular or cell surface proteins that mediate diseases and / or disorders in a subject. The present disclosure addresses this need. Summary of the Invention

[0005] A brief summary of disclosures In one aspect, there is provided a compound of formula (I), or a salt, geometric isomer, stereoisomer, or solvate thereof. The compound of formula (I) has the following structure: [TBM] n -[Linker]m -[LRP1BM] o (I) During the ceremony, m is an integer from 0 to 15; n and o each independently represent an integer of 1 to 15; [TBM] is: (a) A compound selected from TIFF2024507523000002.tif220136, or a derivative or prodrug thereof (In the formula, TIFF2024507523000003.tif6128 indicates possible covalent attachment points to [linker] or [LRP1BM]); (b) Formula (I): Compound of TIFF2024507523000004.tif30128, or a derivative or prodrug thereof (In the formula, A is N or CR 5 and; B is N or CR 6 and; E is N or CR 7 and; L is a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heteroalkylene, a bond, -O-, -NR A -, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR A -, -NR A C(=O)-, -NR A C(=O)R A -, -C(=O)R A -, -NR A C(=O)O-, -NR A C(=O)N(R A )-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R A )-, -S(O)NR A -, -NR AS(O)2-, or a combination thereof; X is a bond or a substituted or unsubstituted C 1~12 alkylene, where one or more carbons are C(=O), O, S, SO2, NH, or halogen, OH, or C 1~6 NC optionally substituted with alkyl 1~6 optionally substituted with alkyl; R 8 is hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1~6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are halogen, SO, NH, or halogen or C. 3~8 Optionally substituted with cycloalkyl 1~6 optionally substituted with alkyl; R 3 Ha-(CH2) n -, -(CH2) n -C(=O), -(CH2) n -C(=O)-O-, -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -A-NR A-(CH2) n -(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; R A each occurrence of R is independently selected from hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or, if attached to a nitrogen atom, a nitrogen protecting group; or A the groups taken together form a substituted or unsubstituted heterocycle; each occurrence of A is independently selected from substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 1 , R 2 , and R 4 ~R 8 are each independently hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3~8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; Here, R 1 ~R 7 One or more carbons in the formula are C(=O), O, S, SO2, NH, NH-C 1~6 Alkyl, NC 1~6 Alkyl, NH2, or N(C 1~6alkyl)2; TIFF2024507523000005.tif6128 indicates the covalent attachment point to [linker] or [LRP1BM]); (c) Formula (II): Compound of TIFF2024507523000006.tif22128, or a derivative or prodrug thereof (In the formula, R1 and R2 are each independently hydrogen, N3, alkynyl, OH, halogen, NH2, N(C 1~6 Alkyl)2, C 1~6 Alkyl, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3~8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 More selected; wherein the aryl and heteroaryl are halogen, -SO2, NO2, -NH2, or halogen or C 3~8 Optionally substituted with cycloalkyl 1~6 optionally substituted with alkyl; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; Here, R 1 or R 2 One or more carbons in the formula are C(=O), O, S, SO2, NH, NH-C 1~6 Alkyl, NC 1~6 Alkyl, NH2, or N(C 1~6 alkyl)2; TIFF2024507523000007.tif6128 indicates the covalent attachment point to [linker] or [LRP1BM]); (d) Formula (III): Compound of TIFF2024507523000008.tif26128, or a derivative or prodrug thereof (In the formula, R1 is selected from benzene, phenyl, cyclohexyl, hydrogen, and CF3; R2 is selected from hydrogen and CF3; TIFF2024507523000009.tif6128 indicates the covalent attachment point to [linker] or [LRP1BM]); (e) Formula (IV): Compound of TIFF2024507523000010.tif45128, or a derivative or prodrug thereof (In the formula, R1 is selected from hydrogen, Cl, OMe, SMe, and CF3; TIFF2024507523000011.tif6128 indicates the covalent attachment point to [linker] or [LRP1BM]); (f) Formula (V): Compound of TIFF2024507523000012.tif44128, or a derivative or prodrug thereof (In the formula, R1 is selected from hydrogen, Cl, OMe, SMe, and CF3; TIFF2024507523000013.tif6128 indicates the covalent attachment point to [Linker] or [LRP1BM]); or (g) Amino acid sequence selected from TIFF2024507523000014.tif33128 represents a target binding motif comprising or consisting of: [LRP1BM] has the following amino acid sequence: TIFF2024507523000015.tif34128 (wherein R8 represents (R)-2-(7-octenyl)Ala-OH and S5 represents (S)-2-(4-pentenyl)Ala-OH, and there is a hydrocarbon bridge between positions 1 and 8); TIFF2024507523000016.tif19128 (where Nle stands for norleucine), TIFF2024507523000017.tif98128, in which an underlined amino acid indicates that the amino acid may or may not be present, and an underlined K / C indicates that K or C may be present; [Linker] represents a polyethylene glycol-containing linker having 1 to 12 ethylene glycol residues, or [Linker] is one of the following: (a) -CH2CH2(OCH2CH2) m OCH2-, -(CH2) m CH2- or -[N(R a )-CH(R b )(C=O)] m - or a polypropylene glycol or polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units (In the formula, Each R a are independently H, C1-C3 alkyl, or C1-C6 alkanol, or R b together with the compound to form a pyrrolidine or hydroxypyrroline group; Each R b is independently selected from the group consisting of hydrogen, methyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)3-guanidine, -CH2C(=O)NH2, -CH2C(=O)OH, -CH2SH, -(CH2)2C(=O)NH2, -(CH2)2C(=O)OH, -(CH2)imidazole, -(CH2)4NH2, -CH2CH2SCH3, benzyl, -CH2OH, -CH(OH)CH3, -(CH2)imidazole, or -(CH2)phenol; m is an integer ranging from 1 to 15); (b) -[N(R'-(CH2) 1~15 -C(=O)] m - (wherein R' is H or C1-C3 alkyl optionally substituted with 1-2 hydroxyl groups, and m is an integer ranging from 1 to 100); (c) -ZD-Z'- (In the formula, Z and Z' are each independently a bond, -(CH2) i -O-, -(CH2) i -S-, -(CH2) i -N(R)-, TIFF2024507523000018.tif10128, -(CH2) i -C(R 2 )=C(R 2 )-(cis or trans), -(CH2) i -≡- or -YC(=O)-Y-, each R is independently H, C1-C3 alkyl, or C1-C6 alkanol; Each R 2 are independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N(R); Each i is independently between 0 and 100; D is a bond, -(CH2) i -YC(=O)-Y-(CH2) i -, -(CH2) m' - or -[(CH2) n -X1)] j with the proviso that Z, Z', and D are not each simultaneously a bond; X1 is O, S, or N(R); j is an integer ranging from 1 to 100; m' is an integer ranging from 1 to 100; n is an integer ranging from 1 to 100); (d) -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n' CH2CH2- or -(CH2CH2CH2O) n - (In the formula, n and n′ each independently represent an integer ranging from 1 to 25; (e) -PEG-CON-PEG- wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues; and CON is TIFF2024507523000019.tif116128, wherein R' and R'' are each independently H, methyl, or a bond; (f) -PEG-CON-PEG- wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues; and CON is -C(=O)-N(R 1 )-(CH2) n'' -N(R 1 )C(=O)-, -N(R 1 )-C(=O)(CH2) n'' -C(=O)N(R 1 )- or -N(R 1 )-C(=O)(CH2) n'' -N(R 1 )C(═O)—, wherein each R 1 are independently H or C1-C3 alkyl, and n'' is independently an integer from 0 to 8; (g) -PEG-CON-PEG- wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON comprises the structure: TIFF2024507523000020.tif14128 formula, R 1a , R 2a , and R 3a are each independently H, -(CH2) M1 -, -(CH2) M2 C(=O) M3 (NR 4 ) M3 -(CH2) M2 -, -(CH2) M2 (NR 4 ) M3 C(O) M3 -(CH2) M2 - or -(CH2) M2 O-(CH2) M1 -C(O)NR 4 - but R 1a , R 2a , and R 3abut not simultaneously H; each M1 is independently 1, 2, 3, or 4, and in certain embodiments, 1 or 2; each M2 is independently 0, 1, 2, 3, or 4, and in certain embodiments 0, 1, or 2; each M3 is independently 0 or 1; Each R 4 are independently H, C1-C3 alkyl, C1-C6 alkanol, or -C(=O)(C1-C3 alkyl), provided that the same R 1a , R 2a , and R 3a M2 and M3 in cannot all be zero at the same time); (h) -PEG-CON-PEG- wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON comprises the structure: TIFF2024507523000021.tif47128); (i) a natural or unnatural amino acid; (j) [Gly-Gly-Gly-Gly-Ser] n (where n is 1, 2, 3, 4, 5, or 6); (k) [Ser-Ser-Ser-Ser-Gly] y (where y is ≧1); or (l) Ser-Gly-Ser-Ser-Ser-Ser-Gly-Ser-Ser-Ser-Ser-Gly-Ser represents a linking group containing the following:

[0006] In one aspect, the compound of formula (I) is useful in the method of treating, ameliorating and / or preventing disease or disorder in a subject.These methods comprise administering a therapeutically effective amount of at least one compound of formula (I), or its salt, geometric isomer, stereoisomer or solvate.In one aspect, the disease or disorder comprises neurological disease or neurological disorder.

[0007] Diseases or disorders that may be treated, ameliorated, or prevented by the compounds of formula (I) include Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer's disease, dementia with Lewy bodies, multiple system atrophy, spinal-bulbar muscular atrophy (Kennedy's disease), Tourette's syndrome, spinocerebellar ataxia (SCA), schizophrenia, age-related memory impairment, autism, migraine, Rett's syndrome, complex regional pain syndrome (CRPS), obsessive-compulsive disorder (OCD), attention deficit disorder, bipolar disorder, hereditary cerebrovascular disease, ATTR amyloidosis, or depression. [Brief description of the drawings]

[0008] The following detailed description of illustrative embodiments of the invention will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the invention, non-limiting embodiments are shown in the drawings. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0009] [Figure 1] 1 is a scheme showing how an exemplary bifunctional molecule of the present disclosure removes a pathogenic target neuroprotein. [Diagram 2] The low density lipoprotein receptor-related protein 1 (LRP1) binding motif is shown. [Diagram 3] 1 shows non-limiting target binding motifs. [Figure 4] 1 shows the structure of Angiopep-2 with non-limiting possible modification sites. [Diagram 5] 1 shows non-limiting target binding motifs used in proof-of-concept studies. [Figure 6] 1 shows saturable delivery of streptavidin AF647 by Angiopep-2. [Figure 7] 1 shows non-limiting results of an ELISA study demonstrating that biotinylated Angiopep-2 binds to streptavidin. [Figure 8]FIG. 1 shows that biotinylated Angiopep-2 delivers streptavidin AF647 to mouse brain endothelial cells. [Figure 9] 1 shows an exemplary Angiopep-2 mediated endocytosis of the non-covalently bound cargo protein streptavidin. [Figure 10] 1 shows exemplary results of an ELISA study demonstrating that DNP-modified Angiopep-2 binds to anti-DNP antibodies. [Figure 11] 1 shows that a non-limiting biotinylated LRP1 targeting peptide (RAP mimetic) binds to streptavidin protein. [Figure 12] 1 shows Ac.Ac.biotin Angiopep-2 mediated degradation of streptavidin AF488. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Detailed Description of the Disclosure In one aspect, the present disclosure provides bifunctional compounds that can be used to promote or enhance the degradation of extracellular or cell surface proteins. In certain embodiments, the extracellular or cell surface proteins mediate disease and / or disorders in a subject, and the treatment or management of the disease and / or disorders requires the degradation, removal, or reduction in concentration of the extracellular or cell surface proteins in the subject. Thus, in certain embodiments, administration of the compounds of the present disclosure to a subject removes the extracellular or cell surface proteins and / or reduces the circulating concentration of the extracellular or cell surface proteins, thus treating, ameliorating, or preventing the disease and / or disorders in the subject. In some embodiments, the extracellular or cell surface proteins are neuronal proteins. In certain embodiments, the extracellular or cell surface proteins mediate neuronal diseases and / or disorders in a subject. In some embodiments, the extracellular or cell surface proteins include pathogenic proteins that accumulate or aggregate in the brain of subjects suffering from neuronal diseases or disorders. In some embodiments, the extracellular or cell surface protein comprises a pathogenic protein that accumulates or aggregates at the blood-brain barrier (BBB) ​​of a subject suffering from a neurological disease or neurological disorder. In certain embodiments, the cell surface protein comprises a pathogenic protein that accumulates or aggregates on endothelial cells in the BBB of a subject suffering from a neurological disease or neurological disorder. In another embodiment, the bifunctional compound of the present disclosure induces the transport of a protein into and / or out of the central nervous system (CNS). In some embodiments, the bifunctional compound can induce the transport of a protein into and / or out of the CNS without degrading the protein.

[0011] In certain embodiments, the compounds of the present disclosure include an LRP1 binding motif that targets low density lipoprotein receptor-related protein 1 (LRP1). In certain embodiments, LRP1 is found in the brain. In some embodiments, the LRP1 binding motif is covalently linked to the target binding motif through an optional linker group. In some embodiments, the target binding motif includes a protein binding moiety. In some embodiments, the protein binding moiety non-covalently binds to a pathogenic protein. In some embodiments, the pathogenic protein includes an extracellular protein. In other embodiments, the pathogenic protein includes a cell surface protein. In certain embodiments, the pathogenic protein is found in the brain or BBB. In some embodiments, the bifunctional compounds of the present disclosure bound to the extracellular or cell surface protein undergo endocytosis, and the extracellular or cell surface protein is eventually degraded, and the bifunctional compound may be degraded or recycled outside the cell. The structure and function of LRP1 are described, for example, in Potere N., et al., "Low Density Lipoprotein Receptor-Related Protein-1 in Cardiac Inflammation and Infarct Healing," Frontiers in Cardiovascular Medicine, vol. 6, 2019.

[0012] In accordance with the present disclosure, there may be used conventional methods of chemical synthesis and pharmaceutical formulation, as well as techniques of pharmacology, molecular biology, microbiology, and recombinant DNA within the skill of the art, which are well known and fully explained elsewhere in the literature.

[0013] Reference will now be made in detail to certain aspects of the disclosed subject matter, some examples of which are illustrated in the accompanying drawings. While the disclosed subject matter will be described in the context of numbered claims, it will be understood that such illustrated subject matter is not intended to limit the scope of the claims to the disclosed subject matter.

[0014] Throughout this document, values ​​expressed in the form of ranges should be interpreted flexibly to include not only the numerical values ​​expressly set forth as the limits of the range, but also all individual numerical values ​​or subranges subsumed within the range, as if each numerical value and subrange were expressly set forth. For example, the range "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also the individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. Unless otherwise indicated, the description "about X to Y" has the same meaning as "about X to about Y". Similarly, unless otherwise indicated, the description "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z".

[0015] In the methods described herein, acts may be performed in any order unless a chronological or operational order is explicitly recited. Moreover, certain acts may be performed simultaneously unless the express language of the claim requires that they must be performed separately. For example, a claimed act of performing X and a claimed act of performing Y may be performed simultaneously in one operation, and the resulting process is within the literal scope of the claimed process.

[0016] definition The term "about" as used herein allows for a variability of a value or range, for example, within 10%, within 5%, or within 1% of a stated value or a stated range limit, and includes the exact value or range stated.

[0017] In this document, the terms "a", "an", or "the" are used to include one or more, unless the context clearly indicates otherwise. The term "or" is used to mean a non-exclusive "or", unless otherwise indicated. The statements "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B". Furthermore, any words or terms used herein and not defined elsewhere should be understood to be for descriptive purposes only and not for limiting purposes. Any use of section headings is intended to aid in the reading of this document and should not be construed as limiting. Information associated with a section heading may occur within or outside that particular section. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety, as if each was incorporated by reference individually.

[0018] The term "heteroalkyl" refers to an alkyl group, which further comprises at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or at one or more terminal positions of the parent chain. In some embodiments, a heteroalkyl group as defined herein is a partially unsaturated group, having one or more heteroatoms in the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may include an amide or ester functionality in the parent chain, such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, the heteroalkyl group in each instance is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~20 In certain embodiments, the heteroalkyl group is an unsubstituted heteroC alkyl group. 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~20In certain embodiments, the heteroalkyl group is an unsubstituted heteroC alkyl group. 1~20 It is an alkyl.

[0019] The term "heteroalkenyl" refers to an alkenyl group that further comprises at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or located at one or more terminal positions of the parent chain. Unless otherwise specified, the heteroalkenyl group in each instance is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl"). In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0020] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or located at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroalkynyl"). 2~10 Unless otherwise specified, each occurrence of the heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted ("substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group refers to an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0021] The term "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 14 ring carbon atoms ("C3~14 The term "carbocyclyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having zero heteroatoms. 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3~8 As the carbocyclyl group, the above C 3~6 Carbocyclyl groups include, but are not limited to, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 As the carbocyclyl group, the above C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10) but are not limited to these. As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group can be monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., a fused, bridged, or spiro ring system, including, for example, a bicyclic ("bicyclic carbocyclyl") or tricyclic ("tricyclic carbocyclyl") ring system, which can be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring, in such cases the number of carbons continues to indicate the number of carbons in the carbocyclyl ring system. Unless otherwise specified, the carbocyclyl group in each instance is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group can be an unsubstituted C 3~14 In certain embodiments, the carbocyclyl group is a substituted C 3~14 It is a carbocyclyl.

[0022] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3~14 C is a cycloalkyl group. 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above C 3~6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, the cycloalkyl group at each occurrence is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is an unsubstituted C 3~14 In certain embodiments, the cycloalkyl group is a substituted C 3~14 It is cycloalkyl.

[0023] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the point of attachment is on the alkyl portion.

[0024] The suffix "-ene" is added to a group to indicate that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0025] Unless expressly indicated otherwise, a group may be substituted. The term "optionally substituted" means substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may be substituted. "Optionally substituted" refers to a group that may be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" heteroalkyl group, a "substituted" or "unsubstituted" heteroalkenyl group, a "substituted" or "unsubstituted" heteroalkynyl group, a "substituted" or "unsubstituted" carbocyclyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with an acceptable substituent, e.g., a substituent that upon substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all acceptable substituents of organic compounds, including any substituents described herein that result in the formation of a stable compound. The present disclosure contemplates all such combinations to arrive at a stable compound. In the present invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The present invention is in no way intended to be limited to the exemplary substituents described herein.

