Dual PTP1B / TC-PTP inhibitors and protein degraders

Abstract

Compounds that are dual inhibitors and dual degraders of protein tyrosine phosphatase 1B (PTP1B) and T-cell PTP (TC-PTP), compositions containing the same, and their use for treating diseases or conditions mediated by PTP1B and TC-PTP.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 443,582, filed February 6, 2023, which is incorporated by reference herein in its entirety.

[0002] Government support statement This invention was made with government support under grant CA069202 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] Technical Field The present disclosure relates to dual inhibitors of protein tyrosine phosphatase 1B (PTP1B) and T-cell PTP (TC-PTP), as well as PTP1B and TC-PTP protein degraders, and their use in the treatment of cancer and other diseases. [Background technology]

[0004] This section introduces aspects that may be helpful in promoting a better understanding of the present disclosure. Accordingly, these statements are to be read in this light and not construed as admissions about what is prior art or what is not prior art.

[0005] Protein tyrosine phosphorylation is a crucial post-translational modification regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) and plays an essential role in regulating essential cellular functions. Given that numerous human diseases are associated with abnormal protein tyrosine phosphorylation, both PTKs and PTPs are highly sought-after targets for drug discovery. Among the members of the PTP family, protein tyrosine phosphatase 1B (PTP1B, also known as PTPN1) and T-cell protein tyrosine phosphatase (TC-PTP, also known as PTPN2) are the two most closely related cytoplasmic PTPs, sharing over 72% amino acid sequence identity between their catalytic domains. Despite their structural similarities, PTP1B and TC-PTP are known to play non-redundant, synergistic roles in coordinating several important signaling pathways.

[0006] PTP1B and TC-PTP have long been known to function cooperatively in regulating both insulin- and leptin-mediated cellular processes. PTP1B negatively regulates the amplitude of insulin action by dephosphorylating the insulin receptor and insulin receptor substrate 1, whereas TC-PTP catalyzes insulin receptor dephosphorylation, limiting the duration of insulin signaling. PTP1B and TC-PTP also attenuate leptin signaling by causing the dephosphorylation of JAK2 and STAT3, respectively.

[0007] PTP1B and TC-PTP play nonredundant roles in attenuating IFN-γ signaling. Elimination of PTP1B increases JAK2 phosphorylation and potentiates IFN-γ-mediated STAT1 activation, whereas TC-PTP removal from tumor cells enhances IFN-γ signaling and antigen presentation as a result of increased phosphorylation of JAK1 and its downstream effector STAT1. Interestingly, PTP1B and TC-PTP also perform unique functions as negative regulators of T cell activation. Toward this goal, PTP1B deficiency in T cells enhances CD8 T cell proliferation against solid tumors via increased JAK2 / STAT5 phosphorylation. + Promotes antigen-induced proliferation and cytotoxicity of T cells. Genetic disruption of TC-PTP in T cells enhances CD8 + Increases T cell proliferation and survival and upregulates CD8 by amplifying LCK and STAT5 phosphorylation + Promotes T cell activation.

[0008] Based on the roles of PTP1B and TC-PTP in cell signaling, simultaneously targeting both enzymes may produce synergistic effects for multiple therapeutic applications, including type II diabetes, obesity, and anti-cancer immunotherapy. However, combination therapy is prone to complex pharmacokinetics / pharmacodynamics, unexpected drug-drug interactions, toxicity, and / or patient compliance issues. Polypharmacology, the design or use of multitarget compounds acting against two or more selected targets, has attracted significant interest in drug discovery due to increasing awareness of the complexity of multifactorial human diseases (Anighoro, A. et al., 2014, J. Med. Chem. 57, 7874-7887). Compared with single-target drugs or multidrug combinations, polypharmacological agents or multitarget ligands offer valuable alternatives with several advantages, such as superior therapeutic efficacy, reduced risk of drug-drug interactions, more predictable pharmacokinetic / pharmacodynamic profiles, and simplified treatment regimens.

[0009] Thus, there is an unmet need for PTP1B / TC-PTP dual inhibitors and PTP1B / TC-PTP dual degraders that have physical and pharmacological properties that enable them to be used in therapeutic applications to treat disease. It is an object of the present disclosure to provide such compounds. This and other objects and advantages, as well as other features of the invention, will become apparent from the detailed description provided herein. Summary of the Invention

[0010] A compound of formula (I) or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof:

[0011] [ka] (In the formula, R1 and R2 are each independently a residue of a carboxylic acid, or a pharmaceutically acceptable salt thereof, and R1 and R2 may be the same or different; R3, R4, R5, R6, R7, and R8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylene, 4- to 6-membered heterocyclyl, and -C1-C6 alkylene-4- to 6-membered heterocyclyl; The alkylene-4- to 6-membered heterocyclyl group is substituted with deuterium, halogen, hydroxy, C═O, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, -C1-C6-alkylene-C3-C6 cycloalkyl, C1-C6 alkyl-S(O)2-, C3-C6 cycloalkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 alkoxy-C(O)-, -NH-C(O)-R a , and -C(O)-NH-R a and optionally substituted on one or more available carbons with one or more substituents each independently selected from R ais deuterium, halogen, hydroxy, C=O, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, -C1-C6-alkylene-C3-C6 cycloalkyl, C1-C6 alkyl-S(O)2-, C1-C6 cycloalkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 alkoxy-C(O)-, -NH-C(O)-R b , and -C(O)-NH-R b and R b are independently selected from deuterium, halogen, hydroxy, C═O, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, —C1-C6-alkylene-C3-C6 cycloalkyl, C1-C6 alkyl-S(O)2—, C3-C6 cycloalkyl-S(O)2—, C1-C6 alkyl-C(O)—, and C1-C6 alkoxy-C(O)—; t is 0 to 6, R9 is H or a group represented by the formula LB, where L is

[0012] [Table 1] is a linker selected from the group consisting of w is 1 to 5, x is 1 to 15, a and b are each independently 0 to 3,

[0013] [ka] The bond indicated by is connected to B and * " represents the point of attachment of R9; B is selected from groups B1, B2, and B3, where B1 has the structure:

[0014] [ka] is represented by R 3a is fluoro, hydrogen, or deuterium, B2 has the structure:

[0015] [ka] is represented by R 3b is fluoro, hydrogen, or deuterium, B3 has the structure:

[0016] [ka] is represented by R4 is methyl, hydrogen, or deuterium. is provided.

[0017] A compound of formula (II) or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer thereof:

[0018] [ka] wherein R1 and R2 are as defined for formula (I) above. is further provided.

[0019] In some embodiments, R1 or R2 is

[0020] [ka] is.

[0021] In some embodiments, R1 or R2 is

[0022] [ka] is.

[0023] In some embodiments, R1 or R2 is

[0024] [ka] is.

[0025] In some embodiments, the compound of formula (II) is

[0026] [ka] or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof.

[0027] A compound of formula (III) or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof:

[0028] [ka] wherein R1, R2, L, and B are as defined for formula (I) above. is further provided.

[0029] In some embodiments, B is B3:

[0030] [ka] wherein R4 is methyl, hydrogen, or deuterium. is.

[0031] In some embodiments, R1 or R2 is

[0032] [ka] is selected from.

[0033] In some embodiments, the linker L is

[0034] [ka] is selected from.

[0035] In some embodiments, the carboxylic acid in the compounds of Formulas (I), (II), and (III) is represented by the formula RCOOH, where R is selected from the group consisting of hydrogen, an aliphatic group, or an aromatic group, the aliphatic group being saturated or unsaturated, and the aliphatic group or aromatic group being C1-C 24 Alkyl, C1-C 24 Alkenyl, C1-C 24 alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl, wherein R groups are C1-C 24 Alkyl, hydroxy, alkoxy, cyano, halo, nitro, aryl, amino, C1-C 24 Alkenyl, C1-C 24 Optionally substituted with at least one of the group selected from alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl.

[0036] In some embodiments, the carboxylic acid is 3-dimethylaminobenzoic acid, 2-(2-cyanophenylthio)benzoic acid, 2-(4-chlorobenzoyl)benzoic acid, (−)-2-oxo-4-thiazolidine-carboxylic acid, (−)-N-acetylneuraminic acid, (+)-6-methoxy-α-methyl-2-naphthaleneacetic acid, (+)-carbobenzyloxy-D-proline, (+)-menthoxyacetic acid, (±)-2-(2-chlorophenoxy)propionic acid, (±) -1-Methyl-2-cyclohexene-1-carboxylic acid, (1-naphthoxy)acetic acid, (1R)-(1a,2b,3a)-(+)-3-methyl-2-nitromethyl-5-oxocyclopentaneacetic acid, (1R,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylic acid, (1S)-(+)-camphanic acid, (1S,3R,4S,5R)-1,3,4,5-tetrahydroxycyclohexanecarboxylic acid, (2,4-di-tert- (pentylphenoxyl)acetic acid, (2-naphthoxy)acetic acid, (2-pyrimidylthio)acetic acid, (4-carboxybutyl)triphenyl-phosphonium bromide, (4-chlorophenylthio)acetic acid, (4-methylphenoxy)acetic acid, (α,α,α-trifluoro-m-tolyl)acetic acid, (E)-2-((4-hydroxyphenyl)diazenyl)benzoic acid, (E)-2-methyl-3-(2,4,5-trimethoxyphenyl)acrylic acid, (methylthio)acetic acid, (R )-(-)-2-Hydroxy-4-phenylbutyric acid, (R)-(-)-3-chloromandelic acid, (R)-(-)-hexahydromandelic acid, (R)-(+)-2-pyrrolidone-5-carboxylic acid, (R)-(+)-citronellic acid, (R)-2-(1-phenylethylcarbamoyl)benzoic acid, (R)-2-hydroxy-2-phenylacetic acid, (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid, (R)-6-hydroxy-2,5,7,8-Tetramethylchroman-2-carboxylic acid, (S)-(-)-indoline-2-carboxylic acid, (S)-(+)-2-oxo-4-phenyl-3-oxazolidineacetic acid, (S)-(+)-5-oxo-2-tetrahydro-furancarboxylic acid, (S)-(+)-hexahydromandelic acid, (S)-(+)-N-[1-(1-naphthyl)-ethyl]-phthalamic acid, (S)-(+)-O-acetylmandelic acid, (S)-2-(1-phenylethylcarbamoyl)benzoic acid, (S)-2-(4-isobutylphenyl)propanoic acid, (S)-2-(phenyl (S)-3-(benzyloxycarbonyl)-2-oxoimidazolidine-4-carboxylic acid, (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid, (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid, (S)-6-methoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, (trimethylsilyl)acetic acid, (Z)-2-cyano-3-(3-hydroxyphenyl)acrylic acid, 1-(4-chlorophenyl)-1-cyclopentanecarboxylic acid, 1-(te rt-butyl) hydrocinnamic acid, 1,2-phenylenedioxydiacetic acid, 1,4-dihydro-2-methylbenzoic acid, 1,4-dihydroxy-2-naphthoic acid, 10-hydroxydecanoic acid, 10-undecynoic acid, 1-admantanecarboxylic acid, 1-cyano-1-cyclopropanecarboxylic acid, 1-hydroxy-2-naphthoic acid, 1-isoquinolinecarboxylic acid, 1-methyl-(1S,2R)-(+)-cis-1,2,3,6-tetrahydrophthalate, 1-methyl-1-cyclohexanecarboxylic acid, 1-methyl-1H-indole-2-carboxylic acid, 1-Methyl-2-pyrrolecarboxylic acid, 1-methylcyclopropanecarboxylic acid, 1-naphthoic acid, 1-phenyl-1-cyclopentanecarboxylic acid, 1-phenyl-1-cyclopropanecarboxylic acid, 1-pyreneacetic acid, 1-pyrenebutyric acid, 1-pyrenecarboxylic acid, 2-((1R,2R,3R,4S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)acetic acid, 2-((benzyloxycarbonyl)(methyl)amino)-2-methylpropanoic acid, 2-(2-(trifluoromethyl)phenyl)acetic acid, 2-(2,4,5-trichlorophenoxy)-propionic acid, 2-(2,4-dichlorophenoxy)-propionic acid, 2-(3,5-dinitrobenzamido)-2-phenylacetic acid, 2-(3,5-dinitrobenzamido)-4-methylpentanoic acid, 2-(3-chlorophenoxy)propionic acid, 2-(4-(trifluoromethyl)phenyl)acetic acid, 2-(4-chloro-3-nitrobenzoyl)-benzoic acid, 2-(4-chlorophenoxy)-2-methyl-propionic acid, 2-(4-chlorophenoxy)propionic acid, 2-(4-fluorobenzoyl)benzoic acid, 2-(4- Hydroxy-3-methoxyphenyl)acetic acid, 2-(4-hydroxyphenoxy)-propionic acid, 2-(4-isobutylphenyl)propanoic acid, 2-(4-nitrophenyl)propionic acid, 2-(benzyloxycarbonylamino)-3-(1H-indol-3-yl)propanoic acid, 2-(trifluoromethyl)acrylic acid, 2-(trifluoromethyl)benzoic