[0026] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR. aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR bb , -SSR CC , -C(=O)R aa , -COH, -CHO, -C(OR cc )3, -COR aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -R bb C(=O)R aa , -R bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=R bb )R aa , -C(=R bb ) OR aa , -OC(=R bb )R aa , -OC(=R bb ) OR aa , -C(=R bb )N(R bb )2, -OC(=R bb )N(R bb )2, -R bb C(=NR bb )N(R bb )2, -C(=O)R bb SO2R aa , -NR^SQzR bb , -SO2N(R bb )2, -SO2R bb , -SO2OR aa , -OSO bb , -S(=O)R aa , -OS(=O)R aa , -SiCR^s, -OSiCR^s, -C(=S)N(R bb)2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SR aa S.R. bb , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -R bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -R bb P(=O)(N(R bb )2)2, -P(R CC )2, -P(OR cc )2, -P(R CC )3 + X - , -P(OR cc )3 + X - , -P(R CC )4, -P(OR cc ) 4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc ) 4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR(OR cc ), C 2~40 Alkyl, C 2~40 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~20 Alkyl, Hetero C 2~10 Alkenyl, Hetero C2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted with an X group; - is a counterion; or the two geminal hydrogens on the carbon atom are =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc is replaced by a group; R in each case aa is independently C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~20 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 or two R groups taken together form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; R in each case bb are independently hydrogen, -OH, -OR cc , -N(R CC )2, -CN, -C(=O)Raa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=R cc ) OR aa , -C(=R CC )N(R CC )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR cc , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR CC , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C6- 14 aryl, and 5- to 14-membered heteroaryl; or two R bb The groups taken together form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted with an X group; - is the counterion; R in each case cc are independently hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl; or two R cc The groups taken together form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; R in each case dd are independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R tt )2, -OC(=O)N(R ff )2, -R ff C(=O)R ee , -R ff CO2R ee , -R ff C(=O)N(R ff )2, -C(=R ff ) OR ee , -OC(=R ff )R ee , -OC(=R ff ) OR ee , -C(=R ff )N(R ff )2, -OC(=R ff )N(R ff )2, -R ff C(=NR ff )N(R ff)2, -R ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R gg or substituted with two geminal R dd The substituents may be taken together to form =O or =S; X - is the counterion; R in each case ee is independently C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; R in each case ff are independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 or two R groups taken together form a 3- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; R in each case gg are independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 Alkyl)2, -N(C 1~6 Alkyl)2, -N(C 1~6 Alkyl)3 + X - , -H(C 1~6 Alkyl)2 + X - , -N2(C 1~6 Alkyl) + X - , -N3 + X - , -N(C 1~6 Alkyl)(C 1~6alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 Alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)H(C 1~6 alkyl), -NHC(=O)NH2, -C(=O)O(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OC(=O)OC 1~6 Alkyl, -C(=O)N(C 1~6 alkyl)2, -C(=O)O(C 1~6 alkyl), -C(=O)NH2, -OC(=O)N(C 1~6 alkyl)2, -OC(=NH)NH(C 1~6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 Alkyl), -SO2N(C 1~6 Alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2(C 1~6 alkyl), -SO2O(C 1~6 alkyl), -OSO2(C 1~6 alkyl), -SO(C 1~6 Alkyl), -Si(C 1~6 alkyl)3, -OSi(C 1~6 Alkyl)3, -C(=S)N(C 1~6 alkyl)2, C(=S)NH(C1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 Alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)C 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 Alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be taken together to form =O or =S; where X - is the counter ion.

[0027] Nitrogen atoms may be substituted or unsubstituted where valence allows, including primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R CC )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR CC )N(R CC )2, -SO2N(R cc )2, -SO2R CC , -SO2OR cc , -SOR^, -C(=S)N(R CC )2, -C(=O)SR CC, -C(=S)SR CC , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5-14 membered heteroaryl; or two R cc The groups taken together form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc , and R dd is as defined herein.

[0028] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include -OH, -OR aa , -N(R CC )2, -C(=O)R aa , -C(=O)N(R CC )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR CC )N(R CC )2, -SO2N(R cc )2, -SO2R cc , -SO2ORcc , -SOR aa , -C(=S)N(R CC )2, -C(=O)SR CC , -C(=S)SR CC , C MO Alkyl (e.g. aralkyl, heteroaralkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl groups, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc , and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999.

[0029] For example, an amide group (e.g., -C(=O)R aaNitrogen protecting groups such as acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0030] Carbamate groups (e.g. -C(=O)OR aa) and nitrogen protecting groups such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethyl Silylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bum eoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, a alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzoisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monyl methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2 -Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1- Methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzyl carbamate.

[0031] Sulfonamide groups (e.g. -S(=O)R aa ) and nitrogen protecting groups such as p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), These include, but are not limited to, 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0032] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilylazacylate. 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fern), N-2-picolylamino N'-oxide, N-1,1-dimethylthio Methyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,These include, but are not limited to, 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). In certain embodiments, the nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0033] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). An oxygen protecting group includes -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb)N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(Raa)3, -P(R CC )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, including, but not limited to, where X - , R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999.

[0034] Exemplary oxygen protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, and 2-methoxyethoxymethyl (MEM). , 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- Methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl , 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl )methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (IPDMS), isopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate ester, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- Methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methyl) The alkyl groups include, but are not limited to, alkyl thio groups ... In certain embodiments, the oxygen protecting group is silyl. In certain embodiments, the oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyloxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0035] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also called a "thiol protecting group"). Sulfur protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa ,-SiCR^s,-P(R CC )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, including, but not limited to, wherein R aa , R bb , and R ccis as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0036] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., contain one formal negative charge). Anionic counterions can also be multivalent (i.e., contain two or more formal negative charges), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , OFT, H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonate ion, trifluoromethanesulfonate ion, 7-toluenesulfonate ion, benzenesulfonate ion, 10-camphorsulfonate ion, naphthalene-2-sulfonate ion, naphthalene-1-sulfonic acid-5-sulfonate ion, ethane-1-sulfonic acid-2-sulfonate ion, etc.), carboxylate ions (e.g., acetate ion, propanoate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, glycolate ion, gluconate ion, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 -, BPh4-, Al(OC(CF3)3)4 - , and carborane anions (e.g., CBnH 12 - or (HCBnMe5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelaate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0037] The term "leaving group" is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or group displaceable by a nucleophile. See, e.g., Smith, March's Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (e.g., F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonate ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), >-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as 7-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. The leaving group may be a phosphine oxide (formed, for example, during the Mitsunobu reaction), or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups include water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further exemplary leaving groups include halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SR aa , -OC(=O)R aa , -OCOR aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb)2, -OS(=O)R aa , -OSO2R aa , -OP(R cc )2, -OP(R cc )3, -OP(=O)2R aa , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -OP(=O)2N(R bb )2, and -OP(=O)(NR bb )2, where R aa , R bb , and R cc are as defined herein).

[0038] The term "acyl" as used herein means a group containing a carbonyl moiety bonded through a carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or to another carbon atom which may be part of an alkyl group, an aryl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, a heteroaryl group, a heteroarylalkyl group, and the like. The acyl group may contain 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. The acyl group may contain double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group may contain heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups. When the group containing the carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl" group. An example is the trifluoroacetyl group.

[0039] The term "alkyl" as used herein refers to straight-chain and branched alkyl groups, as well as cycloalkyl groups, having 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons, or in some embodiments, 1 to 8 carbon atoms. Examples of straight-chain alkyl groups include groups having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl. As used herein, the term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched forms of alkyl. Representative substituted alkyl groups may be substituted one or more times with any of the groups enumerated herein, such as amino groups, hydroxy groups, cyano groups, carboxy groups, nitro groups, thio groups, alkoxy groups, and halogen groups.

[0040] The term "alkenyl" as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, among others.

[0041] The term "alkoxy" as used herein means an oxygen atom connected to an alkyl group, including cycloalkyl groups, as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can contain about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to an oxygen atom, and can further contain double or triple bonds, and can also contain heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in the context in which two adjacent atoms of the structure are replaced therewith.

[0042] The term "alkynyl" as used herein refers to straight and branched chain alkyl groups as defined herein except that at least one triple bond is present between two carbon atoms. Thus, alkynyl groups have 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or 2 to 12 carbons, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3), among others.

[0043] The term "amine" as used herein refers to primary, secondary, and tertiary amines, for example having the formula N(group)3, where each group can be independently H, or non-H, such as alkyl, aryl, etc. Amines include, but are not limited to, R-NH2, such as alkylamines, arylamines, alkylarylamines; R2NH, where each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines, etc.; and R3N, where each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc. The term "amine" as used herein also includes ammonium ions.

[0044] As used herein, the term "amino group" refers to any of the forms -NH2, -NHR, -NR2, -NR3, where each R is independently selected. + and -NR3 which cannot be protonated. + "Amino" refers to the protonated form of each form except for the protonated form of the amino group. Thus, any compound substituted with an amino group can be considered an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes monoalkylamino groups, dialkylamino groups, and trialkylamino groups.

[0045] The term "aminoalkyl" as used herein means an amine attached to an alkyl group, as defined herein. The amine group can occur at any suitable position within the alkyl chain, for example at the terminus of the alkyl chain or anywhere within the alkyl chain.

[0046] The term "aralkyl" as used herein refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups, as well as fused (cycloalkylaryl)alkyl groups, such as 4-ethyl-indanyl. An aralkenyl group refers to an alkenyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein.

[0047] The term "aryl" as used herein means a cyclic aromatic hydrocarbon group that does not contain a heteroatom in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains about 6 to about 14 carbons in the ring portion of the group. The aryl group may be unsubstituted or substituted as defined herein. Representative substituted aryl groups may be mono- or more than twice substituted, such as, but not limited to, a phenyl group substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of the 2-8-positions.

[0048] As used herein, "C 6~10 -C 6~10 The term "biaryl" refers to a C 6~10 C covalently bonded to an aryl moiety 6~10 C means an aryl moiety. 6~10 The aryl moiety can be any suitable aryl group described herein. 6~10 -C 6~10 Non-limiting examples of biaryl include biphenyl and binaphthyl.

[0049] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound described herein and a pharma- ceutical acceptable carrier. Pharmaceutical compositions facilitate the administration of compounds to patients or subjects. There are multiple techniques of administering compounds in the art, including but not limited to intravenous administration, oral administration, aerosol administration, parenteral administration, intraocular administration, intrapulmonary administration, and topical administration.

[0050] The term "cycloalkyl" as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, cycloalkyl groups can have from 3 to about 8-12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Additionally, cycloalkyl groups include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl, as well as fused rings such as, but not limited to, decalinyl. Cycloalkyl groups also include rings substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono- or more than twice substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups or mono-, di-, or trisubstituted norbornyl or cycloheptyl groups, which may be substituted, for example, with amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl," alone or in combination, refers to a cyclic alkenyl group.

[0051] "Disease" refers to a condition in the health of an animal where the animal is unable to maintain homeostasis and where the animal's health will continue to deteriorate if the disease is not remitted.

[0052] In contrast, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's health is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily cause a further deterioration in the animal's health.

[0053] A disease or disorder is "in amelioration" when there is a decrease in the severity of a symptom of the disease or disorder, the frequency with which the symptom is experienced by the patient, or both.

[0054] As used herein, the terms "effective amount", "pharmaceutical effective amount", and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to obtain a desired biological result. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case can be ascertained by one of ordinary skill in the art using routine experimentation.

[0055] As used herein, the term "efficacy" refers to the maximum effect (E) achieved within an assay. max )

[0056] The terms "halo," "halogen," or "halide" group as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0057] The term "haloalkyl" as used herein includes mono-haloalkyl groups, poly-haloalkyl groups in which all halo atoms may be the same or different, and per-haloalkyl groups in which all hydrogen atoms are replaced with halogen atoms such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0058] The term "heteroaryl" as used herein refers to an aromatic ring compound containing five or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S; for example, a heteroaryl ring can have from five to about 8-12 ring members. Heteroaryl groups refer to various heterocyclyl groups that have an aromatic electronic structure. A heteroaryl group referred to as a C2-heteroaryl can be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heteroaryl can be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, and so on. The sum of the number of carbon atoms and the number of heteroatoms equals the total number of ring atoms. Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted or substituted with groups described herein. Representative substituted heteroaryl groups may be substituted one or more times with groups such as those enumerated herein.

[0059] Further examples of aryl and heteroaryl groups include phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzyl, phenyl ... neshydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl) , pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl). ), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-Dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl) nyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl), benzothiazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo[b,f]azepine (5H-dibenzo[b,f]azepin-1-yl, 5H-dibenzo[b,f]azepin-2-yl, 5 H-dibenzo[b,f]azepin-3-yl, 5H-dibenzo[b,f]azepin-4-yl, 5H-dibenzo[b,f]azepin-5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepine (10,11-dihydro-5H-dibenzo[b,f]azepin-1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-4-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl), but are not limited to these.

[0060] The term "heteroarylalkyl," as used herein, means an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heteroaryl group, as defined herein.

[0061] As used herein, "C 6~10 The term "-5-6 membered heterobiaryl" refers to a C-aryl group covalently attached to a 5- or 6-membered heteroaryl moiety through a single bond. 6~10 C means an aryl moiety. 6~10 The aryl and 5- to 6-membered heteroaryl moieties can be any suitable aryl and heteroaryl groups described herein. 6~10 Non-limiting examples of 5-6 membered heterobiaryls include: TIFF2024507523000022.tif20128 is an example. 6~10 When 5-6 membered heterobiaryl is recited as a substituent (e.g., as an "R" group), C 6~10 -5-6 membered heterobiaryl is C 6~10 It is attached to the rest of the molecule through a moiety.

[0062] As used herein, "5- to 6-membered-C 6~10 The term "heterobiaryl" refers to a 5- to 6-membered -C 6~10 When heterobiaryl is recited as a substituent (e.g., as an "R" group), the 5- to 6-membered -C 6~10 C except that the heterobiaryl is attached to the rest of the molecule through a 5- to 6-membered heteroaryl moiety. 6~10 -Same as 5-6 membered heterobiaryl.

[0063] The term "heterocyclyl" as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or any combination thereof, provided that it is polycyclic. In some embodiments, a heterocyclyl group contains from three to about twenty ring members, while other similar groups have from three to about fifteen ring members. A heterocyclyl group referred to as a C2-heterocyclyl can be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heterocyclyl can be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, and so on. The number of carbon atoms and the number of heteroatoms are equal to the total number of ring atoms. A heterocyclyl ring may contain one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species, including species containing fused aromatic and non-aromatic groups. For example, dioxolanyl and benzodioxolanyl ring systems (methylenedioxyphenyl ring systems) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted or substituted as described herein.Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Representative substituted heterocyclyl groups can be groups such as, but not limited to, piperidinyl or quinolinyl groups which are mono- or more than twice substituted, and which are 2-, 3-, 4-, 5- or 6-substituted or disubstituted with groups such as those enumerated herein.

[0064] The term "heterocyclylalkyl" as used herein means an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group, as defined herein, is replaced with a bond to a heterocyclyl group, as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0065] As used herein, the term "independently selected from" means that the referenced groups are the same, different, or a mixture thereof, unless the context clearly dictates otherwise. Thus, based on this definition, "X 1 , X 2 , and X 3 is independently selected from the noble gases" is intended to include, for example, 1 , X 2 , and X3 The scenario where all are the same, X 1 , X 2 , and X 3 In the scenario where all are different, X 1 and X 2 is the same but X 3 This would include scenarios where the sigma ...

[0066] The term "monovalent" as used herein means that the substituent is connected to the substituted molecule by a single bond. If the substituent is monovalent, e.g., F or Cl, the substituent is attached to the atom it replaces by a single bond.

[0067] The term "organic group" as used herein means any carbon-containing functional group. Examples include oxygen-containing groups such as alkoxy groups, aryloxy groups, aralkyloxy groups, and oxo (carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylates, and esters; sulfur-containing groups such as alkylsulfide groups and arylsulfide groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R), CN, CF, OCF, R, C(O), methylenedioxy, ethylenedioxy, N(R), SR, SOR, SO, SO, N(R), SO, C(O)R, C(O)C(O)R, C(O)CHC(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R), OC(O)N(R), C(S)N(R), (CH) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N( R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1~C 100) hydrocarbyl, where R can be hydrogen (in instances containing other carbon atoms) or a carbon-based moiety, which may be substituted or unsubstituted.

[0068] The terms "patient," "subject," or "individual" are used interchangeably herein and refer to any animal, or cells thereof, whether in vitro or in situ, amenable to the methods described herein. In non-limiting aspects, the patient, subject, or individual is a human.

[0069] As used herein, the term "pharmaceutical acceptable" means a material, such as a carrier or diluent, that does not abrogate the biological activity or biological properties of the compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesired biological effects or deleterious interactions with any of the components of the composition contained in the composition.

[0070] As used herein, the phrase "pharmaceutically acceptable salts" refers to salts of the administered compound prepared from pharma- ceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, as well as solvates, hydrates, or clathrates thereof.

[0071] Suitable pharma- ceutically acceptable acid addition salts can be prepared from inorganic or organic acids, examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0072] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts, metal salts including alkali metal salts, alkaline earth metal salts, and transition metal salts, such as, for example, calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines, such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of these salts can be prepared from the corresponding compound, for example, by reacting the compound with an appropriate acid or base.

[0073] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting the compound described herein in or to a patient so that it can perform its intended function. Usually, these compounds are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation containing the compound described herein and not harmful to the patient. Some examples of materials which may serve as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances used in pharmaceutical preparations. As used herein, "pharmaceutically acceptable carrier" includes any coating, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds described herein and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds described herein.Other additional ingredients that may be included in the pharmaceutical compositions used in the methods or compounds described herein are known in the art and described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0074] As used herein, the term "solvent" refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents include silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0075] As used herein, the term "substantially" means "a majority of" or "mostly," similarly meaning at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term "substantially free" as used herein can mean completely free or insignificant, such that the amount of material present does not affect the material properties of a composition containing the material, and thus the material is from about 0% to about 5%, or from about 0% to about 1%, or not more than about 5%, or less than about 4.5%, equal to, or greater than about 4.5%, or not more than 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or not more than about 0.001% by weight of the composition. The term "substantially free" can mean having an insignificant amount, such that a material is between about 0% and about 5%, or between about 0% and about 1%, or less than about 5%, or less than about 4.5%, equal to, or greater than about 4.5%, or less than 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001% or less by weight, or about 0%.

[0076] The term "substituted" as used herein with respect to a molecule or organic group as defined herein means that one or more hydrogen atoms contained therein are replaced with one or more non-hydrogen atoms. The term "functional group" or "substituent" as used herein means a group that can or does substitute on a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxy, alkoxy, aryloxy, aralkyloxy, oxo(carbonyl), carboxylic acid, carboxylate, and carboxylate ester; sulfur atoms in thiol, alkyl and aryl sulfide, sulfoxide, sulfone, sulfonyl, and sulfonamide groups; nitrogen atoms in groups such as amine, hydroxylamine, nitrile, nitro, N-oxide, hydrazide, azide, and enamine; and other heteroatoms in various other groups. Non-limiting examples of substituents that may be attached to a substituted carbon atom (or other atom) include F, Cl, Br, I, OR, OC(O)N(R), CN, NO, NO, ONO, azido, CF, OCF, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R), SR, SOR, SO, SO, N(R), SO, R, C(O)R, C(O)C(O)R, C(O)CHC(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R), OC(O)N(R), C(S)N(R), (CH) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R), N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R), N(R)SOR, N(R)SON(R), N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R), N(R)C(S)N(R), N(COR)COR, N(OR)R, C(=NH)N(R), C(O)N(OR)R, and C(=NOR)R, where R can be hydrogen or a carbon-based moiety, e.g., R can be hydrogen, (C1-C 100) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups attached to a nitrogen atom or adjacent nitrogen atoms can be taken together with one or more of the nitrogen atoms to form a heterocyclyl.

[0077] A "therapeutic" treatment is a treatment administered to a subject who exhibits symptoms of a pathology, with the intent of reducing or eliminating the symptoms.

[0078] The term "thioalkyl" as used herein means a sulfur atom connected to an alkyl group as defined herein. The alkyl group in the thioalkyl can be straight or branched. Examples of straight chain thioalkyl groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiohexyl, and the like. Examples of branched alkoxy include, but are not limited to, isothiopropyl, sec-thiobutyl, tert-thiobutyl, isothiopentyl, isothiohexyl, and the like. The sulfur atom can occur at any suitable position within the alkyl chain, for example, at the end of the alkyl chain or anywhere within the alkyl chain.

[0079] As used herein, the terms "treat," "treating," and "treatment" refer to reducing the frequency or severity of symptoms of a disease or condition experienced by a subject by administering an agent or compound to the subject.