acid, 2-(trifluoromethyl)cinnamic acid, 2,2,3,3-tetramethyl-cyclopropanecarboxylic acid, 2,2-bis(hydroxymethyl)-propionic acid, 2,3,4,5,6-pentafluoropropane Fluoro-cinnamic acid, 2,3,4,5,6-pentafluorophenoxyacetic acid, 2,3,4,5,6-pentafluorophenyl-acetic acid, 2,3,4,5-tetrafluorobenzoic acid, 2,3,4-trifluorocinnamic acid, 2,3,4-trihydroxybenzoic acid, 2,3,4-trimethoxybenzoic acid, 2,3,5,6-tetrafluoro-4-hydroxy-benzoic acid hydrate, 2,3,5,6-tetrafluorobenzoic acid, 2,3,5,6-tetrafluoro-p-toluic acid, 2,3,5-triiodobenzoic acid, 2,3,6-trifluorobenzoic acid, 2,3-dichlorobenzoic acid Benzoic acid, 2,3-difluorobenzoic acid, 2,3-dihydroxybenzoic acid, 2,3-dimethylbenzoic acid, 2,4,5-trichlorophenoxyacetic acid, 2,4,5-trimethoxybenzoic acid, 2,4,6-trichlorobenzoic acid, 2,4,6-trifluorobenzoic acid, 2,4,6-trihydroxybenzoic acid monohydrate, 2,4,6-trimethylbenzoic acid, 2,4-bis(trifluoromethyl)-benzoic acid, 2,4-dichloro-5-fluorobenzoic acid, 2,4-dichloro-5-sulfamoyl-benzoic acid, 2,4-dichlorobenzoic acid, 2,4-dichlorophenylacetic acid, 2,4-Difluorobenzoic acid, 2,4-difluorophenylacetic acid, 2,4-dihydroxybenzoic acid, 2,4-dimethylbenzoic acid, 2,4-dinitrobenzoic acid, 2,4-dinitrophenylacetic acid, 2,4-hexadienoic acid, 2,5-bis(trifluoromethyl)-benzoic acid, 2,5-dichlorobenzoic acid, 2,5-difluorobenzoic acid, 2,5-difluorophenylacetic acid, 2,5-dihydroxybenzoic acid, 2,5-dihydroxyphenylacetic acid, 2,5-Dimethoxybenzoic acid, 2,5-dimethoxycinnamic acid, 2,6-dichloro-3-nitrobenzoic acid, 2,6-difluorobenzoic acid, 2,6-difluorophenylacetic acid, 2,6-dihydroxybenzoic acid, 2,6-dimethoxynicotinic acid, 2,6-dimethylbenzoic acid, 2,6-heptadienoic acid, 2-[4-(dibutylamino)-2-hydroxybenzoyl]benzoic acid, 2-bibenzylcarboxylic acid, 2-biphenylcarboxylic acid, 2-butanol Bromo-3-nitrobenzoic acid, 2-bromo-4,5-dimethoxybenzoic acid, 2-bromo-5-methoxybenzoic acid, 2-bromo-5-nitrobenzoic acid, 2-bromoacrylic acid, 2-bromophenylacetic acid, 2-chloro-3-nitrobenzoic acid, 2-chloro-4,5-difluorobenzoic acid, 2-chloro-4-fluorobenzoic acid, 2-chloro-5-(methylthio)-benzoic acid, 2-chloro-5-(trifluoro-methyl)benzoic acid, 2-chloro- 5-Nitrobenzoic acid, 2-chloro-5-nitrocinnamic acid, 2-chloro-6-fluorobenzoic acid, 2-chloro-6-fluorophenylacetic acid, 2-chloro-6-methylnicotinic acid, 2-chlorobenzoic acid, 2-chloronicotinic acid, 2-chlorophenylacetic acid, 2-chloropropionic acid, 2-ethoxy-1-naphthoic acid, 2-ethoxybenzoic acid, 2-ethyl-2-hydroxybutyric acid, 2-ethylbutyric acid, 2-ethylhexanoic acid, 2-ethylthio-2,2-Diphenyl-acetic acid, 2-fluoro-3-(trifluoromethyl)-benzoic acid, 2-fluoro-4-(trifluoromethyl)-benzoic acid, 2-fluoro-5-methylbenzoic acid, 2-fluoro-5-nitrobenzoic acid, 2-fluoro-6-(trifluoromethyl)-benzoic acid, 2-fluorobenzoic acid, 2-fluorocinnamic acid, 2-fluorophenylacetic acid, 2-hydroxy-3-isopropyl-6-methylbenzoic acid, 2-hydroxy-3-isopropylbenzoic acid, 2-hydroxy-3-methylbutyric acid, 2 -Hydroxy-6-isopropyl-3-methylbenzoic acid, 2-hydroxycaproic acid, 2-hydroxyhippuric acid, 2-hydroxyisobutyric acid, 2-hydroxynicotinic acid, 2-hydroxyphenylacetic acid, 2-iodobenzoic acid, 2-mercaptonicotinic acid, 2-methoxy-2-phenylacetic acid, 2-methoxy-4-(methylthio)-benzoic acid, 2-methoxy-4-nitrobenzoic acid, 2-methoxyphenylacetic acid, 2-methyl-1-cyclohexane-carboxylic acid (cis and trans), 2-methyl-3-nitrobenzoic acid Torobenzoic acid, 2-methyl-3-phenylpropanoic acid, 2-methyl-4-oxo-4-phenylbutyric acid, 2-methyl-6-nitrobenzoic acid, 2-methylbutyric acid, 2-methylcinnamic acid, 2-methylcyclopropane-carboxylic acid (cis and trans), 2-methylhexanoic acid, 2-methylhippuric acid, 2-methylhydrocinnamic acid, 2-methylvaleric acid, 2-naphthoic acid, 2-naphthylacetic acid, 2-nitro-4-(trifluoromethyl)benzoic acid, 2-nitrobenzoic acid, 2-norbornaneacetic acid, 2-oxo-6 -pentyl-2H-pyran-3-carboxylic acid, 2-phenoxybenzoic acid, 2-phenoxybutyric acid, 2-phenoxypropionic acid, 2-propylpentanoic acid, 2-quinoxalinecarboxylic acid, 2-thiopheneacetic acid, 2-thiopheneglyoxylic acid, 3-(2-hydroxyphenyl)propionic acid, 3-(2-thienyl)acrylic acid, 3-(3,4,5-trimethoxyphenyl)-propionic acid, 3-(3,4-dimethoxyphenyl)-propionic acid, 3-(3-hydroxy-2,4,6-Triiodophenyl)pentanoic acid, 3-(3-hydroxyphenyl)-propionic acid, 3-(3-methoxyphenyl)propionic acid, 3-(4-chlorobenzoyl)propionic acid, 3-(4-fluorobenzoyl)propionic acid, 3-(4-hydroxyphenyl)propionic acid, 3-(phenylsulfonyl)propionic acid, 3-(trifluoromethyl)cinnamic acid, 3-(trimethylsilyl)propynoic acid, 3,3,3-triphenylpropionic acid, 3,4-(methylenedioxy)cinnamic acid, 3,4-(methylenedioxy)phenyl-acetic acid, 3,4-dichlorobenzoic acid, 3,4-dichlorophenoxyacetic acid, 3,4-diethoxybenzoic acid, 3,4-difluorobenzoic acid, 3,4-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid Dorocinnamic acid, 3,4-dihydroxyphenylacetic acid, 3,5,6-trichlorosalicylic acid, 3,5-bis(trifluoromethyl)-phenylacetic acid, 3,5-dibromobenzoic acid, 3,5-dichlorosalicylic acid, 3,5-difluorocinnamic acid, 3,5-dihydroxy-2-naphthoic acid, 3,5-dinitrobenzoic acid, 3,5-dinitro-o-toluic acid, 3,5-dinitro-p-toluic acid, 3,5-dinitrosalicylic acid, 3,5-di-tert-butyl-4-hydroxy-benzoic acid, 3,5-di-tert-butylbenzoic acid, 3,7-dihydroxy-2-naphthoic acid, 3-thiopheneacetic acid, 3-benzoyl-2-pyridine-carboxylic acid, 3-benzoylbenzoic acid, 3-bromo-4-fluorobenzoic acid (95%), 3-bromo-4, -methylbenzoic acid, 3-bromo-5-iodobenzoic acid, 3-bromobenzoic acid, 3-bromocinnamic acid, 3-carboxy-proxyl, 3-chloro-2-nitrobenzoic acid, 3-chloro-4-fluorobenzoic acid, 3-chloro-4-hydroxyphenyl-acetic acid, 3-chlorosalicylic acid, 3-cyanobenzoic acid, 3-fluoro-2-methylbenzoic acid, 3-fluoro-4-hydroxy-phenylacetic acid, 3-fluoro-4-methoxybenzoic acid, 3-fluoro phenylacetic acid, 3-furoic acid, 3-hydroxy-2-naphthoic acid, 3-hydroxy-2-quinoxaline-carboxylic acid, 3-hydroxy-4-methoxybenzoic acid, 3-hydroxy-4-methoxy-cinnamic acid, 3-hydroxy-4-nitrobenzoic acid, 3-hydroxybenzoic acid, 3-hydroxybutyric acid, 3-hydroxyphenylacetic acid, 3-indolebutyric acid, 3-indoleglyoxylic acid, 3-indolepropionic acid, 3-iodo-4-methyl Benzoic acid, 3-iodobenzoic acid, 3-isoquinolinecarboxylic acid hydrate, 3-methoxy-4-nitrobenzoic acid, 3-methoxycyclohexane-carboxylic acid (cis and trans), 3-methyl-2-phenylvaleric acid, 3-methylhippuric acid, 3-methylindene-2-carboxylic acid, 3-methylsalicylic acid, 3-methylvaleric acid, 3-nitrobenzoic acid, 3-nitrophenylacetic acid, 3-nitropropionic acid, 3-noradamantanecarboxylic acid, 3- Oxo-1-indancarboxylic acid, 3-phenoxybenzoic acid, 3-phenylbutyric acid, 3-p-tolylpropanoic acid, 3-thiophenecarboxylic acid, 4-(1,3-dioxoisoindolin-2-yl)-2-hydroxybutanoic acid, 4-(2,4,5-trichlorophenoxy)-butyric acid, 4-(2,4-dichlorophenoxy)-butyric acid, 4-(2,4-di-tert-pentylphenoxy)butyric acid, 4-(2-phenoxyethoxy)benzoic acid, 4-(3,4-Dimethoxyphenyl)-butyric acid, 4-(4-methoxyphenyl)butyric acid, 4-(4-nitrophenyl)butyric acid, α-(diethylamino)benzoic acid, 4-(dimethylamino)cinnamic acid, 4-(dimethylamino)phenyl-acetic acid, 4-(ethylthio)benzoic acid, 4-(hydroxymethyl)benzoic acid, 4-(methylsulfonyl)benzoic acid, 4-(methylthio)benzoic acid, 4-(methylthio)phenylacetic acid, 4-(trifluoromethoxy)benzoic acid, 4'-(trifluoromethyl)biphenyl-2 -carboxylic acid, α-(trifluoromethyl)mandelic acid, 4,4,4-trifluoro-3-methyl-2-butenoic acid, 4,4-bis(4-hydroxyphenyl)-valeric acid, 4,5-dimethoxy-2-nitrobenzoic acid, 4,6-dioxoheptanoic acid, 4-[4-(2-carboxybenzoyl)-phenyl]butyric acid, 4-acetamidobenzoic acid, α-acetylbenzoic acid, 4-acetylphenoxyacetic acid, 4-benzyloxy-3-methoxyphenyl-acetic acid, 4-biphenylacetic acid, 4-bromo-3,5 -Dihydroxybenzoic acid, 4-bromobenzoic acid, 4-bromocinnamic acid, 4-bromophenylacetic acid, 4-butoxybenzoic acid, α-butoxyphenylacetic acid, 4-butylbenzoic acid, 4-chloro-2,5-difluorobenzoic acid, 4-chloro-3-sulfamoylbenzoic acid, 4-chlorobenzoic acid, 4-chloro-o-tolyloxyacetic acid, α-chlorophenylacetic acid, 4-chlorosalicylic acid, 4-ethoxycarbonyloxy-3,5-dimethoxybenzoic acid, 4-ethoxyphenylacetic acid, 4-ethylbenzoic acid Acid, 4'-ethylbiphenyl-4-carboxylic acid, 4-fluorenecarboxylic acid, 4-fluoro-1-naphthoic acid, α-fluoro-2-(trifluoromethyl)-benzoic acid, 4-fluoro-3-nitrobenzoic acid, 4-fluorobenzoic acid, 4-fluorobenzoic acid, 4-fluorocinnamic acid, 4-fluorophenoxyacetic acid, α-heptyloxybenzoic acid, 4-hexylbenzoic acid, 4-hexyloxybenzoic acid, 4-hydroxy-3-(morpholino-methyl)benzoic acid hydrate, 4-hydroxy-3,5-Dinitrobenzoic acid, 4-hydroxy-3-methoxy-benzoic acid, 4-hydroxy-3-methoxy-mandelic acid, 4-hydroxy-3-nitrobenzoic acid, 4-hydroxy-3-nitrophenylacetic acid, 4-hydroxybenzoic acid, 4'-hydroxybiphenyl-4-carboxylic acid, 4-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid, α-hydroxyphenylpyruvic acid, 4-iodobenzoic acid, 4-isopropoxybenzoic acid, 4-methoxy-3-nitrobenzoic acid, 4-methoxycyclohexane-carboxylic acid, 4-methoxy Cisalicylic acid, α-methyl-1-cyclohexane-carboxylic acid (cis and trans), 4-methyl-3-nitrobenzoic acid, α-methylhippuric acid, 4-methylsalicylic acid, 4-methylvaleric acid, 4-nitro-3-pyrazolecarboxylic acid, 4-nitrohippuric acid, 4-nonyloxybenzoic acid, 4-octylbenoic acid, 4-oxo-4H-1-benzopyran-2-carboxylic acid, 4-oxo-6-phenyl-5-hexenoic acid, α-pentenoic acid, 4-pentylbenzoic acid, 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid, α- Pentyloxybenzoic acid, 4-pentynoic acid, 4-phenylbutyric acid, 4-propoxybenzoic acid, 4-propylbenzoic acid, 4-pyrazolecarboxylic acid, 4-tert-butylbenzoic acid, 4-tert-butylcyclohexanecarboxylic acid, 4-vinylbenzoic acid, 