[0080] Throughout this disclosure, various aspects of the disclosure can be presented in the form of ranges. It should be understood that the description in the form of ranges is merely for convenience and brevity, and should not be interpreted as a rigid limitation on the scope of the disclosure. Thus, a description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within the range. For example, a description of a range such as 1-6 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and individual numbers within the range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0081] compound In one aspect, the present disclosure relates to a bifunctional molecule of formula (I), or a salt, geometric isomer, stereoisomer, or solvate thereof: [TBM] n -[Linker] m -[LRP1BM] o (I) During the ceremony, [TBM] stands for target binding motif; [LRP1BM] represents the LRP1 binding motif; m is an integer from 0 to 15; n and o each independently represent an integer of 1 to 15.

[0082] In some embodiments, the linker is a group having a valency ranging from 1 to 15. In certain embodiments, the linker has a valency of 1 to 10. In certain embodiments, the linker has a valency of 1 to 5. In certain embodiments, the linker has a valency of 1, 2, or 3. In certain embodiments, the linker covalently links one or more target binding motifs to one or more LRP1 binding motifs.

[0083] In some embodiments, m is an integer ranging from 0 to 15. In certain embodiments, m is an integer ranging from 1 to 15. In certain embodiments, m is an integer ranging from 1 to 10. In certain embodiments, m is an integer ranging from 1 to 5. In certain embodiments, m is an integer ranging from 1 to 3. In certain embodiments, m is 1, 2, or 3.

[0084] In some embodiments, n and o are each independently an integer ranging from 1 to 15. In certain embodiments, n and o are each independently an integer ranging from 1 to 10. In certain embodiments, n and o are each independently an integer ranging from 1 to 5. In certain embodiments, n and o are each independently an integer ranging from 1 to 3. In certain embodiments, n and o are each independently 1, 2, or 3.

[0085] LRP1-binding motif In some embodiments, the LRP1 binding motif comprises a peptide that targets low density lipoprotein receptor-related protein 1 (LRP1). In certain embodiments, the LRP1 binding motif targets LRP1 in the brain and / or BBB. Without wishing to be bound by theory, LRP1 is thought to be involved in intralysosomal trafficking and receptor-mediated transcytosis across the blood-brain barrier, indicating that peptides that target this receptor may be able to both transport and degrade target neuronal proteins.

[0086] In some embodiments, the LRP1 binding motif has the following amino acid sequence: TIFF2024507523000023.tif63152 (where R8 represents (R)-2-(7-octenyl)Ala-OH, S5 represents (S)-2-(4-pentenyl)Ala-OH, and there is a hydrocarbon bridge between positions 1 and 8; Ruan et al., Chemical Engineering Journal, 2021, 403:126296); TIFF2024507523000024.tif34141 (where Nle stands for norleucine; Toldo et al., 2017, JACC: Basic to Translational Science 2.5:561-574); TIFF2024507523000025.tif70154; Sequences derived from the C-terminal sequence of aprotinin, including but not limited to TIFF2024507523000026.tif70144 where an underlined amino acid in the above sequence indicates that the amino acid may or may not be present, and underlined K / C indicates that K or C may be present.

[0087] In certain embodiments, the amino terminus of any of SEQ ID NOs: 1-22 is attached to a linker group or target binding motif. In other embodiments, the carboxylic acid terminus of any of SEQ ID NOs: 1-22 is attached to a linker group or target binding motif. In yet other embodiments, the carboxylic acid terminus of any of SEQ ID NOs: 1-22 is a non-reactive carboxamide group and the amine terminus is covalently linked to a linker group or target binding motif.

[0088] Target-binding motif In some embodiments, the target binding motif comprises a protein-binding moiety. In certain embodiments, the protein-binding moiety binds to a pathogenic protein. In one embodiment, the protein-binding moiety binds to an exosome that contains the pathogenic protein. In some embodiments, the pathogenic protein is found in the brain. In some embodiments, the protein-binding moiety binds non-covalently to the pathogenic protein. In some embodiments, the pathogenic protein is an extracellular protein. In other embodiments, the pathogenic protein is a cell surface protein. In other embodiments, the pathogenic protein is a CNS protein. In some embodiments, the protein-binding moiety binds to a protein that accumulates and / or aggregates in a subject suffering from a neurological disease or disorder. In some embodiments, the protein-binding moiety binds to a protein that accumulates and / or aggregates in the brain of a subject suffering from a neurological disease or disorder.

[0089] The pathogenicity protein can be any pathogenicity protein known to those of skill in the art. Exemplary pathogenicity proteins include complement factor B, complement factor D, DPP4, complement component C3b, IgG, TNFα, lysyl oxidase 2 (LOXL2), IL-17, amyloid beta, tau, hormone-sensitive lipase, lipoprotein-associated phospholipase A2, factor Xa, matrix metalloproteinase IX (MMP-9), thrombin, elastase, factor XI, PKK (prekallikrein), BLyS, B cell activating factor (BAFF), FGF23 (fibroblast growth factor 23), anti-DNA antibodies, extracellular myeloperoxidase (MPO), IL-18, transthyretin (misfolded), myostatin, CD40 (soluble), CXCL12, CD40 ligand (soluble), plasminogen activator inhibitor type 1 (PAI-1), PABA (Bacillus anthracis protective antigen); Edema factor, suPAR (soluble urokinase-type plasminogen activator receptor), PF4, tetanus toxin, IL-6, VEGF, β2-m, IgA, SAA (serum amyloid A), soluble PSMA, MIF, ApoB-100, protein arginine deaminase (PAD, PAD4), C. difficile (C. difficile toxin B, CJD-associated prion, hemolysin, IL-2, botulinum toxin, anti-citrullinated protein antibodies (ACPA), HTT, anti-ganglioside IgG, anti-Klebsiella dipeptidase protein antibodies, anti-anionic phospholipid antibodies, beta-2-glycoprotein-I, IgM, anticardiolipin antibodies, lupus anticoagulant, IgG autoantibodies, anti-vWF antibodies, amyloid light chain, IgA, IgE, anti-thyroid peroxidase IgG autoantibodies, thyroglobulin, TSH receptor, sFlt1, IL-21, IL-13, IL-5, serum amyloid P component, amyloid precursor protein, C-reactive protein (CRP), inflammatory cytokines, calcitonin gene-related peptide (CGRP), CGRP receptor, N-methyl-D-aspartate (NMDA) receptor, alpha-synuclein, IAPP, transthyretin, and combinations thereof.In some embodiments, the pathogenic protein is selected from inflammatory cytokines, calcitonin gene-related peptide (CGRP), CGRP receptor, N-methyl-D-aspartate (NMDA) receptor, myeloperoxidase (MPO), IAPP, transthyretin, extracellular tau, β-amyloid, amyloid precursor protein, prion protein, and α-synuclein. In some embodiments, the target binding motif binds to extracellular tau, β-amyloid, amyloid precursor protein, prion protein, α-synuclein, or a combination thereof.

[0090] In some embodiments, the target binding motif has formula (I): TIFF2024507523000027.tif30128, or a derivative or prodrug thereof, During the ceremony, A is N or CR 5 and; B is N or CR 6 and; E is N or CR 7 and; L is a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heteroalkylene, a bond, -O-, -NR A -, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR A -, -NR A C(=O)-, -NR A C(=O)R A -, -C(=O)R A -, -NR A C(=O)O-, -NR A C(=O)N(R A )-, -OC(=O), -OC(=O)O-, -OC(=O)N(R A )-, -S(O)NR A -, -NR A S(O)2-, or a combination thereof; X is a bond or a substituted or unsubstituted C 1~12 alkylene, where one or more carbons are C(=O), O, S, SO2, NH, or halogen, OH, or C 1~6 NC optionally substituted with alkyl 1~6 optionally substituted with alkyl; R 8 is hydrogen, N3, alkynyl, OH, halogen, NH2, N(C 1~6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are halogen, SO, NH, or halogen or C. 3~8 Optionally substituted with cycloalkyl 1~6 optionally substituted with alkyl; R 3 Ha-(CH2) n -, -(CH2) n -C(=O)-, -(CH2) n -C(=O)-O-, -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -A-NR A -(CH2) n -(C=O)NR A-, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; R A each occurrence of R is independently selected from hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or, if attached to a nitrogen atom, a nitrogen protecting group; or A the groups taken together form a substituted or unsubstituted heterocycle; each occurrence of A is independently selected from substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 1 , R 2 , and R 4 ~R 8 are each independently hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3~8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; Here, R 1 ~R 7 One or more carbons in the formula are C(=O), O, S, SO2, NH, NH-C 1~6 Alkyl, NC 1~6 Alkyl, NH2, or N(C 1~6 may be replaced by alkyl)2.

[0091] In one embodiment, in formula (I), TIFF2024507523000028.tif6128 shows potential covalent attachment points to a linker group or LRP1 binding motif.

[0092] In one embodiment, A is CR 5 and B is CR 6 and E is CR 7 In another embodiment, A, B, and E are each N.

[0093] In one aspect, the target binding motif of formula (I) or a derivative or prodrug thereof binds to extracellular tau.

[0094] In one embodiment, the target binding motif of formula (I) TIFF2024507523000029.tif19128, or a derivative or prodrug thereof, where p is an integer from 1 to 6. In certain embodiments, p is 2. In some embodiments, TIFF2024507523000030.tif19128, and derivatives or prodrugs thereof, bind to extracellular tau. In another embodiment, the target binding motif of formula (I) is TIFF2024507523000031.tif19128, or a derivative or prodrug thereof, where p is an integer from 1 to 6. In certain embodiments, p is 2. In some embodiments, TIFF2024507523000032.tif19128, and derivatives or prodrugs thereof, bind to extracellular tau.

[0095] In other embodiments, the target binding motif has the structure: TIFF2024507523000033.tif165128, or a derivative or prodrug thereof, wherein TIFF2024507523000034.tif6128 shows possible covalent attachment points to a linker group or LRP1 binding motif. TIFF2024507523000035.tif40128, or a derivative or prodrug thereof, acts as a glutamate modulator. TIFF2024507523000036.tif195135, or a derivative or prodrug thereof, acts to target and / or bind to the prion protein. In other embodiments, the target binding motif has the following structure: TIFF2024507523000037.tif52145, or a derivative or prodrug thereof, wherein TIFF2024507523000038.tif6128 shows possible covalent attachment points to a linker group or LRP1 binding motif. TIFF2024507523000039.tif52145, or a derivative or prodrug thereof, binds to CGRP or a CGRP receptor.

[0096] In yet other embodiments, the target binding motif has formula (II): TIFF2024507523000040.tif22128, or a derivative or prodrug thereof, During the ceremony, R1 and R2 are each independently hydrogen, -N3, alkynyl, -OH, halogen, -NH2, -N(C 1~6 Alkyl)2, C 1~6 Alkyl, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3~8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 More selected; wherein the aryl and heteroaryl are halogen, -SO2, NO2, -NH2, or halogen or C 3~8 Optionally substituted with cycloalkyl 1~6 optionally substituted with alkyl; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; Here, R 1 or R 2 One or more carbons in the formula are C(=O), O, S, SO2, NH, NH-C 1~6 Alkyl, NC 1~6 Alkyl, NH2, or N(C 1~6 may be replaced by alkyl)2.

[0097] In one embodiment, in formula (II), TIFF2024507523000041.tif6128 shows potential covalent attachment points to a linker group or LRP1 binding motif.

[0098] In one embodiment, the target binding motif of formula (II) or a derivative or prodrug thereof binds to transthyretin.

[0099] In one embodiment, R1 and R2 of formula (II) are each independently F, Cl, Br, or I. In a particular embodiment, R1 and R2 of formula (II) are each Cl.

[0100] In other embodiments, the target binding motif has formula (III): TIFF2024507523000042.tif26128, or a derivative or prodrug thereof, During the ceremony, R1 is selected from benzene, phenyl, cyclohexyl, hydrogen, and CF3; R2 is selected from hydrogen and CF3; TIFF2024507523000043.tif6128 shows the linker group or the covalent attachment point to the LRP1 binding motif.

[0101] In one aspect, the target binding motif of formula (III), or a derivative or prodrug thereof, acts to target and / or bind to a prion protein.

[0102] In other embodiments, the target binding motif has formula (IV): TIFF2024507523000044.tif45128, or a derivative or prodrug thereof, During the ceremony, R1 is selected from hydrogen, Cl, OMe, SMe, and CF3; TIFF2024507523000045.tif6128 shows the linker group or the covalent attachment point to the LRP1 binding motif.

[0103] In one aspect, the target binding motif of formula (IV), or a derivative or prodrug thereof, acts to target and / or bind to a prion protein.

[0104] In other embodiments, the target binding motif has formula (V): TIFF2024507523000046.tif44128, or a derivative or prodrug thereof, During the ceremony, R1 is selected from hydrogen, Cl, OMe, SMe, and CF3; TIFF2024507523000047.tif6128 shows the linker group or the covalent attachment point to the LRP1 binding motif.

[0105] In one aspect, the target binding motif of formula (V), or a derivative or prodrug thereof, acts to target and / or bind to a prion protein.

[0106] In certain embodiments, derivatives of the above structures contain one or more functional groups as described elsewhere herein.

[0107] In other embodiments, the target binding motif has the following amino acid sequence that targets extracellular tau: TIFF2024507523000048.tif26144, and SEQ ID NOs 23 and 24 may be linked to the linker or LPR1 binding motif through their C-terminus or N-terminus.

[0108] In other embodiments, the target binding motif has the following amino acid sequence that targets amyloid beta: TIFF2024507523000049.tif41142, and SEQ ID NOs. 25-27 may be linked to a linker or LPR1 binding motif through the C-terminus or N-terminus. In some embodiments, the bolded portion of the N-Pr or N-Aβ sequence includes amino acids that target amyloid beta.

[0109] In certain embodiments, the amino terminus of any of SEQ ID NOs:23-27 is linked to a linker group or an LPR1 binding motif. In other embodiments, the carboxylic acid terminus of any of SEQ ID NOs:23-27 is linked to a linker group or an LPR1 binding motif. In yet other embodiments, the carboxylic acid terminus of any of SEQ ID NOs:23-27 is a non-reactive carboxamide group and the amine terminus is covalently linked to a linker group or an LPR1 binding motif.

[0110] Meanwhile, TBM (Trival Biological Membrane) is Reshitko, GS, et al., "Synthesis and Evaluation of New Trivalent Ligands for Hepatocyte Targeting via the Asialoglycoprotein Receptor," Bioconjugate Chem. doi: 10.1021 / acs.bioconjchem.0c00202; Majouga, AG, et al., “Identification of Novel Small-Molecule ASGP-R Ligands,” Current Drug Delivery, 2016, 13, 1303–1312; Olshanova, AS, et al., "Synthesis of a new betulinic acid glycoconjugate with N-acetyl-D-galactosamine for the targeted delivery to hepatocellular carcinoma cells," Russian Chemical Bulletin, International Edition, Vol. 69, No. 1, pp. 158-163, January 2020; Yamansarov, E. Yu., et al., "New ASGPR-targeted ligands based on glycoconjugated natural triterpenoids," Russian Chemical Bulletin, International Edition, Vol. 68, No. 12, pp. 2331-2338, December 2019; Congdon , MD , et al., "Enhanced Binding and Reduced Immunogenicity of Glycoconjugates Prepared via Solid-State Photoactivation of Aliphatic Diazirine Carbohydrates," Bioconjugate Chem, doi: 10.1021 / acs.bioconjchem.0c00555; and Dhawan, V., et al., "Polysaccharide conjugates surpass monosaccharide ligands in hepatospecific targeting - Synthesis and comparative in silico and in vitro assessment," Carbohydrate Research 509 (2021) 108417, doi: 10.1016 / j.carres.2021.108417.

[0111] Linker In certain embodiments, m in formula (I) is 0, the linker is absent and the target binding motif is covalently linked to the LRP1 binding motif.

[0112] In certain embodiments, the linker is an amino acid, wherein the amino acid is any natural or unnatural amino acid. In one embodiment, the amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In one embodiment, the unnatural amino acid is selected from hydroxyproline, β-alanine, citrulline, ornithine, norleucine, 3-nitrotyrosine, nitroarginine, naphthylalanine, aminobutyric acid, 2,4-diaminobutyric acid, methionine sulfoxide, methionine sulfone, and pyroglutamic acid. In one embodiment, the linker is lysine, glutamic acid, or aspartic acid, the side chain forms an amide bond with the target binding motif or the LRP1 binding motif.

[0113] In certain embodiments, the linker is a glycine-rich peptide. In one embodiment, the linker has the sequence [Gly-Gly-Gly-Gly-Ser], where n is 1, 2, 3, 4, 5, or 6. n (SEQ ID NO:28).

[0114] In certain embodiments, the linker is a serine-rich peptide. In one embodiment, the linker has the sequence [Ser-Ser-Ser-Ser-Gly], where y is ≧1. y (SEQ ID NO:29). In one embodiment, y is 1, 2, 3, 4, 5, or 6. In one embodiment, the linker is a serine rich peptide having the sequence Ser-Gly-Ser-Ser-Ser-Ser-Gly-Ser-Ser-Ser-Ser-Gly-Ser (SEQ ID NO:30).

[0115] In certain embodiments, the linker is a polyethylene glycol-containing linker having 1 to 12 ethylene glycol residues.

[0116] In certain embodiments, the linker has the structure: -CH2CH2(OCH2CH2) m OCH2-, -(CH2) m CH2-, -[N(R a )-CH(R b )(C=O)] m - or a polypropylene glycol group or a polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units, During the ceremony, Each R a are independently H, C1-C3 alkyl, or C1-C6 alkanol, or R b together with the compound to form a pyrrolidine or hydroxypyrroline group; Each R b is independently selected from the group consisting of hydrogen, methyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)3-guanidine, -CH2C(=O)NH2, -CH2C(=O)OH, -CH2SH, -(CH2)2C(=O)NH2, -(CH2)2C(=O)OH, -(CH2)imidazole, -(CH2)4NH2, -CH2CH2SCH3, benzyl, -CH2OH, -CH(OH)CH3, -(CH2)imidazole, or -(CH2)phenol; m is an integer ranging from 1 to 15.

[0117] In certain embodiments, the linker has the structure: -[N(R ' -(CH2) 1~15 -C(=O)] m - wherein R' is H or a C1-C3 alkyl optionally substituted with 1-2 hydroxyl groups, and m is an integer ranging from 1 to 100.