5-(4-chlorophenyl)-2-furoic acid, 5,6-dichloronicotinic acid, 5-bromo-2,4-dihydroxybenzoic acid, 5-fluoro-2-methylbenzoic acid, 5-fluoroindole-2-carboxylic acid, 5-fluorosalicylic acid, 5-hydantoinacetic acid, 5-hydroxy- 2-Indole-carboxylic acid, 5-methoxy-1-indanone-3-acetic acid, 5-methoxy-2-methyl-3-indoleacetic acid, 5-methoxy-2-nitrobenzoic acid, 5-methoxysalicylic acid, 5-methyl-2-nitrobenzoic acid, 5-methyl-2-pyrazine-carboxylic acid, 5-nitro-2-furoic acid, 5-nitro-3-pyrazolecarboxylic acid, 5-phenylvaleric acid, 6-(carbobenzyloxyamino)-caproic acid, 6-acetamidohexanoic acid, 6-bromohexanoic acid, 6-chloronicotinic acid, 6-hydroxy-2,5,7,8-Tetramethylchroman-2-carboxylic acid, 6-methylchromone-2-carboxylic acid, 6-methylnicotinic acid, 6-nitrocaproic acid, 6-oxoheptaoic acid, 6-phenylhexanoic acid, 7-(carboxymethyoxy)-4-methylcoumarin, 7-hydroxycoumarin-4-acetic acid, 7-methoxy-2-benzofuran-carboxylic acid, 7-methoxycoumarin-4-acetic acid, 7-oxooctanoic acid, 9-anthracenecarboxylic acid, 9-fluoreneacetic acid, 9-fluorenone-1-carboxylic acid, α,α,α-trifluoro-m-toluic acid, α-acetamidocinnamic acid, abietic acid, acetic acid, acetyl-L-asparagine, acetylsalicylic acid, α-cyano-4-hydroxycinnamic acid, adipic acid monoethyl ester, α-hydroxyhippuric acid, anthranilic acid, anti-3-oxotricyclo[2.2.1.0, 2,6]Heptane-7-carboxylic acid, α-phenylcyclopentaneacetic acid, α-phenyl-o-toluic acid, atrolactic acid, benzilic acid, benzotriazole-5-carboxylic acid, benzoylformic acid, bis(4-chlorophenyl)acetic acid, carbobenzyloxy-DL-alanine, carbobenzyloxy-L-alanine, carbobenzyloxy-l-glutamine, carbobenzyloxy-L-valine, cis-2-methoxycinnamic acid, crotonic acid, cyclohexanebutyric acid, cyclohexanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanepropionic acid Acid, Cyclopentylacetic acid, D,L-3,4-dihydroxymandelic acid, D-3-phenyllactic acid, Decanoic acid, Dicyclohexylacetic acid, Diethylphosphonoacetic acid, Dikeglac hydrate, Diphenylacetic acid, Fumaric acid monoethyl ester, Fusaric acid, Gallic acid, Gelanic acid, Glycolic acid, Heptadecafluorononanoic acid, Heptanoic acid, Hexanoic acid, Hippuric acid, Hydrocinnamic acid, Indole-3-carboxylic acid, Indole-4-carboxylic acid, Isovaleric acid, L-3-phenyllactic acid, Lauric acid, L-Lactic acid (85%), Maleamic acid, Methoxyacetic acid, Phthalic acid mono- (1R)-(-)-Menthyl, mono-(1S)-(+)-menthyl phthalate, monomethyl cis-5-norbornene-endo-2,3-dicarboxylate, monomethyl phthalate, monomethyl terephthalate, N-(2-furoyl)glycine, N-(3,5-dinitrobenzoyl)-DL-α-phenylglycine, N-(3-indolylacetyl)-L-alanine, N-(3-indolylacetyl)-L-isoleucine, N-(3-indolylacetyl)-L-leucine, N-(3-indolylacetyl)-L-phenylalanine, N-(3-indolylacetyl)-L-phenylalanine, N-(3-indolylacetyl)-L-isoleucine, N-(3-indolylacetyl)-L-leucine, N-(3-indolylacetyl)-L-phenylalanine, N-acetyl)-L-valine, N-(carbobenzyloxy)-1-phenylalanine, N,N-diethyl-3,6-difluorophthalamic acid, N-[(R)-1-(1-naphthyl)ethyl]-phthalamic acid, N-[5-(trifluoromethyl)-2-pyridyl]-L-valine, N-acetyl-4-fluoro-DL-phenylalanine, N-acetyl-DL-tryptophan, N-acetyl-1-leucine, N-acetyl-L-methionine, N-acetyl-L-phenylalanine, N-acetyl-1-tyrosine, N-benzoyl-(2R,3S)-3-Phenyl-isoserine, N-benzoyl-L-threonine, N-carbobenzyloxy-2-methyl-alanine, N-carbobenzyloxy-L-glutamic acid 1-methyl ester, N-carbobenzyloxy-L-isoleucine, N-carbobenzyloxy-L-leucine, N-carbobenzyloxy-1-threonine, N-ethoxycarbonyl-1-phenylalanine, nonanoic acid, Np-tosylglycine, Np-tosyl-L-phenylalanine, o-anisic acid, p-anisic acid, pentafluorobenzoic acid, phenoxyethanol Cinnamic acid, phenylacetic acid, podocarpic acid, pyruvic acid, rhodanine-3-acetic acid, S-(thiobenzoyl)thioglycolic acid, S-benzyl-n-carbobenzyloxy-l-cysteine, sebacic acid monomethyl ester, succinamic acid, succinic acid 2,2-dimethylhydrazide, tetrahydro-2-furoic acid, trans-1-acetyl-4-hydroxy-L-proline, trans-2,3-dimethoxycinnamic acid, trans-2,4-dichlorocinnamic acid, trans-2,4-difluorocinnamic acid, trans-2,5-di Fluorocinnamic acid, trans-2,6-difluorocinnamic acid, trans-2-chloro-6-fluoro-cinnamic acid, trans-2-hexenoic acid, trans-3-(2,3,5,6-tetramethyl-benzoyl)acrylic acid, trans-3-(2,5-dimethylbenzo-yl)-acrylic acid, trans-3-(4-ethoxy-benzoyl)acrylic acid, trans-3-(4-methoxybenzoyl)-acrylic acid, trans-3-(4-methylbenzoyl)-acrylic acid, trans-3,4-difluorocinnamic acid, t trans-3-fluorocinnamic acid, trans-3-furanacrylic acid, trans-3-hexenoic acid, trans-4-chloro-3-nitrocinnamic acid, trans-4-hydroxy-3-methoxy-cinnamic acid, trans-4-methyl-1-cyclohexanecarboxylic acid, trans-4-pentylcyclohexanecarboxylic acid, trans-5-bromo-2-methoxycinnamic acid, trans-styrylacetic acid, tridecafluoroheptanoic acid, trimethylacetic acid, triphenylacetic acid, valeric acid, and yohimbinic acid monohydrate.