[0118] In certain embodiments, the linker has the structure: -ZD-Z'- Including, During the ceremony, Z and Z' are each independently a bond, -(CH2) i -O-, -(CH2)i -S-, -(CH2) i -N(R)-, TIFF2024507523000050.tif10128, -(CH2) i -C(R 2 )=C(R 2 )- (cis or trans), -(CH2) i -≡- or -YC(=O)-Y-; each R is independently H, C1-C3 alkyl, or C1-C6 alkanol; Each R 2 are independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N(R); each i is independently 0 to 100; in certain embodiments, 0 to 75; in certain embodiments, 1 to 60; in certain embodiments, 1 to 55; in certain embodiments, 1 to 50; in certain embodiments, 1 to 45; in certain embodiments, 1 to 40; in certain embodiments, 2 to 35; in certain embodiments, 3 to 30; in certain embodiments, 1 to 15; in certain embodiments, 1 to 10; in certain embodiments, 1 to 8; in certain embodiments, 1 to 6; in certain embodiments, 0, 1, 2, 3, 4, or 5; D is a bond, -(CH2) i -YC(=O)-Y-(CH2) i -, -(CH2) m' - or -[(CH2) n -X1)] j with the proviso that Z, Z', and D are not each simultaneously a bond; X 1 is O, S, or N(R); j is an integer ranging from 1 to 100; in certain embodiments, from 1 to 75; in certain embodiments, from 1 to 60; in certain embodiments, from 1 to 55; in certain embodiments, from 1 to 50; in certain embodiments, from 1 to 45; in certain embodiments, from 1 to 40; in certain embodiments, from 2 to 35; in certain embodiments, from 3 to 30; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 10; in certain embodiments, from 1 to 8; in certain embodiments, from 1 to 6; in certain embodiments, from 1, 2, 3, 4, or 5; m' is an integer ranging from 1 to 100; in certain embodiments, from 1 to 75; in certain embodiments, from 1 to 60; in certain embodiments, from 1 to 55; in certain embodiments, from 1 to 50; in certain embodiments, from 1 to 45; in certain embodiments, from 1 to 40; in certain embodiments, from 2 to 35; in certain embodiments, from 3 to 30; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 10; in certain embodiments, from 1 to 8; in certain embodiments, from 1 to 6; in certain embodiments, from 1, 2, 3, 4, or 5; n is an integer ranging from 1 to 100; in certain embodiments, from 1 to 75; in certain embodiments, from 1 to 60; in certain embodiments, from 1 to 55; in certain embodiments, from 1 to 50; in certain embodiments, from 1 to 45; in certain embodiments, from 1 to 40; in certain embodiments, from 2 to 35; in certain embodiments, from 3 to 30; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 10; in certain embodiments, from 1 to 8; in certain embodiments, from 1 to 6; and in certain embodiments, from 1, 2, 3, 4, or 5.

[0119] In certain embodiments, the linker has the structure: -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n' CH2CH2- or -(CH2CH2CH2O) n - Including, In the formula, each n and n' is independently an integer ranging from 1 to 25; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 12; in certain embodiments, from 2 to 11; in certain embodiments, from 2 to 10; in certain embodiments, from 2 to 8; in certain embodiments, from 2 to 6; in certain embodiments, from 2 to 5; in certain embodiments, from 2 to 4; in certain embodiments, from 2 or 3; and in certain embodiments, from 1, 2, 3, 4, 5, 6, 7, or 8.

[0120] In certain embodiments, the linker has the structure: -PEG-CON-PEG- Including, wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON is a triazole group. The file is TIFF2024507523000051.tif15128.

[0121] In certain embodiments, CON has the structure: Contains TIFF2024507523000052.tif85134, wherein R′ and R″ are each independently H, methyl, or a bond.

[0122] In certain embodiments, CON has the diamide structure: -C(=O)-N(R 1 )-(CH2) n'' -N(R 1 )C(=O)-, -N(R 1 )-C(=O)(CH2) n'' -C(=O)N(R 1 )-,or -N(R 1 )-C(=O)(CH2) n'' -N(R 1 )C(=O)- Including, In the formula, each R 1 is independently H or C1-C3 alkyl, and n'' is independently an integer from 0 to 8, and in certain embodiments 1 to 7, and in certain embodiments 1, 2, 3, 4, 5, or 6.

[0123] In certain embodiments, CON has the structure: TIFF2024507523000053.tif14128, During the ceremony, R 1a , R 2a , and R 3a are each independently H, -(CH2) M1 -, -(CH2) M2 C(=O) M3 (NR 4 ) M3 -(CH2) M2 -, -(CH2) M2 (NR 4 ) M3 C(O) M3 -(CH2) M2 - or -(CH2) M2 O-(CH2) M1 -C(O)NR4 - but R 1a , R 2a , and R 3a but not simultaneously H; each M1 is independently 1, 2, 3, or 4, and in certain embodiments, 1 or 2; each M2 is independently 0, 1, 2, 3, or 4, and in certain embodiments 0, 1, or 2; each M3 is independently 0 or 1; Each R 4 are independently H, C1-C3 alkyl, C1-C6 alkanol, or -C(=O)(C1-C3 alkyl), provided that the same R 1a , R 2a , and R 3a M2 and M3 in cannot all be 0 at the same time.

[0124] In certain embodiments, CON has the structure: Contains TIFF2024507523000054.tif36128.

[0125] In another embodiment, CON has the structure: Includes TIFF2024507523000055.tif14128.

[0126] Further galactose- and talose-based ASGPR binding moieties In one aspect, the invention relates to compounds of the general chemical structure of Formula II that are useful for clearing circulating proteins associated with a disease state or condition in a patient or subject. TIFF2024507523000056.tif17128

[0127] As used herein, the term "extracellular protein targeting ligand" is used interchangeably with the term CPBM (cellular protein binding moiety). As used herein, the term "ASGPR ligand" is used interchangeably with the asialoglycoprotein receptor (ASGPR) binding moiety as defined herein.

[0128] In compounds of formula II, each [CON] is an optional connecting chemical moiety, which, if present, is either directly connected to a [CPBM] or a [CRBM] or connects a [Linker-2] to a [CPBM] or a [CRBM].

[0129] In the compound of formula II, [Linker-2] is a chemical moiety having a valence of 1-15 that is covalently attached to one or more [CRBM] and / or [CPBM] groups through [CON], which optionally contains a [MULTICON] group, where said [Linker-2] may itself contain one or more [CON] or [MULTICON] groups; k' is an integer from 1 to 15; j' is an integer from 1 to 15; h and h' are each independently an integer of 0 to 15; i L is an integer between 0 and 15, where h, h', and i L at least one of is at least 1, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0130] The [MULTICON] group may connect one or more [CRBM]s or [CPBM]s to one or more [Linker-2]s. In various embodiments, [Linker-2] has a valence of 1-10. In various embodiments, [Linker-2] has a valence of 1-5. In various embodiments, [Linker-2] has a valence of 1, 2, or 3. In various embodiments, in the compound of formula II, [Linker-2] is one or more linkers as defined herein. A , Linker B , Linker C , Linker D , and / or combinations thereof.

[0131] In compounds of formula II, xx is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.

[0132] In compounds of Formula II, yy is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.

[0133] In compounds of formula II, zz is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.

[0134] In the compound of formula II, X 1 is O, S, N(R b ), and C(R 4 )(R 4 ) 1 to 5 adjacent atoms independently selected from 1 If is one atom, X 1 is O, S, N(R 6 ), or C(R 4 )(R 4 ) and X 1 If there are two atoms, X 1 Not more than one atom of 6 ) and X 1 If X has 3, 4, or 5 atoms, 1 Up to two atoms of are O, S, or N(R 6 ) and; R 3 is independently selected at each occurrence from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, and -CF2CF3), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and heteroaryl, heterocycle, -OR 8 , and -NR 8 R 9More selected; R 4 is independently at each occurrence hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 , -NR 6 R 7 More selected; R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 More selected; R 8 and R 9 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0135] A. Galactose-Based ASGPR-Binding Cell Receptor Binding Moieties of Formula II In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000057.tif88128TIFF2024507523000058.tif228146TIFF2024507523000059.tif210 158TIFF2024507523000060.tif156136TIFF2024507523000061.tif131132TIFF2024507523000062.ti f205148TIFF2024507523000063.tif150141TIFF2024507523000064.tif178136TIFF202450752300006 5.tif133146TIFF2024507523000066.tif197144TIFF2024507523000067.tif227154TIFF20245075230 00068.tif192136TIFF2024507523000069.tif187145TIFF2024507523000070.tif229151TIFF2024507 523000071.tif208149TIFF2024507523000072.tif230104TIFF2024507523000073.tif220150TIFF202 4507523000074.tif179143TIFF2024507523000075.tif112154TIFF2024507523000076.tif227135TIF F2024507523000077.tif233119TIFF2024507523000078.tif34134TIFF2024507523000079.tif204128

[0136] In one embodiment, the compound of formula II has one of the following structures: TIFF2024507523000080.tif197138

[0137] In various embodiments, the ASGPR ligand is reacted with C to form a decomposition compound. 1 or C 5 (R 1 or R 5 In various embodiments, the ASGPR ligand is linked at the C 6For example, the ASGPR ligand is TIFF2024507523000081.tif37128, non-limiting examples of ASGPR binding compounds of formula II include TIFF2024507523000082.tif80137, or a di- or tri-substituted version thereof, or a pharma- ceutically acceptable salt thereof, where di- or tri-substituted refers to the number of additional galactose derivatives bound to the linker moiety.

[0138] In any embodiment herein in which an ASGPR ligand is selected for use in a degradation agent, the ASGPR ligand is typically linked to an extracellular protein targeting ligand. 5 At the position (e.g., adjacent C 6 The linker and the extracellular protein targeting ligand are linked via a C 1 When attached through a position, the carbon is appropriately functionalized for linkage with, for example, a hydroxyl group, an amino group, an allyl group, an alkyne group, or a hydroxyl-allyl group.

[0139] In various embodiments, the ASGPR ligand is C 3 or C 4 The ASGPR ligands are not linked at positions A, B, C, D, E, F, F, G, H, G, I ... TIFF2024507523000083.tif97152TIFF2024507523000084.tif168138TIFF2024507523000085.tif214151TIFF20245075230 00086.tif210148TIFF2024507523000087.tif225148TIFF2024507523000088.tif187149TIFF2024507523000089.tif212144 TIFF2024507523000090.tif135143TIFF2024507523000091.tif226148TIFF2024507523000092.tif218149TIFF20245075230 00093.tif154145TIFF2024507523000094.tif213145TIFF2024507523000095.tif200144TIFF2024507523000096.tif170152

[0140] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000097.tif144144TIFF2024507523000098.tif232149TIFF2024507523 000099.tif182153TIFF2024507523000100.tif163144TIFF2024507523000101.tif69150

[0141] B. Talc-based ASGPR-binding cell receptor binding moieties of formula II In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000102.tif114128TIFF2024507523000103.tif185135TIFF2024507523000104.tif91146TIFF2024507523000105.tif145128TIFF2024507523000106.tif225150TIFF2024507523000107.tif216129TIFF2024507523000108.tif163128TIFF2024507523000109.tif219123TIFF2024507523000110.tif148128TIFF2024507523000111.tif185135TIFF2024507523000112.tif238123TIFF2024507523000113.tif228140TIFF2024507523000114.tif245144TIFF2024507523000115.tif205137TIFF2024507523000116.tif233140TIFF2024507523000117.tif218155TIFF2024507523000118.tif145141TIFF2024507523000119.tif176155TIFF2024507523000120.tif173148TIFF2024507523000121.tif225135TIFF2024507523000122.tif128144TIFF2024507523000123.tif159139TIFF2024507523000124.tif228144TIFF2024507523000125.tif232144TIFF2024507523000126.tif235121TIFF2024507523000127.tif224131TIFF2024507523000128.tif238144TIFF2024507523000129.tif192138TIFF2024507523000130.tif205134TIFF2024507523000131.tif169145TIFF2024507523000132.tif182133TIFF2024507523000133.tif171139TIFF2024507523000134.tif167143TIFF2024507523000135.tif221146TIFF2024507523000136.tif236145TIFF2024507523000137.tif224112TIFF2024 507523000138.tif234118TIFF2024507523000139.tif211142TIFF2024507523000140.tif217147TIFF2024507523000141.tif20 5127TIFF2024507523000142.tif230109TIFF2024507523000143.tif232110TIFF2024507523000144.tif132128TIFF202450752 3000145.tif102128TIFF2024507523000146.tif232116TIFF2024507523000147.tif229118TIFF2024507523000148.tif111128.

[0142] In one aspect, the compound of formula II is an extracellular proteolytic compound, where the ASGPR ligand is a ligand described herein. TIFF2024507523000149.tif75128

[0143] In one embodiment, in the compound of formula II, the ASGPR ligand is a ligand selected from C1 or C5 (R 1 or R 5 In one embodiment, in the compound of formula II, the ASGPR ligand is linked at C6. In various embodiments, the ASGPR ligand is TIFF2024507523000150.tif31128, non-limiting examples of ASGPR binding compounds of formula II include TIFF2024507523000151.tif152128, or a di- or tri-substituted version thereof, or a pharma- ceutically acceptable salt thereof, where di- or tri-substituted refers to the number of additional galactose derivatives attached to the linker moiety. In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000152.tif193126 wherein, in certain embodiments, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0144] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000153.tif196137TIFF2024507523000154.tif207135In certain embodiments, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0145] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000155.tif211149TIFF2024507523000156.tif220144In certain embodiments, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0146] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000157.tif198139TIFF2024507523000158.tif215140In certain embodiments, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0147] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000159.tif197139TIFF2024507523000160.tif214139In certain embodiments, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0148] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000161.tif190133TIFF2024507523000162.tif203132In certain embodiments, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0149] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000163.tif197138TIFF2024507523000164.tif204133In certain embodiments, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0150] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000165.tif203143TIFF2024507523000166.tif208136In certain embodiments, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0151] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000167.tif203139TIFF2024507523000168.tif214140In certain embodiments, R 2 -NR b COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0152] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000169.tif202137TIFF2024507523000170.tif206134TIFF2024507523000171.tif207135In certain embodiments, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0153] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000172.tif219150TIFF2024507523000173.tif215140In certain embodiments, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0154] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000174.tif209143TIFF2024507523000175.tif210137In certain embodiments, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0155] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000176.tif197134TIFF2024507523000177.tif209136In certain embodiments, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0156] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000178.tif206140TIFF2024507523000179.tif209136In certain embodiments, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Groups may also be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0157] In certain embodiments, the compound of formula II is selected from the following: TIFF2024507523000180.tif211144TIFF2024507523000181.tif222139TIFF2024507523000182.tif166128TIFF202 4507523000183.tif196129TIFF2024507523000184.tif201123TIFF2024507523000185.tif210144TIFF2024507523 000186.tif215134TIFF2024507523000187.tif226141TIFF2024507523000188.tif227143TIFF2024507523000189. tif220144TIFF2024507523000190.tif202138TIFF2024507523000191.tif172134TIFF2024507523000192.tif90144

[0158] In certain embodiments, ASGPR ligands useful for incorporation into compounds of formula II are selected from the following: TIFF2024507523000193.tif77140TIFF2024507523000194.tif197139TIFF2024507523000195.tif159144TIFF2024507523000196.ti f202142TIFF2024507523000197.tif189138TIFF2024507523000198.tif217144TIFF2024507523000199.tif178147TIFF20245075230 00200.tif127134TIFF2024507523000201.tif191148TIFF2024507523000202.tif165142TIFF2024507523000203.tif200148TIFF202 4507523000204.tif158140TIFF2024507523000205.tif198144TIFF2024507523000206.tif192152TIFF2024507523000207.tif58148

[0159] C. ASGPR Ligand / Binding Moieties in Compounds of Formula II In certain embodiments, in the compound of formula II, R 1 is hydrogen.

[0160] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2024507523000208.tif6128.

[0161] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2024507523000209.tif6128.

[0162] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2024507523000210.tif6128.

[0163] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2024507523000211.tif6128.

[0164] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2024507523000212.tif6128.

[0165] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2024507523000213.tif6128.

[0166] In certain embodiments, in the compound of formula II, R 1 is a C0-C6 alkyl-cyano optionally substituted with 1, 2, 3, or 4 substituents.

[0167] In certain embodiments, in the compound of formula II, R 1 is alkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0168] In certain embodiments, in the compound of formula II, R 1 is alkenyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is alkynyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is haloalkyl, optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is F.

[0169] In certain embodiments, in the compound of formula II, R 1 is Cl.

[0170] In certain embodiments, in the compound of formula II, R 1 is Br.

[0171] In certain embodiments, in the compound of formula II, R 1 is aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0172] In certain embodiments, in the compound of formula II, R 1 is arylalkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0173] In certain embodiments, in the compound of formula II, R 1 is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.

[0174] In certain embodiments, in the compound of formula II, R 1 is heteroarylalkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0175] In certain embodiments, in the compound of formula II, R 1 is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents.

[0176] In certain embodiments, in the compound of formula II, R 1 is heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0177] In certain embodiments, in the compound of formula II, R 1 is haloalkoxy optionally substituted with 1, 2, 3, or 4 substituents.

[0178] In certain embodiments, in the compound of formula II, R 1 -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 , C0-C6 alkyl-SR 6, C0-C6 alkyl-NR 6 R 7 , C0-C6 alkyl-C(O)R 3 , C0-C6 alkyl-S(O)R 3 , C0-C6 alkyl-C(S)R 3 , C0-C6 alkyl-S(O)2R 3 , C0-C6 alkyl-N(R 8 )-C(O)R 3 , C0-C6 alkyl-N(R 8 )-S(O)R 3 , C0-C6 alkyl-N(R 8 )-C(S)R 3 , C0-C6 alkyl-N(R 8 )-S(O)2R 3 , C0-C6 alkyl-OC(O)R 3 , C0-C6 alkyl-OS(O)R 3 , C0-C6 alkyl-OC(S)R 3 , -N=S(O)(R 3 )2, C0-C6 alkylN3, or C0-C6 alkyl-OS(O)2R 3 each of which may be optionally substituted with 1, 2, 3, or 4 substituents.

[0179] In certain embodiments, in the compound of formula II, R 2 is aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0180] In certain embodiments, in the compound of formula II, R 2 is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents.

[0181] In certain embodiments, in the compound of formula II, R 2 is heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted with 1, 2, 3, or 4 substituents.

[0182] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2024507523000214.tif30128.

[0183] In certain embodiments, in the compound of formula II, R 2 is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents.

[0184] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -S(O)-R 3 It is.

[0185] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -C(S)-R 3 It is.

[0186] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -S(O)(NR 6 )-R 3 It is.

[0187] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with one, two, three or four substituents -N=S(O)(R 3 )2.

[0188] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 C(O)NR 9 S(O)2R 3 It is.

[0189] In certain embodiments, in the compound of formula II, R 2is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -S(O)2-R 10 It is.

[0190] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -C(NR 6 )-R 3 It is.

[0191] In certain embodiments, in the compound of formula II, R 2 is hydrogen.

[0192] In certain embodiments, in the compound of formula II, R 2 is R 10 It is.

[0193] In certain embodiments, in the compound of formula II, R 2 is alkyl-C(O)-R 3 It is.

[0194] In certain embodiments, in the compound of formula II, R 2 -C(O)-R 3 It is.

[0195] In certain embodiments, in the compound of formula II, R 2 is alkyl.

[0196] In certain embodiments, in the compound of formula II, R 2 is haloalkyl.

[0197] In certain embodiments, in the compound of formula II, R 2 HA-OC(O)R 3 It is.

[0198] In certain embodiments, in the compound of formula II, R 2 -NR 8 -C(O)R 10 It is.

[0199] In certain embodiments, in the compound of formula II, R 2 is alkenyl optionally substituted with 1, 2, 3, or 4 substituents.

[0200] In certain embodiments, in the compound of formula II, R 2 is aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0201] In certain embodiments, in the compound of formula II, R 2 is alkynyl optionally substituted with 1, 2, 3, or 4 substituents.

[0202] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 6 -alkenyl.

[0203] In certain embodiments, in the compound of formula II, R 2 is --O-alkenyl optionally substituted with 1, 2, 3, or 4 substituents.

[0204] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 6 -alkynyl.

[0205] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 6 -heteroaryl.

[0206] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 6 -aryl.

[0207] In certain embodiments, in the compound of formula II, R 2 is --O-heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.

[0208] In certain embodiments, in the compound of formula II, R 2 is --O-aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0209] In certain embodiments, in the compound of formula II, R 2 is --O-alkynyl optionally substituted with 1, 2, 3, or 4 substituents.

[0210] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000215.tif11128

[0211] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000216.tif22149

[0212] In certain embodiments, in the compound of formula II, R 2 is selected from: TIFF2024507523000217.tif115146 where R is an optional substituent as defined herein.

[0213] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000218.tif59138

[0214] In certain embodiments, in the compound of formula II, R 2A is selected from: TIFF2024507523000219.tif114143 where R is an optional substituent as defined herein.