[0037] In some embodiments, the compound of formula (III) is

[0038] [Table 2-1]

[0039] [Table 2-2]

[0040] [Table 2-3]

[0041] [Table 2-4]

[0042] [Table 2-5]

[0043] [Table 2-6]

[0044] [Table 2-7]

[0045] [Table 2-8]

[0046] [Table 2-9]

[0047] [Table 2-10]

[0048] Table 2-11

[0049] Table 2-12

[0050] Table 2-13

[0051] Table 2-14

[0052] Table 2-15

[0053] Table 2-16

[0054] Table 2-17

[0055] Table 2-18

[0056] Table 2-19

[0057] Table 2-20

[0058] [Table 2-21]

[0059] or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof.

[0060] Further provided are pharmaceutical compositions comprising one or more compounds of formula (I), or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof, and a pharmaceutically acceptable carrier or excipient. Further provided are pharmaceutical compositions comprising one or more compounds of formula (II), or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof, and a pharmaceutically acceptable carrier or excipient. Further provided are pharmaceutical compositions comprising one or more compounds of formula (III), or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof, and a pharmaceutically acceptable carrier or excipient.

[0061] Further provided is a method for treating or preventing cancer in a patient, the method comprising the step of inhibiting dual protein tyrosine phosphatase 1B (PTP1B) and T-cell PTP (TC-PTP) inhibitor by administering to a patient in need thereof an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer of any of the foregoing, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing cancer in the patient.

[0062] Further provided is a method of treating or preventing cancer in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or (III), or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer of any of the foregoing, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby degrading dual PTP1B and TC-PTP proteins, thereby treating or preventing cancer in the patient.

[0063] In some embodiments, the cancer is colon cancer, lung adenocarcinoma, squamous cell carcinoma, and melanoma.The compound is administered orally.

[0064] Further provided is a method of treating or preventing type II diabetes in a patient, the method comprising the step of inhibiting a dual PTP1B and TC-PTP inhibitor by administering to a patient in need thereof an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer of any of the foregoing, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing type II diabetes in the patient.

[0065] Further provided is a method of treating or preventing type II diabetes in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or (III), or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer of any of the foregoing, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby degrading dual PTP1B and TC-PTP proteins, thereby treating or preventing type II diabetes in the patient.

[0066] Further provided is a method of treating or preventing obesity in a patient, the method comprising the step of inhibiting a dual PTP1B and TC-PTP inhibitor by administering to a patient in need thereof an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer of any of the foregoing, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing obesity in the patient.

[0067] Further provided is a method of treating or preventing obesity in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or (III), or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer of any of the foregoing, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby degrading dual PTP1B and TC-PTP proteins, thereby treating or preventing obesity in the patient.

[0068] Provided is a method for inhibiting or degrading dual PTP1B and TC-PTP in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I), (II) or (III), or a pharmaceutical composition comprising the same, such that dual PTP1B and TC-PTP are inhibited or degraded in the patient. In some embodiments, the patient has colon cancer, lung adenocarcinoma, squamous cell carcinoma, or melanoma. In some embodiments, the patient has type II diabetes. In some embodiments, the patient is obese.

[0069] Provided is the use of a compound of formula (I) in the treatment of a disease or condition treatable by inhibiting or degrading dual PTP1B or TC-PTP protein. Further provided is the use of a compound of formula (II) in the treatment of a disease or condition treatable by inhibiting dual PTP1B or TC-PTP protein. Further provided is the use of a compound of formula (III) in the treatment of a disease or condition treatable by degrading dual PTP1B or TC-PTP protein. In some embodiments, the treatable disease or condition is cancer, type II diabetes, or obesity.