[0215] In certain embodiments, in the compound of formula II, R 2A is selected from the following: TIFF2024507523000220.tif57131

[0216] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000221.tif171149

[0217] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000222.tif162141

[0218] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000223.tif9128

[0219] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000224.tif9128

[0220] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000225.tif52130

[0221] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000226.tif52129

[0222] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000227.tif27128

[0223] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000228.tif24128

[0224] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000229.tif54136

[0225] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000230.tif53132

[0226] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000231.tif17128

[0227] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000232.tif17128

[0228] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000233.tif51148

[0229] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000234.tif46140

[0230] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000235.tif69128

[0231] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000236.tif77140

[0232] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000237.tif44137

[0233] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000238.tif45139

[0234] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000239.tif90134

[0235] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000240.tif90132

[0236] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000241.tif27128

[0237] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000242.tif32128

[0238] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000243.tif31128

[0239] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000244.tif33128

[0240] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000245.tif26128

[0241] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000246.tif28128

[0242] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000247.tif29128

[0243] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000248.tif31128

[0244] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000249.tif114139

[0245] In certain embodiments, in the compound of formula II, R 2 or R 2A is selected from the following: TIFF2024507523000250.tif132130

[0246] In certain embodiments, in the compound of formula II, R2 is selected from the following: TIFF2024507523000251.tif17149

[0247] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000252.tif19161

[0248] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000253.tif15128

[0249] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2024507523000254.tif15128

[0250] In certain embodiments, in the compound of formula II, R 2 is selected from the following:

[0251] In certain embodiments, in the compound of formula II, R 2 is a spirocyclic heterocycle, e.g. TIFF2024507523000255.tif19128 but not limited to it.

[0252] In certain embodiments, in the compound of formula II, R 2 is a silicon-containing heterocycle, e.g. TIFF2024507523000256.tif20128 but not limited to it.

[0253] In certain embodiments, in the compound of formula II, R 2 is replaced by SF5, e.g. TIFF2024507523000257.tif32128 but not limited to it.

[0254] In certain embodiments, in the compound of formula II, R 2 is substituted with sulfoxime, e.g. TIFF2024507523000258.tif26128 but not limited to it.

[0255] In certain embodiments, in the compound of formula II, R 10 is selected from bicyclic heterocycles.

[0256] In certain embodiments, in the compound of formula II, R 10 is selected from spirocyclic heterocycles.

[0257] In certain embodiments, in the compound of formula II, R 10 -NR 6 -heterocycles.

[0258] In certain embodiments, in the compound of formula II, R 10 is selected from the following: TIFF2024507523000259.tif18128

[0259] In certain embodiments, in the compound of formula II, R 10 is selected from the following: TIFF2024507523000260.tif48131

[0260] In certain embodiments, in the compound of formula II, R 10 is selected from the following: TIFF2024507523000261.tif27128

[0261] In certain embodiments, in the compound of formula II, R 10 is selected from the following: TIFF2024507523000262.tif39143

[0262] In certain embodiments, in the compound of formula II, the ring is selected from the following: TIFF2024507523000263.tif170145

[0263] In certain embodiments, in the compound of formula II, R 30 is selected from the following: TIFF2024507523000264.tif42150

[0264] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2024507523000265.tif21128.

[0265] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2024507523000266.tif16128.

[0266] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2024507523000267.tif14128.

[0267] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2024507523000268.tif12128.

[0268] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2024507523000269.tif14128.

[0269] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2024507523000270.tif14128.

[0270] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2024507523000271.tif14128.

[0271] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2024507523000272.tif14128.

[0272] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2024507523000273.tif12128.

[0273] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2024507523000274.tif13128.

[0274] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2024507523000275.tif12128.

[0275] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2024507523000276.tif12128.

[0276] Linker In a non-limiting embodiment, in the compound of formula II, the linker A and linker B are independently selected from: TIFF2024507523000277.tif10128 formula, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20represents independently at each occurrence a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 6 -, -NR 6 C(O)-, -O-, -S-, -NR 6 -, -C(R 21 R 21 )-, -P(O)(R 3 )O-, -P(O)(R 3 )-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, and heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2] n -O-, CH2CH2-[O-(CH2)2] n -NR 6 -, -CH2CH2-[O-(CH2)2] n -, -[-(CH2)2-O-] n -, -[O-(CH2)2] n -, -[O-CH(CH3)C(O)] n -, -[C(O)-CH(CH3)-O] n -, -[O-CH2C(O)] n -, -[C(O)-CH2-O] n -, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or dicarboxylic acid; 21 optionally substituted with 1, 2, 3, or 4 more independently selected substituents; n is independently selected in each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R 21 each occurrence independently represents hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azido, amino, cyano, -NR 6 R 7 , -NR 8 SO2R 3 , -NR 8 S(O)R 3 , haloalkyl, heteroalkyl, and heteroaryl, and heterocycle; The remaining variables are as defined herein.

[0277] In one embodiment, in the compound of formula II, the linker A is a bond and a linker B teeth The file is TIFF2024507523000278.tif10128.

[0278] In one embodiment, in the compound of formula II, the linker B is a bond and a linker A teeth The file is TIFF2024507523000279.tif10128.

[0279] In one embodiment, in the compound of formula II, the divalent residue of an amino acid is selected from: TIFF2024507523000280.tif211139 where the amino acids can be oriented in either direction and the amino acids can be in the L- or D-form, or a mixture thereof.

[0280] In one embodiment, in the compound of formula II, the divalent residue of a dicarboxylic acid is generated by a nucleophilic addition reaction. TIFF2024507523000281.tif30128

[0281] Non-limiting examples of divalent residues of dicarboxylic acids produced by nucleophilic addition reactions include the following: TIFF2024507523000282.tif60129

[0282] In one embodiment, in the compound of formula II, the divalent residue of a dicarboxylic acid is produced by a condensation reaction. TIFF2024507523000283.tif29128

[0283] Non-limiting examples of divalent residues of dicarboxylic acids produced by the condensation reaction include the following: TIFF2024507523000284.tif67128

[0284] Non-limiting examples of divalent residues of saturated dicarboxylic acids include: TIFF2024507523000285.tif54136

[0285] Non-limiting examples of divalent residues of saturated dicarboxylic acids include: TIFF2024507523000286.tif28128

[0286] Non-limiting examples of divalent residues of saturated monocarboxylic acids include butyric acid (-OC(O)(CH2)2CH2-), caproic acid (-OC(O)(CH2)4CH2-), caprylic acid (-OC(O)(CH2)5CH2-), capric acid (-OC(O)(CH2)8CH2-), lauric acid (-OC(O)(CH2) 10 CH2-), myristic acid (-OC(O)(CH2) 12 CH2-), pentadecanoic acid (-OC(O)(CH2) 13 CH2-), palmitic acid (-OC(O)(CH2) 14 CH2-), stearic acid (-OC(O)(CH2) 16 CH2-), behenic acid (-OC(O)(CH2) 20 CH2-), and lignoceric acid (-OC(O)(CH2) 22 CH2-).

[0287] Non-limiting embodiments of divalent residues of fatty acids include residues selected from linoleic acid, palmitoleic acid, vaccenic acid, paulic acid, oleic acid, elaidic acid, gondoic acid, gadoleic acid, nervonic acid, myristoleic acid, and erucic acid. TIFF2024507523000287.tif99140

[0288] Non-limiting examples of divalent residues of fatty acids include linoleic acid (-C(O)(CH2)7(CH)2CH2(CH)2(CH2)4CH2-), docosahexaenoic acid (-C(O)(CH2)2(CHCHCH2)6CH2-), eicosapentaenoic acid (-C(O)(CH2)3(CHCHCH2)5CH2-), α-linolenic acid (-C(O)(CH2)7(CHCHCH2)3CH2-), stearidonic acid (-C(O)(CH2)4(CHCHCH2)4CH2-), y- Linolenic acid (-C(O)(CH2)4(CHCHCH2)3(CH2)3CH2-), arachidonic acid (-C(O)(CH2)3, (CHCHCH2)4(CH2)4CH2-), docosatetraenoic acid (-C(O)(CH2)5(CHCHCH2)4(CH2)4CH2-), palmitoleic acid (-C(O)(CH2)7CHCH(CH2)5CH2-), vaccenic acid (-C(O)(CH2)9CHCH(CH2)5CH2-), paulinic acid (-C(O)(CH2) 11 CHCH(CH2)5CH2-), oleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), elaidic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), gondoic acid (-C(O)(CH2)9CHCH(CH2)7CH2-), gadoleic acid (-C(O)(CH2)7CHCH(CH2)9CH2-), nervonic acid (-C(O)(CH2) 13 CHCH(CH2)3CH2-), mead acid (-C(O)(CH2)3(CHCHCH2)3(CH2)6CH2-), myristoleic acid (-C(O)(CH2)7CHCH(CH2)3CH2-), and erucic acid (-C(O)(CH2) 11 CHCH(CH2)7CH2-).

[0289] In certain embodiments, in the compound of formula II, the linker C is selected from: TIFF2024507523000288.tif41128In formula, R 22 each occurrence independently represents alkyl, -C(O)N-, -NC(O)-, -N-, -C(R 21 )-, -P(O)O-, -P(O)-, -P(O)(NR 6R 7 ) selected from the group consisting of N-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is R 21 optionally substituted with 1, 2, 3, or 4 more independently selected substituents; The remaining variables are as defined herein.

[0290] In certain embodiments, in the compound of formula II, the linker D is selected from: TIFF2024507523000289.tif54128 formula, R 32 each occurrence independently represents alkyl, N + is selected from the group consisting of X-, -C-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is R 21 optionally substituted with 1, 2, 3, or 4 more independently selected substituents; X- is an anionic group, e.g., Br- or Cl - and; All other variables are as defined herein.

[0291] In certain embodiments, in the compound of formula II, the linker A is selected from: TIFF2024507523000290.tif26128 wherein the heteroaryl, heterocycle, cycloalkyl, and aryl may each be substituted with 1, 2, 3, or 4 of halogen, alkyl, haloalkyl, and any combination of heteroaryl, heterocycle, or cycloalkyl, as valences permit.

[0292] In certain embodiments, in the compound of formula II, the linker A is selected from: TIFF2024507523000291.tif104132 wherein heteroaryl, heterocycle, cycloalkyl, and may each be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as valences allow.

[0293] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000292.tif96128

[0294] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000293.tif138128TIFF2024507523000294.tif80128

[0295] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D is selected from: TIFF2024507523000295.tif107133, wherein tt is independently selected from 1, 2, or 3, and ss is 3 minus tt (3-tt).

[0296] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D is selected from: TIFF2024507523000296.tif55136 where tt and ss are as defined herein.

[0297] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D is selected from: TIFF2024507523000297.tif157128TIFF2024507523000298.tif232101TIFF2024507523000299.tif236103TIFF2024507523000300.tif232102TIFF2024507523000301.tif50128 wherein heteroaryl, heterocycle, cycloalkyl, and aryl may each be optionally substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as valences permit; and tt and ss are as defined herein.

[0298] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D is selected from: TIFF2024507523000302.tif141128TIFF2024507523000303.tif196122 wherein heteroaryl, heterocycle, cycloalkyl, and aryl may each be substituted, valences permitting, with 1, 2, 3, or 4 of halogen, alkyl, haloalkyl, and any combination of heteroaryl, heterocycle, or cycloalkyl; tt and ss are as defined herein.

[0299] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D is selected from: TIFF2024507523000304.tif72128 wherein heteroaryl and aryl may each be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as valences permit; tt and ss are as defined herein.

[0300] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000305.tif60129

[0301] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000306.tif61128

[0302] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000307.tif62141

[0303] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000308.tif66148

[0304] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000309.tif87130

[0305] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000310.tif91143

[0306] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000311.tif223134

[0307] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000312.tif226133TIFF2024507523000313.tif72139

[0308] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000314.tif42128

[0309] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000315.tif106132

[0310] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000316.tif156134

[0311] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000317.tif81128

[0312] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000318.tif154146

[0313] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000319.tif61149

[0314] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000320.tif167128

[0315] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000321.tif174141

[0316] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2024507523000322.tif148141

[0317] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2024507523000323.tif52128TIFF2024507523000324.tif153133

[0318] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2024507523000325.tif111128

[0319] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2024507523000326.tif123132TIFF2024507523000327.tif80141

[0320] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2024507523000328.tif71148

[0321] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2024507523000329.tif150128

[0322] In certain embodiments, in the compound of formula II, the linker Dis selected from the following: TIFF2024507523000330.tif82128TIFF2024507523000331.tif128143

[0323] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000332.tif28144

[0324] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000333.tif16137

[0325] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000334.tif124143

[0326] In certain embodiments, the linker A is the following: Selected from TIFF2024507523000335.tif174145, both R 21 It may be substituted with 1, 2, 3, or 4 substituents selected from:

[0327] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000336.tif24128

[0328] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000337.tif41129

[0329] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000338.tif42128

[0330] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000339.tif43138

[0331] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000340.tif58147

[0332] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000341.tif20137

[0333] In certain embodiments, in the compound of formula II, the linker A is selected from the following:

[0334] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000342.tif175144TIFF2024507523000343.tif171141

[0335] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000344.tif132128

[0336] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000345.tif165142

[0337] In certain embodiments, in the compound of formula II, the linker Ais selected from the following: TIFF2024507523000346.tif47129

[0338] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000347.tif44132

[0339] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000348.tif97128

[0340] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000349.tif69136

[0341] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2024507523000350.tif78141

[0342] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000351.tif37130

[0343] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000352.tif14138

[0344] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000353.tif49134

[0345] In certain embodiments, in the compound of formula II, the linker B is selected from the following, each of which is R 21 It may be substituted with 1, 2, 3, or 4 substituents selected from:

[0346] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000354.tif59137

[0347] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000355.tif26145

[0348] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000356.tif31128

[0349] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000357.tif43132

[0350] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000358.tif58133

[0351] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000359.tif52137

[0352] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000360.tif110136

[0353] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2024507523000361.tif73143

[0354] In certain embodiments, in the compound of formula II, the linker B -Linker A is selected from the following: TIFF2024507523000362.tif23132

[0355] In certain embodiments, in the compound of formula II, the linker B -Linker A is selected from the following: TIFF2024507523000363.tif51128

[0356] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000364.tif47141

[0357] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000365.tif72128

[0358] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000366.tif46131

[0359] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000367.tif109142

[0360] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000368.tif72128

[0361] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000369.tif98128

[0362] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000370.tif107134TIFF2024507523000371.tif200138TIFF2024507523000372.tif62128

[0363] In certain embodiments, in the compound of formula II, the linker C is selected from the following, each of which is R 21 It may be substituted with 1, 2, 3, or 4 substituents selected from:

[0364] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000373.tif81128

[0365] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000374.tif23128

[0366] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000375.tif28128

[0367] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000376.tif56133

[0368] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000377.tif50146

[0369] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000378.tif38132

[0370] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000379.tif54134

[0371] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2024507523000380.tif96128

[0372] In certain embodiments, in the compound of formula II, the linker C -(Linker A )2 is selected from the following: TIFF2024507523000381.tif64134

[0373] In certain embodiments, in the compound of formula II, the linker C -(Linker A )2 is selected from the following: TIFF2024507523000382.tif148128

[0374] In certain embodiments, in the compound of formula II, the linker C -(Linker A)2 is selected from the following: TIFF2024507523000383.tif29137

[0375] In certain embodiments, in the compound of formula II, the linker C -(Linker A )2 is selected from the following: TIFF2024507523000384.tif117128TIFF2024507523000385.tif104128

[0376] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2024507523000386.tif55128

[0377] In certain embodiments, in the compound of formula II, the linker D is the following: Selected from TIFF2024507523000387.tif100128, both R 21 It may be substituted with 1, 2, 3, or 4 substituents selected from:

[0378] In certain embodiments, in the compound of formula II, the linker B -(Linker A ) is selected from the following: TIFF2024507523000388.tif74128

[0379] In certain embodiments, in the compound of formula II, the linker C -(Linker A ) is selected from the following: TIFF2024507523000389.tif221147

[0380] In certain embodiments, in the compound of formula II, the linker D -(Linker A ) is selected from the following: TIFF2024507523000390.tif123142

[0381] In various embodiments, R 4 is independently at each occurrence hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 , -NR 6 R 7 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 is selected from.

[0382] In various embodiments, in the compound of formula II, R 5 are independently hydrogen, heteroalkyl, TIFF2024507523000391.tif27128, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 , C0-C6 alkyl-SR 6 , C0-C6 alkyl-NR 6 R 7 , C0-C6 alkyl-C(O)R 3 , C0-C6 alkyl-S(O)R 3 , C0-C6 alkyl-C(S)R 3 , C0-C6 alkyl-S(O)2R 3 , C0-C6 alkyl-N(R 8 )-C(O)R 3 , C0-C6 alkyl-N(R 8 )-S(O)R 3 , C0-C6 alkyl-N(R 8 )-C(S)R 3 , C0-C6 alkyl-N(R 8 )-S(O)2R 3 , C0-C6 alkyl-OC(O)R 3 , C0-C6 alkyl-OS(O)R 3, C0-C6 alkyl-OC(S)R 3 , -N=S(O)(R 3 )2, C0-C6 alkylN3, and C0-C6 alkyl-OS(O)2R 3 any of which may be substituted with 1, 2, 3, or 4 substituents.

[0383] In various embodiments, in the compound of formula II, R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 is selected from.

[0384] In various embodiments, in the compound of formula II, R 8 and R 9 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0385] In various embodiments, the compound of formula II has the structure of formula II-A: In various embodiments, in the compound of formula II-A, [TBM] and [LRP1BM] are as defined herein.