[0070] The present disclosure will be more readily understood from the detailed description of the embodiments presented below, taken in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0071] [Figure 1] Figure 1 shows that the compound of Example 7 is a potent and selective protein tyrosine phosphatase 1B (PTP1B) / T-cell PTP (TC-PTP) dual competitive inhibitor. (A) shows the effect of the compound of Example 7 on pNPP hydrolysis catalyzed by PTP1B. (B) shows the effect of the compound of Example 7 on pNPP hydrolysis catalyzed by TC-PTP. Lineweaver-Burk plots showed a characteristic pattern of intersecting lines consistent with competitive inhibition. The concentrations of the compound of Example 7 were 0 (●), 5 (black squares), and 10 (black triangles), respectively. The compound of Example 7 inhibits PTP1B and TC-PTP with Ki values ​​of 2.4 and 3.6 nM, respectively. (C) shows the selectivity of the compound of Example 7 against the entire panel of 12 mammalian PTPs. [Figure 2-1] Figure 2A shows a Western blot of whole cell lysates from the indicated cell lines treated with the indicated concentrations of compound 47 for 16 hours (4 hours where specified) and stimulated with 10 ng / ml IFN-γ for 15 minutes. [Figure 2-2]Figure 2B shows a Western blot of whole cell lysates from the indicated cell lines treated with the indicated concentrations of compound 47 for 16 hours (4 hours where specified) and stimulated with 10 ng / ml IFN-γ for 15 minutes. [Figure 3-1] Figure 3A is a graph showing quantification of PTP1B and TC-PTP levels after compound 47 induces PTP1B and TC-PTP degradation. GAPDH protein was used as a loading control. Compound 47 induces PTP1B and TC-PTP degradation in all tested cell lines at low nanomolar DC50. [Figure 3-2] Figure 3B is a graph showing quantification of pSTAT1 levels after Compound 47 upregulated STAT1 phosphorylation in multiple cell lines. GAPDH protein was used as a loading control. Compound 47 treatment enhanced pSTAT1 levels in all cell lines. Changes in pSTAT1 levels were positively correlated with TC-PTP / PTP1B degradation in all cell lines. [Figure 4] MC38 cells were treated with DMSO or 500 nM Compound 47 for 16 hours to degrade PTP1B and TC-PTP, and then stimulated with mouse IFN-γ for 48 hours to induce MHC-I expression. Mouse MHC-I complexes were stained with mouse H2K(b) / H2D(b) antibody and measured by flow cytometry. Compound 47-treated MC38 cells exhibited increased expression of MHC-I. [Figure 5]Figure 1 shows that compound 47 effectively depletes PTP1B and TC-PTP proteins in mouse MC38 syngeneic tumors and suppresses xenograft tumor growth. (A) shows the mouse blood concentration of compound 47 over time after a single intraperitoneal (ip) injection of 25 (closed squares) or 50 (●) mg / kg compound 47. (B) shows MC38 tumor growth curves during 10 days of treatment with 25 (closed squares) and 50 mg / kg (closed triangles) compound 47 or saline (●), demonstrating that compound 47 significantly inhibits MC38 tumor growth. (C) shows the change in mouse weight over the 10-day treatment period. (D) shows immunoblots of MC38 tumor extracts from mice treated with 25 mg / kg compound 47, 50 mg / kg compound 47, or saline, demonstrating PTP1B and TC-PTP degradation after compound 47 treatment in vivo. (E and F) show images and quantification of mouse CD8α immunohistochemistry (IHC) staining of MC38 tumor slides from mice treated with 25 mg / kg Compound 47 or saline. Tumors from Compound 47-treated mice exhibit high levels of CD8+ T cell infiltration. Quantification was performed based on six representative images from six sections. [Figure 6]Figure 6A shows that Compound 47 is a dual PTP1B / TC-PTP PROTAC. The figure shows a mechanistic study of Compound 47-induced PTP1B / TC-PTP degradation in HEK293 cells. Cells were pretreated with the indicated concentrations of MLN4924 (prevents ubiquitination), MG132 (blocks proteasome activity), lenalidomide (prevents CRBN binding), or (S,R,S)-AHPC-Me (prevents VHL binding), followed by treatment with 100 nM Compound 47 for 4 hours, demonstrating that Compound 47-mediated PTP1B / TC-PTP degradation is dependent on the ubiquitination-proteasome pathway. No degradation was observed when cells were treated with 100 nM cis-Compound 47 (an inactivating degrader) for 4 hours. Figures 6B-6C show immunofluorescence of PTP1B and TC-PTP using U2OS cells treated with DMSO and 1 μM Compound 47 for 3 and 24 hours. Compound 47 degraded cytoplasmic PTP1B and both nuclear and cytoplasmic TC-PTP. MG132 (20 μM) was used with Compound 47 to block PTP1B and TC-PTP degradation. [Figure 7] 1 is a graph showing a proteomic analysis demonstrating the specificity of Compound 47 for PTP1B degradation when HEK293 cells were treated with DMSO or 100 nM Compound 47 for 4 hours. [Figure 8]This figure shows immunoblots of whole-cell lysates from wild-type, PTP1B-deficient, or TC-PTP-deficient MEF cells treated with 0.5 μM compound 47 for 16 hours and stimulated with 20 ng / ml mouse IFN-γ for 15 minutes. Deficiency of TC-PTP or PTP1B abolished compound 47-induced phosphorylation of the TC-PTP substrate JAK1 or the PTP1B substrate JAK2. Thus, compound 47 efficiently amplifies cellular IFN-γ signaling by degrading PTP1B and TC-PTP. U2OS cells were treated with DMSO or 0.2 μM compound 47 for 16 hours and stimulated with 20 ng / ml IFN-γ for 30 minutes. Immunofluorescence shows that compound 47 dramatically enhanced IFN-γ-mediated STAT1 phosphorylation and nuclear translocation. DAPI was used to stain cell nuclei. [Figure 9-1] Graphs showing that compound 47 induces PTP1B and TC-PTP degradation in CD8+ naive T cells, enhances STAT1 and STAT5 phosphorylation, and promotes CD8+ T cell activation. In (A), purified CD8+ naive T cells from control (Ptpn2fl / fl) and Lck-Cre;Ptpn2fl / fl mice (n=3 / genotype / condition) were incubated with IL-7 for 48 hours in the presence or absence of compound 47 as indicated, and TC-PTP and PTP1B protein levels were monitored by flow cytometry. [Figure 9-2](B) Vehicle-treated control, TCPTP-deficient Lck-Cre;Ptpn2fl / fl, and Compound 47-treated control naive CD8+ T cells were stimulated with plate-bound α-CD3 / α-CD28 for 48 hours to promote T cell activation. Basal STAT-1 (p(Y701)STAT-1) and STAT-5 (p(Y694)STAT-5) phosphorylation was assessed by flow cytometry. (C) Cell size (FSC-A) and T cell activation markers CD25, CD69, and CD44 (MFI; mean fluorescence intensity) were measured by flow cytometry. (Dots (●) represent Ptpn2fl / fl + vehicle; squares (closed squares) represent Lck-Cre;Ptpn2fl / fl + vehicle; and triangles (closed triangles) represent Ptpn2fl / fl + Compound 47.) [Figure 10] Figure 1 shows a pharmacokinetic study of Compound 47 in mice. Plasma concentrations of Compound 47 were measured by LCMS at the indicated time points after ip injection with various formulations. [Figure 11] Figure 1 shows graphs demonstrating that Compound 47 reduces blood glucose levels in high-fat-fed (HFD) mice. (A) shows the reduction in blood glucose levels in male mice (approximately 50 g) fed a high-fat diet when injected with 0, 15, or 50 mg / kg of Compound 47. Blood glucose levels were measured 24 or 48 hours after injection. No fasting was applied. NFD = mice fed a normal fat diet. (B) shows blood glucose levels in an MC38 synergistic tumor study. Mice were treated daily with 25 or 50 mg / kg of Compound 47 via ip injection. Blood glucose levels were measured several times before injection throughout the experiment. [Figure 12]Figure 12A shows a diagram illustrating Western blotting. Wild-type HEK293 cells were treated with compound 47 or ABBV-CLS-484 for 16 hours and stimulated with 20 ng / ml IFN-γ to induce JAK-STAT signaling pathway activation. Western blotting showed that compound 47 induced TC-PTP degradation and pSTAT1 elevation, and ABBV-CLS-484 also increased pSTAT1 levels. Compound 47 activated pSTAT1 more efficiently in HEK293 cells than ABBV-CLS-484. Figure 12B is a graph showing the quantification of pSTAT1 levels based on Western blotting results. DETAILED DESCRIPTION OF THE INVENTION

[0072] To promote an understanding of the principles of the present disclosure, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to describe the embodiments illustrated in the drawings, it being understood, however, that no limitation of the scope of the invention as claimed is intended thereby.

[0073] The term "PTP1B / TC-PTP dual inhibitor" refers to a compound that inhibits both protein tyrosine phosphatase 1B (PTP1B, tyrosine-protein phosphatase non-receptor type 1; protein tyrosine phosphatase non-receptor type 1; protein tyrosine phosphatase, placental; PTPN1; EC 3.1.3.48 and PTP-1B) and T-cell protein tyrosine phosphatase (TC-PTP, also known as PTPN2; protein tyrosine phosphatase non-receptor type 2; TCELLPTP, T-cell protein tyrosine phosphatase) proteins.

[0074] The term "PTP1B / TC-PTP dual degrader" refers to a compound that degrades both the PTP1B and TC-PTP proteins.