[0386] A compound of formula II-A, or a salt, stereoisomer, or solvate thereof, having the structure: TIFF2024507523000392.tif19128 formula, [TBM] is: (a) A compound selected from TIFF2024507523000393.tif79136 and TIFF2024507523000394.tif139135, or a derivative or prodrug thereof. (In the formula, TIFF2024507523000395.tif6128 indicates possible covalent attachment points to [linker] or [LRP1BM]); (b) Formula (I): Compound of TIFF2024507523000396.tif30128, or a derivative or prodrug thereof (In the formula, A is N or CR 5 and; B is N or CR 6 and; E is N or CR 7 and; L is a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heteroalkylene, a bond, -O-, -NR A -, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR A -, -NR A C(=O)-, -NR A C(=O)R A -, -C(=O)R A -, -NR A C(=O)O-, -NR A C(=O)N(R A )-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R A )-, -S(O)NR A -, -NR A S(O)2-, or a combination thereof; X is a bond or a substituted or unsubstituted C 1~12 alkylene, where one or more carbons are C(=O), O, S, SO2, NH, or halogen, OH, or C 1~6NC optionally substituted with alkyl 1~6 optionally substituted with alkyl; R 8 is hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1~6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are halogen, SO, NH, or halogen or C. 3~8 Optionally substituted with cycloalkyl 1~6 optionally substituted with alkyl; R 3 Ha-(CH2) n -, -(CH2) n -C(=O), -(CH2) n -C(=O)-O-, -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2)n -AS(O)2NR A - and; R A each occurrence of R is independently selected from hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or, if attached to a nitrogen atom, a nitrogen protecting group; or A the groups taken together form a substituted or unsubstituted heterocycle; each occurrence of A is independently selected from substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 1 , R 2 , and R 4 ~R 8 are each independently hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3~8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; Here, R 1 ~R 7 One or more carbons in the formula are C(=O), O, S, SO2, NH, NH-C 1~6 Alkyl, NC 1~6 Alkyl, NH2, or N(C 1~6 alkyl)2; TIFF2024507523000397.tif6128 indicates the covalent attachment point to [linker] or [LRP1BM]); (c) Formula (II): Compound of TIFF2024507523000398.tif22128, or a derivative or prodrug thereof (In the formula, R1 and R2 are each independently hydrogen, N3, alkynyl, OH, halogen, NH2, N(C 1~6 Alkyl)2, C 1~6 Alkyl, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3~8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 More selected; wherein the aryl and heteroaryl are halogen, -SO2, NO2, -NH2, or halogen or C 3~8 Optionally substituted with cycloalkyl 1~6 optionally substituted with alkyl; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; Here, R 1 or R 2 One or more carbons in the formula are C(=O), O, S, SO2, NH, NH-C 1~6 Alkyl, NC 1~6 Alkyl, NH2, or N(C 1~6 alkyl)2; TIFF2024507523000399.tif6128 indicates the covalent attachment point to [linker] or [LRP1BM]); (d) Formula (III): Compound of TIFF2024507523000400.tif26128, or a derivative or prodrug thereof (In the formula, R1 is selected from benzene, phenyl, cyclohexyl, hydrogen, and CF3; R2 is selected from hydrogen and CF3; TIFF2024507523000401.tif6128 indicates the covalent attachment point to [linker] or [LRP1BM]); (e) Formula (IV): Compound of TIFF2024507523000402.tif45128, or a derivative or prodrug thereof (In the formula, R1 is selected from hydrogen, Cl, OMe, SMe, and CF3; TIFF2024507523000403.tif6128 indicates the covalent attachment point to [linker] or [LRP1BM]); (f) Formula (V): Compound of TIFF2024507523000404.tif44128, or a derivative or prodrug thereof (In the formula, R1 is selected from hydrogen, Cl, OMe, SMe, and CF3; TIFF2024507523000405.tif6128 indicates the point of covalent attachment to [Linker] or [LRP1BM]); or (g) Amino acid sequence selected from TIFF2024507523000406.tif33128 represents a target binding motif comprising or consisting of: [LRP1BM] has the following amino acid sequence: TIFF2024507523000407.tif34128 (wherein R8 represents (R)-2-(7-octenyl)Ala-OH and S5 represents (S)-2-(4-pentenyl)Ala-OH, and there is a hydrocarbon bridge between positions 1 and 8); TIFF2024507523000408.tif19128 (where Nle stands for norleucine), TIFF2024507523000409.tif98128, in which an underlined amino acid indicates that the amino acid may or may not be present, and an underlined K / C indicates that K or C may be present; [LIN] is [LINKER] or [LINKER-2], either of which is a chemical moiety having a valence of 1-15, covalently attached to one or more [TBM] or [LRP1BM] groups, optionally via [CON], where said [LIN] may itself contain one or more [CON] groups; k' is an integer ranging from 1 to 15; j' is an integer ranging from 1 to 15; h and h' are each independently an integer ranging from 0 to 15; i L is between 0 and 15, where h, h', and i L At least one of is at least 1.

[0387] The compounds described herein may have one or more stereocenters, and each stereocenter may independently exist in the (R) or (S) configuration. In certain embodiments, the compounds described herein exist as optically active or racemic forms. It should be understood that the compounds described herein encompass racemates, optically active forms, regioisomers, and stereoisomers, or combinations thereof, that have the therapeutically useful properties described herein. Preparation of optically active forms is accomplished in any suitable manner, including, but not limited to, resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases. In certain embodiments, a mixture of one or more isomers is utilized as the therapeutic compound described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. Resolution of the compounds and their isomers can be achieved by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0388] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharma- ceutically acceptable salts of compounds having the structures of any of the compounds described herein, as well as metabolites and active metabolites of these compounds that exhibit the same activity. Solvates include solvates with water, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohols (e.g., ethanol), acetate esters, and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharma- ceutically acceptable solvents, such as water and ethanol. In other embodiments, the compounds described herein exist in unsolvated forms.

[0389] In certain aspects, the compounds described herein can exist as tautomers, and all tautomers are included within the scope of the compounds presented herein.

[0390] In certain embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted to the parent drug in vivo. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmacologic, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized to the biologically, pharmacologic, or therapeutically active form of the compound by one or more steps or processes.

[0391] In certain embodiments, sites on the aromatic ring moiety of the compounds described herein are susceptible to various metabolic reactions. By incorporating suitable substituents on the aromatic ring structure, this metabolic pathway can be reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, deuterium, halogen, or alkyl groups.

[0392] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced with an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, and 35 In certain embodiments, isotope-labeled compounds are useful in drug distribution studies and / or substrate tissue distribution studies. In other embodiments, substitution with heavy isotopes such as deuterium provides increased metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In yet other embodiments, 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process that employs an appropriately isotopically labeled reagent in place of an otherwise non-labeled reagent.

[0393] In certain aspects, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0394] The compounds described herein, and other related compounds having different substituents, can be prepared using the techniques and materials described herein and in other publications such as Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001) and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999), the disclosures of which are all incorporated by reference. The general methods for the preparation of the compounds described herein are modified by the use of appropriate reagents and conditions to introduce the various moieties found in the formulas shown herein.

[0395] The compounds described herein are synthesized using any suitable procedure starting from compounds available from commercial sources or prepared using the procedures described herein.

[0396] In certain embodiments, reactive functional groups such as hydroxyl, amino, imino, thio, or carboxy groups are protected to avoid their undesired participation in reactions. Protecting groups are used to block some or all reactive moieties to prevent them from participating in chemical reactions until the protecting group is removed. In other embodiments, each protecting group is removable by a different means. The need for differential removal is met by protecting groups that are cleaved under completely different reaction conditions.

[0397] In certain embodiments, the protecting groups are removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are acid labile and are used to protect carboxy- and hydroxy-reactive moieties in the presence of Cbz-protected amino groups, which are hydrogenolysis-removable, and Fmoc-protected amino groups, which are base labile. Carboxylic acid- and hydroxy-reactive moieties are blocked with base-labile groups, such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines blocked with acid-labile groups, such as t-butyl carbamate, or blocked with carbamates, which are acid- and base-stable, but hydrolytically removable.

[0398] In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protecting groups such as benzyl groups, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds exemplified herein, including conversion to alkyl esters, or are blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while concurrent amino groups are blocked with fluoride labile silyl carbamates.

[0399] Allyl blocking groups are useful in the presence of acid and base protecting groups because the former are stable and subsequently removed by metal or pi-acid catalysis. For example, allyl blocking carboxylic acids are deprotected by palladium catalysis in the presence of acid labile t-butyl carbamate or base labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and will not react. When released from the resin, the functional group becomes available for reaction.

[0400] Typically, the blocking / protecting group may be selected from: TIFF2024507523000410.tif79128

[0401] Other protecting groups, along with detailed descriptions of techniques applicable to the creation and removal of protecting groups, are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, the disclosures of which are incorporated herein by reference.

[0402] composition Compositions comprising the compounds described herein include pharmaceutical compositions comprising at least one compound described herein and at least one pharma- ceutically acceptable carrier. In certain embodiments, the compositions are formulated for oral or parenteral administration, such as transdermal, transmucosal (e.g., sublingual, intralingual, buccal (transbuccal), urethral (transurethral), intravaginal (e.g., vaginal and perivaginal), nasal (intranasal), and rectal (rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0403] Treatment In another aspect, the present disclosure relates to a method of treating, ameliorating, and / or preventing a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

[0404] The disease or disorder may be any disease or disorder known to those skilled in the art. Exemplary diseases or disorders include Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (APIS), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, Cold agglutinin disease, essential mixed cryoglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful adiposity, adult Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatism, Parry-Romberg syndrome, Parsonage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, rheumatoid arthritis ... Hunitzler's syndrome, systemic lupus erythematosus, undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barro concentric sclerosis, Bickerstaff brainstem encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis (pattern II), Oshtora n syndrome, childhood autoimmune neuropsychiatric disorder associated with streptococci (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff-person syndrome, Sydenham's chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan's syndrome, Graves' ophthalmopathy, intermediate uveitis, lignoconjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Susac syndrome, sympathetic ophthalmia, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Bechet's diseasedisease), eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA), immunoglobulin A vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatic vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, pyoderma gangrenosum, prostate cancer, metastatic prostate Cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, renal cancer, lymphoma, inflammatory neurodegenerative diseases, immune response deficiency diseases that cause inflammation, chronic Inflammatory diseases, hyperglycemic disorders, diabetes mellitus (types I and II), pancreatic beta cell death and associated hyperglycemic disorders, liver disease, kidney disease, cardiovascular disease, muscle degeneration and atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury, arteriosclerosis, Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer's disease, dementia with Lewy bodies, multiple system atrophy, spinal and bulbar muscular atrophy (Kennedy's disease), Tourette's syndrome, spinocerebellar ataxia (SCA) (e.g. SCA type 1, SCA type 2) These conditions include, but are not limited to, SCA2, SCA3 / MJD, SCA6, SCA7, SCA8, Friedreich's ataxia, and Dentatorubral-Pallidoluysian atrophy (DRPLA / Haw-River syndrome), schizophrenia, age-related memory impairment, autism, migraine, Rett syndrome, complex regional pain syndrome (CRPS), obsessive-compulsive disorder (OCD), attention deficit disorder, bipolar disorder, depression, migraine due to degradation of CGRP or CGRP receptors, ATTR amyloidosis, hereditary cerebrovascular disorders, and combinations thereof.

[0405] In some embodiments, the disease or disorder is a neurological disease or disorder. Exemplary neurological diseases or disorders include Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer's disease, dementia with Lewy bodies, multiple system atrophy, spinal-bulbar muscular atrophy (Kennedy's disease), Tourette's syndrome, spinocerebellar ataxias (SCAs) (e.g., SCA1 type 1, SCA2 type 2, SCA3 / MJD type 3 (Machado-Joseph disease), SCA6 type 6, SCA7, SCA8, SCA9, SCA10, SCA11, SCA12, SCA13, SCA14, SCA15, SCA16, SCA17, SCA18, SCA19, SCA20, SCA21, SCA22, SCA23, SCA24, SCA25, SCA26, SCA27, SCA28, SCA29, SCA210, SCA211, SCA212, SCA22, SCA23, SCA24, SCA25, SCA26, SCA27, SCA28, SCA29, SCA211, SCA212, SCA213, SCA214, SCA215, SCA216, SCA217, SCA217, SCA218, SCA219, SCA221 ... The neurological disease or disorder includes, but is not limited to, Alzheimer's disease, migraine, hereditary cerebrovascular disease, or ATTR amyloidosis, as well as combinations thereof. In some embodiments, the neurological disease or disorder is Alzheimer's disease, migraine, hereditary cerebrovascular disease, or ATTR amyloidosis.

[0406] In some embodiments, the compound of formula (I) comprises any amyloid beta or extracellular tau binding motif disclosed elsewhere herein, and the method treats, ameliorates, and / or prevents Alzheimer's disease in a subject. In other embodiments, the compound of formula (I) comprises any amyloid beta binding motif disclosed elsewhere herein, and the method treats, ameliorates, and / or prevents inherited cerebrovascular disorders in a subject. In other embodiments, the compound of formula (I) comprises any glutamate modulator disclosed elsewhere herein, and the method treats, ameliorates, and / or prevents Alzheimer's disease, OCD, SCA, CRPS, Rett's syndrome, or a combination thereof in a subject. In other embodiments, the compound of formula (I) comprises any CGRP or CGRP receptor binding motif disclosed elsewhere herein, and the method treats, ameliorates, and / or prevents migraine in a subject. In other embodiments, the compound of formula (I) comprises any of the transthyretin binding motifs described elsewhere herein, and the method treats, ameliorates, and / or prevents ATTR amyloidosis in a subject. The methods described herein include administering to a subject a therapeutically effective amount of at least one compound described herein, which may be formulated in a pharmaceutical composition. In various embodiments, the therapeutically effective amount of at least one compound described herein present in the pharmaceutical composition is the only therapeutically active compound in the pharmaceutical composition. In certain embodiments, the method further includes administering to a subject an additional therapeutic agent that treats a disease or disorder.

[0407] The additional therapeutic agent may be any therapeutic agent known to those skilled in the art for treating, ameliorating, or preventing a disease or disorder. In some embodiments, in which the method includes treating, ameliorating, and / or preventing Alzheimer's disease, the additional therapeutic agent is selected from the group consisting of Aricept (donepezil), Exelon (rivastigmine), Namenda (memantine), Namzaric (memantine-donepezil), Razadyne (galantamine), and combinations thereof.

[0408] In certain embodiments, administration of a compound described herein to a subject allows for the administration of a lower dose of an additional therapeutic agent compared to the dose of the additional therapeutic agent alone required to achieve a similar result in treating a disease or disorder in the subject. For example, in certain embodiments, the compound described herein enhances the activity of the additional therapeutic compound, thereby reducing the dose of the additional therapeutic compound to achieve the same effect.

[0409] In certain embodiments, the compounds described herein and the therapeutic agent are administered simultaneously to a subject. In other embodiments, the compounds described herein and the therapeutic agent are co-formulated and administered simultaneously to a subject.

[0410] In certain embodiments, the subject is a mammal. In other embodiments, the mammal is a human.

[0411] Combination therapy The compounds useful within the methods described herein can be used in combination with one or more additional therapeutic agents useful for treating a disease or disorder, and / or additional therapeutic agents that reduce or ameliorate the symptoms of a disease or disorder and / or the side effects of therapeutic agents used in treating a disease or disorder. These additional therapeutic agents can include compounds that are commercially available or available to those skilled in the art by synthesis. When additional therapeutic agents useful for treating a disease or disorder are used, these additional therapeutic agents are known to treat the disease or disorder or reduce its symptoms.

[0412] In various embodiments, synergistic effects are observed when the compounds described herein are administered with one or more additional therapeutic agents or compounds. Synergistic effects can be observed, for example, with sigmoid-E maxThe combination of drugs can be calculated using any suitable method, for example, the concentration-effect curve, the isobologram curve, and the combination index curve, by applying the above-mentioned equations to the experimental data.

[0413] Administration / Dosage / Formulation The dosing regimen may affect what constitutes an effective amount. The therapeutic formulation may be administered before or after the onset of a disease or disorder in the subject. Furthermore, several divided and staggered doses may be administered daily or sequentially, or the dose may be continuously infused or bolus injected. Furthermore, the dosage of the therapeutic formulation may be proportionally increased or decreased as required by the therapeutic or prophylactic situation.

[0414] The administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, can be carried out using known procedures at dosages and for periods of time effective to treat the disease or disorder in the patient. The effective amount of the therapeutic compound required to achieve a therapeutic effect can vary according to factors such as the current state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat the disease or disorder in the patient. The administration regimen can be adjusted to achieve an optimal therapeutic response. For example, several divided doses can be administered daily, or the dose can be proportionally reduced as required by the therapeutic situation. A non-limiting example of an effective amount range for the therapeutic compounds described herein is about 1 to 5,000 mg / kg body weight / day. One skilled in the art would be able to consider the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0415] Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response, desired composition, and desired mode of administration for a particular patient, without being toxic to the patient.

[0416] In particular, the selected dosage level will depend on a variety of factors, including the activity of the particular compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, or materials used in combination with the compound, the age, sex, weight, physical condition, general health, and prior medical history of the patient being treated, and similar factors well known in the medical arts.

[0417] A medical practitioner, such as a physician or veterinarian, having ordinary skill in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, the physician or veterinarian can start the dosage of the compound described herein used in the pharmaceutical composition at a level lower than that required to obtain the desired therapeutic effect, and gradually increase the dosage until the desired effect is obtained.

[0418] In certain embodiments, it is particularly advantageous to formulate the compound in unit dosage form for ease of administration and uniformity of dosage.As used herein, unit dosage form refers to a physically separate unit suitable as a unit dosage form for the patient to be treated, each unit containing a predetermined amount of therapeutic compound calculated to produce a desired therapeutic effect, in combination with a required pharmaceutical medium.The unit dosage form of the compound described herein is determined by and directly depends on (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the field of compounding / formulating said therapeutic compound.

[0419] In certain embodiments, the compositions described herein are formulated using one or more pharma- ceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the compounds described herein and a pharma- ceutically acceptable carrier.

[0420] The carrier can be a solvent or dispersion medium, for example, containing water, ethanol, polyol (for example, glycerin, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable composition can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0421] In certain embodiments, the compositions described herein are administered to a patient at a dosing frequency ranging from 1 to 5 or more times per day. In other embodiments, the compositions described herein are administered to a patient at a dosing frequency ranging from, but not limited to, once a day, once every 2 days, once every 3 days to once a week, and once every 2 weeks. Those skilled in the art will appreciate that the dosing frequency of the various combination compositions described herein will vary from individual to individual depending on many factors, including, but not limited to, age, disease or disorder to be treated, sex, general health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed as being limited to any particular dosing regime, and the exact dosing frequency and composition administered to any patient will be determined by the attending physician taking into account all other factors related to the patient.

[0422] The compounds described herein for administration may be administered in the form of a single dose in the range of about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about 40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg to about 7,500 mg, about 200 μg to about 7,000 mg, about 350 μg to about 6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000 mg, about 1 mg to about 3,000 mg, or about 2 mg to about 4,000 mg. The amount may be within the range of about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all integer or decimal increments therebetween.

[0423] In some embodiments, the dosage of the compounds described herein is from about 1 mg to about 2,500 mg. In some embodiments, the dosage of the compounds described herein used in the compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dose of the second compound described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all integer or fractional increments thereof.

[0424] In certain embodiments, the compositions described herein are packaged pharmaceutical compositions comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second agent, and instructions for using the compound to treat a disease or disorder or reduce one or more symptoms thereof in a patient.

[0425] The preparations can be used in admixture with conventional excipients, i.e., pharma- ceutically acceptable organic or inorganic carrier substances, suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable administration mode known in the art.The pharmaceutical preparations may be sterilized, and if desired, may be mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring substances, flavoring substances, and / or aromatic substances.If desired, they may be combined with other effective agents, such as other analgesics.

[0426] The route of administration of any composition described herein includes oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical.The compound used in the composition described herein can be formulated for administration by any suitable route, for example, oral or parenteral administration, for example, transdermal, transmucosal (e.g. sublingual, intralingual, buccal (buccal), urethral (urethral), intravaginal (e.g. vaginal and perivaginal), intranasal (intranasal), and rectal (rectal)), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0427] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, electuaries, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosol formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions described herein are not limited to the specific formulations and compositions described herein.

[0428] Oral route For oral application, tablets, dragees, liquids, drops, suppositories, or capsules, caplets, and gel capsules are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and these compositions may contain one or more agents selected from the group consisting of inert and non-toxic pharmaceutical excipients suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques to improve appearance or to delay the release of the active ingredient. Oral preparations may be presented as hard gelatin capsules in which the active ingredient and inert diluents are mixed.

[0429] For oral administration, the compounds described herein may be in the form of tablets or capsules prepared by conventional means with pharma- ceutically acceptable excipients, such as binders (e.g., polyvinylpyrrolidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose); fillers (e.g., corn starch, lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). If desired, tablets can be coated using suitable methods and coating materials, such as the OPADRY™ film coating system available from Colorcon, West Point, Pennsylvania (e.g., OPADRY™ OY type, OYC type, organic enteric OY-P type, aqueous enteric OY-A type, OY-PM type, and OPADRY™ White, 32K18400). Liquid formulations for oral administration can be in the form of solutions, syrups, or suspensions. Liquid preparations can be prepared in a conventional manner with pharma- ceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid).

[0430] Parenteral Administration For parenteral administration, the compounds described herein can be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous vehicles, which may contain other formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents, can be used.

[0431] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile fixed oils are usually used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oily solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Swiss Pharmacopoeia or similar alcohols.

[0432] Further dosage forms Additional dosage forms suitable for use with the compounds and compositions described herein include those described in U.S. Patent Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compounds and compositions described herein also include those described in U.S. Patent Application Publication Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional suitable formulations for use with the compounds and compositions described herein include those described in PCT Application Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.

[0433] Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the formulations described herein can be, but are not limited to, short-term release formulations, rapid release formulations, and controlled release formulations, including sustained release formulations, delayed release formulations, and pulsatile release formulations.

[0434] The term sustained release is used in its ordinary sense to refer to a drug formulation that gradually releases drug over an extended period of time and that can, but does not necessarily, result in substantially constant blood levels of drug over an extended period of time, which can be as long as a month or more and should be a longer release than the same amount of agent administered in bolus form.

[0435] For sustained release, the compound can be formulated with suitable polymer or hydrophobic material that provides sustained release to the compound.Therefore, the compound used in the methods described herein can be administered in the form of microparticles, for example, by injection, or in the form of wafer or disk, by implantation.

[0436] In some cases, the dosage form used can be realized as slow release or controlled release of one or more active ingredients in the dosage form, for example, by using hydropropylmethylcellulose, other polymer matrices, gels, osmotic membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, or microspheres, or their combinations in various ratios to achieve desired release profile.Suitable controlled release formulations known to those skilled in the art, including those described herein, can be easily selected for use in the pharmaceutical compositions described herein.Therefore, the single unit dosage form suitable for oral administration, such as tablets, capsules, gel capsules, and caplets, which are adapted for controlled release, are included in the compositions and dosage forms described herein.

[0437] Most controlled release formulations have a common goal of improving drug therapy compared to that achieved by the corresponding non-controlled formulation.Ideally, the use of an optimally designed controlled release formulation in medical treatment is characterized by a minimum amount of drug substance used to cure or control a condition in a minimum amount of time.The advantages of controlled release formulations include prolonged drug activity, reduced dosing frequency, and increased patient compliance.In addition, controlled release formulations can be used to affect the onset of action or other characteristics such as blood levels of the drug, and therefore can affect the occurrence of side effects.

[0438] Most controlled release formulations are designed to initially release an amount of drug that rapidly produces the desired therapeutic effect, and then slowly and continuously release other amounts of drug that maintain this level of therapeutic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.

[0439] The controlled release of active ingredient can be stimulated by various inducers, such as pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlled release component" is defined herein as a compound including, but not limited to, a polymer, a polymer matrix, a gel, a permeable membrane, a liposome or a microsphere, or a combination thereof that facilitates the controlled release of active ingredient. In some embodiments, the compounds described herein are administered to patients alone or in combination with another agent using sustained release formulations. In some embodiments, the compounds described herein are administered to patients alone or in combination with another agent using sustained release formulations.

[0440] The term delayed release is used herein in its ordinary sense to refer to a drug formulation that provides for initial release of drug after some delay following drug administration, which may include, but is not necessarily, a delay of from about 10 minutes to about 12 hours.

[0441] The term pulsatile release is used herein in its ordinary sense to refer to a drug formulation that provides release of drug in a manner that produces a pulsatile plasma profile of the drug following drug administration.

[0442] The term immediate release is used in its ordinary sense to refer to a drug formulation that provides for release of drug immediately following drug administration.

[0443] Short term, as used herein, means any period of time up to about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all integer or fractional increments therein.

[0444] As used herein, rapidly means any period of time up to about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes after drug administration, and any and all integer or fractional increments therein.

[0445] Administration The therapeutically effective amount or dose of the compounds described herein depends on the age, sex, and weight of the patient, the patient's current medical condition, and the progression of the disease or disorder in the patient being treated. Those skilled in the art can determine the appropriate dosage depending on these and other factors.

[0446] Suitable doses of the compounds described herein may range from about 0.01 mg to about 5,000 mg per day, e.g., from about 0.1 mg to about 1,000 mg per day, e.g., from about 1 mg to about 500 mg, e.g., from about 5 mg to about 250 mg. Doses can be administered in single or multiple doses, e.g., from 1 to 4 or more times per day. When multiple doses are used, the amount in each dose can be the same or different. For example, a dose of 1 mg per day can be administered as two 0.5 mg doses with an interval of about 12 hours between the doses.

[0447] It will be understood that the amount of compound administered per day can be administered, in non-limiting examples, every day, every other day, every second day, every third day, every fourth day, or every fifth day. For example, for every other day administration, a dose of 5 mg per day can be administered starting on Monday, a first subsequent dose of 5 mg per day can be administered on Wednesday, and a second subsequent dose of 5 mg per day can be administered on Friday.

[0448] If the patient's condition improves, at the physician's discretion, administration of the compounds described herein may continue, or the dose of the drug administered may be temporarily reduced or temporarily discontinued for a period of time (i.e., a "drug holiday"). The length of the drug holiday may vary anywhere from 2 days to 1 year, and includes, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reductions during drug holidays include 10% to 100%, by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0449] When improvement of the patient's condition occurs, a maintenance dose is administered if necessary. The dosage or frequency of administration, or both, is then reduced to a level at which improvement in the disease is maintained. In certain embodiments, the patient may require long-term intermittent treatment for any recurrence of symptoms and / or infection.

[0450] The compounds described herein can be formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage form for a patient to be treated, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect, optionally in combination with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily administration, or for one of multiple daily administrations (e.g., about 1-4 or more times per day). When multiple daily administrations are used, the unit dosage form can be the same or different for each administration.

[0451] The toxicity and therapeutic efficacy of the treatment regimen in question are optionally determined in cell culture or experimental animals, and the LD 50 (a dose lethal to 50% of the population) and ED 50These include, but are not limited to, determining the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 and ED 50 The data obtained from cell culture assays and animal studies may be used in formulating a range of dosages for use in humans. The dosages of these compounds are administered at ED 100 mg / kg with minimal toxicity. 50 It is preferred that the dosage form be within a circulating concentration range that includes the active ingredient(s) and ... are within a range of circulating concentrations that include the active ingredient(s). The dosage amount optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0452] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, aspects, claims, and examples described herein. These equivalents are considered to be within the scope of this disclosure and are considered to be covered by the claims appended hereto. For example, it should be understood that within the scope of this application, it is possible to modify reaction conditions, including but not limited to reaction time, reaction size / volume, experimental reagents such as solvents, catalysts, pressure, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, by art-recognized substitutes and using no more than routine experimentation.

[0453] Wherever values ​​and ranges are recited herein, it should be understood that all values ​​and ranges subsumed within those values ​​and ranges are intended to be encompassed within the scope of the disclosure. Moreover, all values ​​that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the application.

[0454] The following examples further illustrate aspects of the present disclosure, but do not in any way limit the teachings or disclosure of the present disclosure set forth herein. EXAMPLES

[0455] Experimental Example The present invention will be further described with reference to the following experimental examples. These examples are presented for illustrative purposes only and are not intended to be limiting unless otherwise specified. Therefore, the present invention should not be interpreted as being limited to the following examples in any way, but rather as embracing any variations that become evident as a result of the teachings presented herein.

[0456] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following examples, make and utilize the compounds of the present invention, and practice the claimed methods. Thus, the following examples specifically illustrate preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

[0457] Example 1 Bifunctional molecules for targeted removal of neural proteins material and method Synthesis Overview Peptides are synthesized using standard Fmoc-based solid phase peptide synthesis, with Wang resin or CTC resin used as the C-terminal carboxylic acid linker and Rink Amide resin used as the C-terminal amide linker. The terminal amino acid is deprotected using 20% ​​piperidine in DMF and coupled with a mixture of Fmoc-amino acid-OH, Oxyma, and diisopropylcarbodiimide in DMF. Peptides are capped in a 9:1 pyridine:acetic anhydride solution.

[0458] Results and Discussion The present invention aims to treat neurological diseases by removing pathogenic proteins from the brain. While existing proteolytic technologies target intracellular or extracellular circulating proteins, the present disclosure extends targeted proteolysis to extracellular neuronal targets. Since several neurological diseases are caused by the accumulation and aggregation of pathogenic proteins, there are many opportunities to apply this proteolytic platform. Current treatment options, especially for Alzheimer's disease, aim to improve symptoms without addressing the underlying cause or slowing the progression of the disease.

[0459] The present disclosure provides bifunctional molecules composed of a protein-binding moiety coupled to a brain-targeting peptide. Brain targeting is achieved by low-density lipoprotein receptor-related protein 1 (LRP1). LRP1 is involved in intralysosomal trafficking and receptor-mediated transcytosis across the blood-brain barrier, suggesting that peptides targeting this receptor can both transport and degrade target neuronal proteins. Current attempts are being made to utilize the asialoglycoprotein receptor (ASGPr) in the liver for targeted degradation of extracellular proteins. However, since ASGPr is primarily expressed on hepatocytes, it is effective against extracellular targets throughout the body but cannot be used for selective degradation of neuronal proteins. In contrast, LRP1 is expressed in many tissues and is involved in both degradation and transcytosis across the blood-brain barrier. Ligands designed to target this ligand promoted receptor-mediated transcytosis across the blood-brain barrier of cargos ranging from small molecules to nanoparticles. Thus, ligands that target LRP1 would extend targeted degradation to neural protein targets (FIG. 1).

[0460] The bifunctional molecules use the LRP1 binding motif to transport non-covalent cargo and have the general structure shown below. The LRP1 binding motif is shown in Figure 2 and the target binding motif is shown in Figure 3. The non-covalent nature of this transport system allows for targeting of endogenous proteins and thus redirecting protein trafficking. In contrast to current technologies that target either systemic proteins or intracellular targets, the bifunctional molecules extend protein degradation to extracellular neuronal targets. Furthermore, this innovation extends targeted extracellular protein degradation to LRP1, which will be useful in disease states where the ASGPr is downregulated. TIFF2024507523000411.tif17140

[0461] Furthermore, instead of inhibiting targeted neuronal proteins, the novel bifunctional molecules allow both the trafficking and degradation of these proteins. This allows targeting of the undruggable proteome through the use of any protein ligand instead of dedicated inhibitors. This approach also uses the cellular machinery to degrade extracellular proteins, which allows for permanent removal of pathogenic species instead of temporary inhibition. This disclosure also enables a platform approach to the degradation and removal of pathogenic species from the brain. This synthetic peptide / small molecule combination encompasses a modular approach that facilitates modification and optimization during platform development.

[0462] It has been shown that Angiopep-2 can transport non-covalently bound protein cargo into endothelial cells and astrocytes in mouse brain. This allows the peptide to be used to target and redirect the transport of endogenous proteins. Therefore, it was decided to form bifunctional molecules containing modified Angiopep-2 as an LRP1 binding motif, where Angiopep-2 was modified by acetylation and / or substitution with a rhodamine fluorescent label (Figure 4). For use in the current proof-of-concept studies, modified Angiopep-2 was conjugated to biotin or ethoxylated dinitrophenyl target binding motifs (Figure 5).

[0463] These studies demonstrated that bifunctional molecules derived from Angiopep-2 can non-covalently transport streptavidin into mouse brain endothelial cells and astrocytes. Specifically, the data herein show that biotinylated Angiopep-2 can induce endocytosis of streptavidin, demonstrating the ability of this peptide to promote the transport of non-covalently bound cargo (Figures 6-9). Figure 6 shows saturation levels of target (streptavidin) uptake with increasing concentrations of bifunctional molecules. Figure 7 shows ELISA studies demonstrating the interaction of LRP1BM-TBM(Angiopep-2-biotin) with the target protein streptavidin. Cellular assays show LRP1BM-TBM(Angiopep-2-biotin)-mediated internalization of the target protein streptavidin into mouse brain endothelial cells (Figures 8 and 9) as well as astrocytes (Figure 9).

[0464] The trends seen in Figure 8 correlate with the binding results in Figure 7. Figure 10 shows an ELISA study demonstrating the interaction of LRP1BM-DNP(TBM) Angiopep-2 with the target protein anti-DNP antibody. The data on the bifunctional molecule formed from Angiopep-2 and an ethoxylated DNP molecule further demonstrates that DNP-modified Angiopep-2 binds to the anti-DNP antibody (Figure 10). These findings represent a significant improvement over all previous uses of this peptide, which required covalent modification of the cargo with Angiopep-2.

[0465] While the data herein demonstrate the potential of Angiopep 2 to promote both transcytosis and intralysosomal targeting, future studies will involve applying this platform to therapeutically relevant targets to evaluate the contribution of cargo size, valency, and transport mechanism. Several tests have been performed on other bifunctional molecules (which also non-covalently bind to streptavidin) containing the LRP1-binding motif and the biotin target-binding motif shown in Figure 2 (Figure 11). Specifically, Figure 11 shows an ELISA study demonstrating the interaction of LRP1BM-Biotin (TBM) with the target protein streptavidin. Figure 12 shows the degradation of a target protein using the LRP1-binding motif.

[0466] The disclosures of all patents, patent applications, and publications cited in this specification are incorporated herein by reference in their entirety. Although the present disclosure has been disclosed with reference to certain embodiments, it is clear that those skilled in the art can devise other embodiments and variations of the present disclosure without departing from the spirit and scope of the present disclosure. The appended claims are intended to be interpreted to include all such embodiments and equivalent variations.

[0467] Numbered Aspects The following numbered aspects are presented, however, the numbering should not be construed as indicating any level of importance.

[0468] Aspect 1 provides: A compound of formula (I) or a salt, geometric isomer, stereoisomer, or solvate thereof: [TBM] n -[Linker] m -[LRP1BM] o (I) During the ceremony, m is an integer from 0 to 15; n and o each independently represent an integer of 1 to 15; [TBM] is: (a) A compound selected from TIFF2024507523000412.tif79136 and TIFF2024507523000413.tif139135, or a derivative or prodrug thereof (In the formula, TIFF2024507523000414.tif6128 indicates possible covalent attachment points to [linker] or [LRP1BM]); (b) Formula (I): Compound of TIFF2024507523000415.tif30128, or a derivative or prodrug thereof (In the formula, A is N or CR 5 and; B is N or CR 6 and; E is N or CR 7 and; L is a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heteroalkylene, a bond, -O-, -NR A -, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR A -, -NR A C(=O)-, -NR A C(=O)R A -, -C(=O)R A -, -NR AC(=O)O-, -NR A C(=O)N(R A )-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R A )-, -S(O)NR A -, -NR A S(O)2-, or a combination thereof; X is a bond or a substituted or unsubstituted C 1~12 alkylene, where one or more carbons are C(=O), O, S, SO2, NH, or halogen, OH, or C 1~6 NC optionally substituted with alkyl 1~6 optionally substituted with alkyl; R 8 is hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1~6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are halogen, SO, NH, or halogen or C. 3~8 Optionally substituted with cycloalkyl 1~6 optionally substituted with alkyl; R 3 Ha-(CH2) n -, -(CH2) n -C(=O), -(CH2) n -C(=O)-O-, -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n-(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; R A each occurrence of R is independently selected from hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or, if attached to a nitrogen atom, a nitrogen protecting group; or A the groups taken together form a substituted or unsubstituted heterocycle; each occurrence of A is independently selected from substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 1 , R 2 , and R 4 ~R 8 are each independently hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3~8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; Here, R1 ~R 7 One or more carbons in the formula are C(=O), O, S, SO2, NH, NH-C 1~6 Alkyl, NC 1~6 Alkyl, NH2, or N(C 1~6 alkyl)2; TIFF2024507523000416.tif6128 indicates the covalent attachment point to [linker] or [LRP1BM]); (c) Formula (II): Compound of TIFF2024507523000417.tif22128, or a derivative or prodrug thereof (In the formula, R1 and R2 are each independently hydrogen, N3, alkynyl, OH, halogen, NH2, N(C 1~6 Alkyl)2, C 1~6 Alkyl, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3~8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 More selected; wherein the aryl and heteroaryl are halogen, -SO2, NO2, -NH2, or halogen or C 3~8 Optionally substituted with cycloalkyl 1~6 optionally substituted with alkyl; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; Here, R 1 or R 2 One or more carbons in the formula are C(=O), O, S, SO2, NH, NH-C 1~6 Alkyl, NC 1~6 Alkyl, NH2, or N(C 1~6 alkyl)2; TIFF2024507523000418.tif6128 indicates the covalent attachment point to [linker] or [LRP1BM]); (d) Formula (III): Compound of TIFF2024507523000419.tif26128, or a derivative or prodrug thereof (In the formula, R1 is selected from benzene, phenyl, cyclohexyl, hydrogen, and CF3; R2 is selected from hydrogen and CF3; TIFF2024507523000420.tif6128 indicates the covalent attachment point to [linker] or [LRP1BM]); (e) Formula (IV): Compound of TIFF2024507523000421.tif45128, or a derivative or prodrug thereof (In the formula, R1 is selected from hydrogen, Cl, OMe, SMe, and CF3; TIFF2024507523000422.tif6128 indicates the covalent attachment point to [linker] or [LRP1BM]); (f) Formula (V): Compound of TIFF2024507523000423.tif44128, or a derivative or prodrug thereof (In the formula, R1 is selected from hydrogen, Cl, OMe, SMe, and CF3; TIFF2024507523000424.tif6128 indicates the covalent attachment point to [Linker] or [LRP1BM]); or (g) Amino acid sequence selected from TIFF2024507523000425.tif33128 represents a target binding motif comprising or consisting of: [LRP1BM] has the following amino acid sequence: TIFF2024507523000426.tif34128 (wherein R8 represents (R)-2-(7-octenyl)Ala-OH and S5 represents (S)-2-(4-pentenyl)Ala-OH, and there is a hydrocarbon bridge between positions 1 and 8); TIFF2024507523000427.tif19128 (where Nle stands for norleucine), TIFF2024507523000428.tif98128, in which an underlined amino acid indicates that the amino acid may or may not be present, and an underlined K / C indicates that K or C may be present; [Linker] represents a polyethylene glycol-containing linker having 1 to 12 ethylene glycol residues, or [Linker] is one of the following: (a) -CH2CH2(OCH2CH2) m OCH2-, -(CH2) m CH2- or -[N(R a )-CH(R b )(C=O)] m - or a polypropylene glycol or polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units (In the formula, Each R a are independently H, C1-C3 alkyl, or C1-C6 alkanol, or R b together with the compound to form a pyrrolidine or hydroxypyrroline group; Each R b is independently selected from the group consisting of hydrogen, methyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)3-guanidine, -CH2C(=O)NH2, -CH2C(=O)OH, -CH2SH, -(CH2)2C(=O)NH2, -(CH2)2C(=O)OH, -(CH2)imidazole, -(CH2)4NH2, -CH2CH2SCH3, benzyl, -CH2OH, -CH(OH)CH3, -(CH2)imidazole, or -(CH2)phenol; m is an integer ranging from 1 to 15); (b) -[N(R'-(CH2) 1~15 -C(=O)] m - (wherein R' is H or C1-C3 alkyl optionally substituted with 1-2 hydroxyl groups, and m is an integer ranging from 1 to 100); (c) -ZD-Z'- (In the formula, Z and Z' are each independently a bond, -(CH2) i -O-, -(CH2) i -S-, -(CH2) i -N(R)-, TIFF2024507523000429.tif10128, -(CH2) i -C(R 2 )=C(R 2 )-(cis or trans), -(CH2) i -≡- or -YC(=O)-Y-, each R is independently H, C1-C3 alkyl, or C1-C6 alkanol; Each R 2 are independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N(R); Each i is independently between 0 and 100; D is a bond, -(CH2) i -YC(=O)-Y-(CH2) i -, -(CH2) m' - or -[(CH2) n -X1)] j with the proviso that Z, Z', and D are not each simultaneously a bond; X1 is O, S, or N(R); j is an integer ranging from 1 to 100; m' is an integer ranging from 1 to 100; n is an integer ranging from 1 to 100); (d) -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n' CH2CH2- or -(CH2CH2CH2O) n - (In the formula, n and n′ each independently represent an integer ranging from 1 to 25; (e) -PEG-CON-PEG- wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues; and CON is TIFF2024507523000430.tif117128, wherein R' and R'' are each independently H, methyl, or a bond; (f) -PEG-CON-PEG- wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues; and CON is -C(=O)-N(R 1 )-(CH2) n'' -N(R 1 )C(=O)-, -N(R 1 )-C(=O)(CH2) n'' -C(=O)N(R 1 )- or -N(R 1 )-C(=O)(CH2) n'' -N(R 1 )C(═O)—, wherein each R 1 are independently H or C1-C3 alkyl, and n'' is independently an integer from 0 to 8; (g) -PEG-CON-PEG- wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON comprises the structure: TIFF2024507523000431.tif14128In formula, R 1a , R 2a , and R 3a are each independently H, -(CH2) M1 -, -(CH2) M2 C(=O) M3 (NR 4 ) M3 -(CH2) M2 -, -(CH2) M2 (NR 4 ) M3 C(O) M3 -(CH2) M2 - or -(CH2) M2 O-(CH2)M1 -C(O)NR 4 - but R 1a , R 2a , and R 3a but not simultaneously H; each M1 is independently 1, 2, 3, or 4, and in certain embodiments, 1 or 2; each M2 is independently 0, 1, 2, 3, or 4, and in certain embodiments 0, 1, or 2; each M3 is independently 0 or 1; Each R 4 are independently H, C1-C3 alkyl, C1-C6 alkanol, or -C(=O)(C1-C3 alkyl), provided that the same R 1a , R 2a , and R 3a M2 and M3 in cannot all be zero at the same time); (h) -PEG-CON-PEG- wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON comprises the structure: TIFF2024507523000432.tif47128); (i) a natural or unnatural amino acid; (j) [Gly-Gly-Gly-Gly-Ser] n (where n is 1, 2, 3, 4, 5, or 6); (k) [Ser-Ser-Ser-Ser-Gly] y (where y is ≧1); or (l) Ser-Gly-Ser-Ser-Ser-Ser-Gly-Ser-Ser-Ser-Ser-Gly-Ser represents a linking group containing the following:

[0469] Aspect 2 provides: The compound of embodiment 1, wherein the linker has a valency of 1, 2, or 3.

[0470] Aspect 3 provides: The compound of any one of embodiments 1-2, wherein m is 1, 2, or 3.

[0471] Aspect 4 provides: The compound of any one of embodiments 1-3, wherein n and o are each independently 1, 2, or 3.

[0472] Aspect 5 provides the following: The compound of any one of embodiments 1-4, wherein the target binding motif non-covalently binds to an extracellular or cell surface protein.

[0473] Aspect 6 provides the following: The compound of any one of embodiments 1-5, wherein the extracellular or cell surface protein comprises calcitonin gene-related peptide (CGRP), a CGRP receptor, an N-methyl-D-aspartate (NMDA) receptor, myeloperoxidase (MPO), alpha-synuclein, IAPP, transthyretin, extracellular tau, amyloid precursor protein, prion protein, or amyloid beta.

[0474] Aspect 7 provides the following: The compound of any one of embodiments 1-6, wherein the extracellular or cell surface protein comprises extracellular tau or amyloid beta.

[0475] Aspect 8 provides the following: The compound of any one of embodiments 1-7, wherein the extracellular or cell surface protein is found in the brain or central nervous system.

[0476] Aspect 9 provides the following: [TBM], TIFF2024507523000433.tif19128 (wherein p is an integer from 1 to 6); and TIFF2024507523000434.tif22128 (wherein R1 and R2 are each independently selected from F, Cl, Br, and I). The compound of any one of embodiments 1 to 8, selected from:

[0477] Aspect 10 provides the following: The compound of any one of embodiments 1-9, wherein LRP1BM comprises the peptide of SEQ ID NO: 1.

[0478] Aspect 11 provides the following: The compound of any one of embodiments 1-10, wherein the C-terminal cysteine ​​residue is not present in the peptide of SEQ ID NO:1.

[0479] Aspect 12 provides the following: The compound of any one of embodiments 1-11, wherein the peptide of SEQ ID NO: 1 is linked to the linker through its N-terminal tyrosine (Tyr1), Lys10, or Lys15.

[0480] Aspect 13 provides the following: A pharmaceutical composition comprising at least one pharma- ceutically acceptable excipient and at least one compound according to any one of aspects 1-12.

[0481] Aspect 14 provides the following: The pharmaceutical composition of embodiment 13, further comprising another therapeutically active compound.

[0482] Aspect 15 provides the following: 1. A method of treating, ameliorating, or preventing a disease or disorder in a subject, comprising: administering a therapeutically effective amount of a composition comprising at least one compound of embodiment 1, or a salt, geometric isomer, stereoisomer, or solvate thereof. The method comprises:

[0483] Aspect 16 provides the following: The method of embodiment 15, wherein the disease or disorder is a neurological disease or disorder.

[0484] Aspect 17 provides the following: 17. The method of embodiment 16, wherein the neurological disease or disorder is at least one of Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer's disease, dementia with Lewy bodies, multiple system atrophy, spinal-bulbar muscular atrophy (Kennedy disease), Tourette's syndrome, spinocerebellar ataxia (SCA), schizophrenia, age-related memory impairment, autism, migraine, Rett's syndrome, complex regional pain syndrome (CRPS), obsessive-compulsive disorder (OCD), attention deficit disorder, bipolar disorder, hereditary cerebrovascular disease, ATTR amyloidosis, or depression.

[0485] Aspect 18 provides the following: The method of embodiment 16, wherein the neurological disease or disorder is Alzheimer's disease.

[0486] Aspect 19 provides the following: The method of any one of embodiments 15-18, wherein at least one additional therapeutic agent that treats, ameliorate, or prevent said disease or disorder is further administered to the subject.

[0487] Aspect 20 provides the following: The method of any one of embodiments 15 to 19, wherein the subject is a mammal.

[0488] Aspect 21 provides the following: The method of any one of embodiments 15 to 20, wherein the subject is a human.

[0489] Aspect 22 provides the following: The method of any one of aspects 15-21, wherein the composition comprises at least one pharma- ceutically acceptable carrier or excipient.

Claims

1. A compound of formula (I) or a salt, geometric isomer, stereoisomer, or solvate thereof: [TBM] n -[Linker] m -[LRP1BM] o (I) During the ceremony, m is an integer from 0 to 15; n and o are each independently an integer from 1 to 15; [TBM] is: (a) A compound selected from the group consisting of: (In the formula, indicates a possible covalent attachment point to [Linker] or [LRP1BM]); (b) Formula (I): or a derivative or prodrug thereof (In the formula, A is N or CR 5 and; B is N or CR 6 and; E is N or CR 7 and; L is a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heteroalkylene, a bond, -O-, -NR A -, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR A -, -NR A C(=O)-, -NR A C(=O)R A -, -C(=O)R A -, -NR A C(=O)O-, -NR A C(=O)N(R A )-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R A )-, -S(O) 2 NR A -, -NR A S(O) 2 - or a combination thereof; X is a bond or a substituted or unsubstituted C 1～12 Alkylene, where one or more carbons are C(=O), O, S, SO 2 , NH, or halogen, OH, or C 1～6 NC optionally substituted with alkyl 1～6 optionally substituted with alkyl; R 8 is hydrogen, -N 3 , alkynyl, OH, halogen, NH 2 , N(C 1～6 Alkyl) 2 , aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are halogen, SO 2 , N.H. 2 , or halogen or C 3～8 C optionally substituted with cycloalkyl 1～6 optionally substituted with alkyl; R 3 is -(CH 2 ) n -, -(CH 2 ) n -C(=O)-, -(CH 2 ) n -C(=O)-O-, -(CH 2 ) n -O-, -A-(CH 2 ) n -O-, -(CH 2 ) n -A-O-, -A-O-(CH 2 ) n -(C=O)NR A -, -(CH 2 ) n -S-, -A-(CH 2 ) n -S-, -(CH 2 ) n -A-S-, -A-S-(CH 2 ) n -(C=O)NR A -, -(CH 2 ) n -NR A -, -A-(CH 2 ) n -NR A -, -(CH 2 ) n -A-NR A -, -(CH 2 ) n -(C=O)NR A -, -A-(CH 2 ) n -(C=O)NR A -, -(CH 2 ) n -A-(C=O)NR A -, -A-NR A -(CH 2 ) n -(C=O)NR A -, -(CH 2 ) n -S(O) 2 NR A -, -A-(CH 2 ) n -S(O) 2 NR A -, or -(CH 2 ) n -AS(O) 2 NR A - and; R A each occurrence of R is independently selected from hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or, if attached to a nitrogen atom, a nitrogen protecting group; or A the groups taken together form a substituted or unsubstituted heterocycle; each occurrence of A is independently selected from substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 1 , R 2 , and R 4 ~R 8 are independently hydrogen, OH, halogen, and NH 2 , C.H. 3 , S.O. 2 , NO 2 , leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 ) 2 C 3～8 Cycloalkyl, N(R 12 ) 2 Heterocyclyl, or -(CH 2 ) n -R 12 and; R 12 is hydrogen, -CH 3 , aryl, or heteroaryl; n is 0 to 12; Here, R 1 ~R 7 One or more carbons in the group are C(=O), O, S, SO 2 , NH, NH-C 1～6 Alkyl, NC 1～6 Alkyl, NH 2 , or N(C 1～6 Alkyl) 2 may be replaced by; indicates the point of covalent attachment to [linker] or [LRP1BM]); (c) Formula (II): or a derivative or prodrug thereof (In the formula, R 1 and R 2 are each independently hydrogen, N 3 , alkynyl, OH, halogen, NH 2 , N(C 1～6 Alkyl) 2 , C 1～6 Alkyl, aryl, heteroaryl, NHR 12 , N(R 12 ) 2 C 3～8 Cycloalkyl, N(R 12 ) 2 Heterocyclyl, or -(CH 2 ) n -R 12 More selected; wherein the aryl and heteroaryl are halogen, -SO 2 , NO 2 , -NH 2 , or halogen or C 3～8 C optionally substituted with cycloalkyl 1～6 optionally substituted with alkyl; R 12 is hydrogen, -CH 3 , aryl, or heteroaryl; n is 0 to 12; Here, R 1 or R 2 One or more carbons in the group are C(=O), O, S, SO 2 , NH, NH-C 1～6 Alkyl, NC 1～6 Alkyl, NH 2 , or N(C 1～6 Alkyl) 2 may be replaced by; indicates the point of covalent attachment to [linker] or [LRP1BM]); (d) Formula (III): or a derivative or prodrug thereof (In the formula, R 1 is benzene, phenyl, cyclohexyl, hydrogen, and CF 3 More selected; R 2 is hydrogen and CF 3 More selected; indicates the point of covalent attachment to [linker] or [LRP1BM]); (e) Formula (IV): or a derivative or prodrug thereof (In the formula, R 1 is hydrogen, Cl, OMe, SMe, and CF 3 More selected; indicates the point of covalent attachment to [linker] or [LRP1BM]); (f) Formula (V): or a derivative or prodrug thereof (In the formula, R 1 is hydrogen, Cl, OMe, SMe, and CF 3 More selected; indicates the point of covalent attachment to [Linker] or [LRP1BM]; or (g) An amino acid sequence selected from represents a target binding motif comprising or consisting of: [LRP1BM] has the following amino acid sequence: (where R 8 represents (R)-2-(7-octenyl)Ala-OH, and S 5 represents (S)-2-(4-pentenyl)Ala-OH, with a hydrocarbon bridge between the 1- and 8-positions); (wherein Nle stands for norleucine), wherein an underlined amino acid in the above sequence indicates that the amino acid may be present or absent, and an underlined K / C indicates that K or C may be present; [Linker] represents a polyethylene glycol-containing linker having 1 to 12 ethylene glycol residues, or [Linker] is one of the following: (a) -CH 2 CH 2 (OCH 2 CH 2 ) m OCH 2 -, -(CH 2 ) m CH 2 - or -[N(R a )-CH(R b )(C=O)] m - or a polypropylene glycol or polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units (In the formula, Each R a are independently H, C 1 ~C 3 Alkyl or C 1 ~C 6 alkanol, or R b together with the compound to form a pyrrolidine or hydroxypyrroline group; Each R b are independently hydrogen, methyl, isopropyl, -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -(CH 2 ) 3 -Guanidine, -CH 2 C(=O)NH 2 , -CH 2 C(=O)OH, -CH 2 SH, -(CH 2 ) 2 C(=O)NH 2 , -(CH 2 ) 2 C(=O)OH, -(CH 2 )imidazole, -(CH 2 ) 4 NH 2 , -CH 2 CH 2 SCH 3 , benzyl, -CH 2 OH, -CH(OH)CH 3 , -(CH 2 ) imidazole, or -(CH 2 ) phenols; m is an integer ranging from 1 to 15); (b) -[N(R'-(CH 2 ) 1～15 -C(=O)] m - (wherein R' is H or C optionally substituted with 1 to 2 hydroxyl groups) 1 ~C 3 alkyl, and m is an integer ranging from 1 to 100; (c) -ZD-Z'- (In the formula, Z and Z' each independently represent a bond, -(CH 2 ) i -O-, -(CH 2 ) i -S-, -(CH 2 ) i -N(R)-, , -(CH 2 ) i -C(R 2 )=C(R 2 )-(cis or trans), -(CH 2 ) i -≡- or -YC(=O)-Y-, Each R is independently H, C 1 ~C 3 Alkyl, or C 1 ~C 6 is an alkanol, Each R 2 are independently H or C 1 ~C 3 is alkyl, each Y is independently a bond, O, S, or N(R); Each i is independently between 0 and 100; D is a bond, -(CH 2 ) i -YC(=O)-Y-(CH 2 ) i -, -(CH 2 ) m' - or -[(CH 2 ) n -X 1 )] j with the proviso that Z, Z', and D are not each simultaneously a bond; X 1 is O, S, or N(R), j is an integer ranging from 1 to 100; m' is an integer ranging from 1 to 100; n is an integer ranging from 1 to 100); (d) -CH 2 -(OCH 2 CH 2 ) n -CH 2 -、-(CH 2 CH 2 O) n' CH 2 CH 2 -、 or -(CH 2 CH 2 CH 2 O) n - wherein n and n' are each independently an integer ranging from 1 to 25; (e) -PEG-CON-PEG- wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues; and CON is wherein R′ and R″ are each independently H, methyl, or a bond; (f) -PEG-CON-PEG- where each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON is -C(=O)-N(R 1 )-(CH 2 ) n'' -N(R 1 )C(=O)-, -N(R 1 )-C(=O)(CH 2 ) n'' -C(=O)N(R 1 )-, or -N(R 1 )-C(=O)(CH 2 ) n'' -N(R 1 )C(═O)—, wherein each R 1 are independently H or C 1 ~C 3 alkyl, and n'' is independently an integer from 0 to 8; (g) -PEG-CON-PEG- wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON comprises the structure: During the ceremony, R 1a , R 2a , and R 3a are each independently H, -(CH 2 ) M1 -, -(CH 2 ) M2 C(=O) M3 (NR 4 ) M3 -(CH 2 ) M2 -, -(CH 2 ) M2 (NR 4 ) M3 C(O) M3 -(CH 2 ) M2 - or -(CH 2 ) M2 O-(CH 2 ) M1 -C(O)NR 4 - but R 1a , R 2a , and R 3a but not simultaneously H; each M1 is independently 1, 2, 3, or 4, and in certain embodiments, 1 or 2; each M2 is independently 0, 1, 2, 3, or 4, and in certain embodiments 0, 1, or 2; each M3 is independently 0 or 1; Each R 4 are independently H, C 1 ~C 3 Alkyl, C 1 ~C 6 Alkanol, or -C(=O)(C 1 ~C 3 alkyl), but with the same R 1a , R 2a , and R 3a M2 and M3 in cannot all be 0 at the same time); (h) -PEG-CON-PEG- wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON comprises the structure: ）; (i) a natural or unnatural amino acid; (j) [Gly-Gly-Gly-Gly-Ser] n (where n is 1, 2, 3, 4, 5, or 6); (k) [Cheese-Cheese-Cheese-Gly] y (where y is ≥ 1); or (l) Ser-Gly-Ser-Ser-Ser-Ser-Gly-Ser-Ser-Ser-Ser-Gly-Ser represents a linking group containing the following:

2. 2. The compound of claim 1, wherein the linker has a valency of 1, 2, or 3.

3. 2. The compound of claim 1, wherein m is 1, 2, or 3.

4. 2. The compound of claim 1, wherein n and o are each independently 1, 2, or 3.

5. The compound of claim 1, wherein the target binding motif non-covalently binds to an extracellular or cell surface protein.

6. 6. The compound of claim 5, wherein the extracellular or cell surface protein comprises calcitonin gene-related peptide (CGRP), a CGRP receptor, an N-methyl-D-aspartate (NMDA) receptor, myeloperoxidase (MPO), alpha-synuclein, IAPP, transthyretin, extracellular tau, amyloid precursor protein, prion protein, or amyloid beta.

7. 7. The compound of claim 5 or 6, wherein the extracellular or cell surface protein comprises extracellular tau or amyloid beta.

8. The compound of any one of claims 5 to 7, wherein the extracellular or cell surface protein is found in the brain or central nervous system.

9. [TBM], where p is an integer from 1 to 6; and (In the formula, R 1 and R 2 are each independently selected from F, Cl, Br, and I.

2. The compound of claim 1, selected from:

10. The compound of claim 1, wherein LRP1BM comprises a peptide of SEQ ID NO:

1.

11. 11. The compound of claim 10, wherein the C-terminal cysteine ​​residue is not present in the peptide of SEQ ID NO:

1.

12. The compound of claim 11, wherein the peptide of SEQ ID NO: 1 is linked to the linker through its N-terminal tyrosine (Tyr1), Lys10, or Lys15.

13. 13. A pharmaceutical composition comprising at least one pharma- ceutically acceptable excipient and at least one compound of claim 1.

14. 14. The pharmaceutical composition of claim 13, further comprising another therapeutically active compound.

15. A pharmaceutical composition for treating, ameliorating, or preventing a disease or disorder in a subject, comprising a therapeutically effective amount of at least one compound described in claim 1, or a salt, geometric isomer, stereoisomer, or solvate thereof.

16. 16. The pharmaceutical composition of claim 15, wherein the disease or disorder is a neurological disease or disorder.

17. 17. The pharmaceutical composition of claim 16, wherein the neurological disease or disorder is at least one of Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer's disease, dementia with Lewy bodies, multiple system atrophy, spinal-bulbar muscular atrophy (Kennedy disease), Tourette's syndrome, spinocerebellar ataxia (SCA), schizophrenia, age-related memory impairment, autism, migraine, Rett's syndrome, complex regional pain syndrome (CRPS), obsessive-compulsive disorder (OCD), attention deficit disorder, bipolar disorder, hereditary cerebrovascular disease, ATTR amyloidosis, or depression.

18. 17. The pharmaceutical composition of claim 16, wherein the neurological disease or disorder is Alzheimer's disease.

19. 16. The pharmaceutical composition of claim 15, wherein the composition is administered to a subject in combination with at least one additional therapeutic agent that treats, ameliorates, or prevents the disease or disorder.

20. 16. The pharmaceutical composition of claim 15, wherein the subject is a mammal.

21. 16. The pharmaceutical composition of claim 15, wherein the subject is a human.

22. The pharmaceutical composition of claim 15, comprising at least one pharma- ceutically acceptable carrier or excipient.

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