[0075] The term "protein degrader" or "proteolysis targeting chimera (PROTAC)" refers to a heterobifunctional compound composed of three components: a ligand that binds to a target protein to be degraded, a linker that can remove specific unwanted proteins, and a protein-binding moiety that binds to an E3 ubiquitin ligase ligand.

[0076] The term von Hippel-Lindau (VHL) E3 ligase ligand "(S,R,S)-AHPC" refers to the following compound:

[0077] [ka] Refers to...

[0078] The term VHL E3 ligase ligand "(S,R,S)-AHPC-Me" refers to the following compound:

[0079] [ka] Refers to...

[0080] PTP1B and TC-PTP play non-redundant negative regulatory roles in T cell activation, tumor antigen presentation, insulin, and leptin signaling, and are potential targets for several therapeutic applications. Compound-mediated degradation of PTP1B and TC-PTP depends on both the target protein and the VHL E3 ligase ligand and is ubiquitination- and proteasome-dependent. The ubiquitin-proteasome pathway (UPP) can be used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and synthetic small molecule probes to induce proteasome-dependent degradation.

[0081] The present disclosure provides compounds that are dual inhibitors and dual degraders of PTP1B and TC-PTP.

[0082] A compound of formula (I) or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof:

[0083] [ka] (In the formula, R1 and R2 are each independently a residue of a carboxylic acid, or a pharmaceutically acceptable salt thereof, and R1 and R2 may be the same or different; R3, R4, R5, R6, R7, and R8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkylene, 4- to 6-membered heterocyclyl, and -C1-C6 alkylene-4- to 6-membered heterocyclyl; The alkylene-4- to 6-membered heterocyclyl group is substituted with deuterium, halogen, hydroxy, C═O, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, -C1-C6-alkylene-C3-C6 cycloalkyl, C1-C6 alkyl-S(O)2-, C3-C6 cycloalkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 alkoxy-C(O)-, -NH-C(O)-R a , and -C(O)-NH-R a and optionally substituted on one or more available carbons with one or more substituents each independently selected from R a is deuterium, halogen, hydroxy, C=O, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, -C1-C6-alkylene-C3-C6 cycloalkyl, C1-C6 alkyl-S(O)2-, C1-C6 cycloalkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 alkoxy-C(O)-, -NH-C(O)-R b , and -C(O)-NH-R band R b are independently selected from deuterium, halogen, hydroxy, C═O, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, —C1-C6-alkylene-C3-C6 cycloalkyl, C1-C6 alkyl-S(O)2—, C3-C6 cycloalkyl-S(O)2—, C1-C6 alkyl-C(O)—, and C1-C6 alkoxy-C(O)—; t is 0 to 6, R9 is H or a group represented by the formula LB, where L is

[0084] [Table 3] is a linker selected from the group consisting of w is 1 to 5, x is 1 to 15, a and b are each independently 0 to 3,

[0085] [ka] The bond indicated by is connected to B and * " represents the point of attachment of R9; B is selected from groups B1, B2, and B3, where B1 has the structure:

[0086] [ka] is represented by R 3a is fluoro, hydrogen, or deuterium, B2 has the structure:

[0087] [ka] is represented by R 3b is fluoro, hydrogen, or deuterium, B3 has the structure:

[0088] [ka] is represented by R4 is methyl, hydrogen, or deuterium. is provided.

[0089] In some embodiments, the compound of Formula (I) has the structure:

[0090] [ka] and which binds to the PTP1B / TC-PTP protein; (ii) a second ligand B which binds to the E3 ligase and is selected from groups B1, B2, and B3 as defined above; and (iii) a linker L which links the first and second ligands, wherein L, R1, R2, R3, R4, R5, R6, R7, R8, and t are as defined above.

[0091] A compound of formula (II) which is a dual inhibitor of PTP1B / TC-PTP, or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof:

[0092] [ka] wherein R1 and R2 are as defined for formula (I) above. is provided.

[0093] In some embodiments, R1 or R2 is

[0094] [ka] is.

[0095] In some embodiments, R1 or R2 is

[0096] [ka] is.

[0097] In some embodiments, R1 or R2 is

[0098] [ka] is.

[0099] In some embodiments, the compound of formula (II) is

[0100] [ka] or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof is.

[0101] In some embodiments, PROTAC compounds are provided that include (i) a first target protein-binding ligand that binds to PTP1B and TC-PTP target proteins, (ii) a linker that tethers both the first and second ligands, and (iii) a second ligand that binds to an E3 ligase that utilizes the cellular ubiquitin-proteasome system to achieve selective targeted protein degradation. These simultaneously bind to the E3 ligase, PTP1B, and TC-PTP, thereby bringing PTP1B and TC-PTP into close proximity with the E3 ligase for efficient ubiquitination and subsequent proteasome-mediated degradation, thereby inducing the formation of a ternary complex.

[0102] A compound of formula (III) which is a PTP1B / TC-PTP dual degrader:

[0103] [ka] or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof wherein R1, R2, L, and B are as defined for formula (I) above. is further provided.

[0104] In some embodiments, R1 or R2 is

[0105] [ka] is selected from.

[0106] In some embodiments, the linker L is

[0107] [ka] is selected from.

[0108] In some embodiments, the carboxylic acid in the compounds of Formulas (I), (II), and (III) is represented by the formula RCOOH, wherein R is selected from the group consisting of hydrogen, an aliphatic group, or an aromatic group, wherein the aliphatic group is saturated or unsaturated, and the aliphatic group or the aromatic group is C1-C 24 Alkyl, C1-C 24 Alkenyl, C1-C 24 alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl, wherein R groups are C1-C 24 Alkyl, hydroxy, alkoxy, cyano, halo, nitro, aryl, amino, C1-C 24 Alkenyl, C1-C 24Optionally substituted with at least one of the group selected from alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl.

[0109] In some embodiments, the carboxylic acid is 3-dimethylaminobenzoic acid, 2-(2-cyanophenylthio)benzoic acid, 2-(4-chlorobenzoyl)benzoic acid, (−)-2-oxo-4-thiazolidine-carboxylic acid, (−)-N-acetylneuraminic acid, (+)-6-methoxy-α-methyl-2-naphthaleneacetic acid, (+)-carbobenzyloxy-D-proline, (+)-menthoxyacetic acid, (±)-2-(2-chlorophenoxy)propionic acid, (±) -1-Methyl-2-cyclohexene-1-carboxylic acid, (1-naphthoxy)acetic acid, (1R)-(1a,2b,3a)-(+)-3-methyl-2-nitromethyl-5-oxocyclopentaneacetic acid, (1R,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylic acid, (1S)-(+)-camphanic acid, (1S,3R,4S,5R)-1,3,4,5-tetrahydroxycyclohexanecarboxylic acid, (2,4-di-tert- (pentylphenoxyl)acetic acid, (2-naphthoxy)acetic acid, (2-pyrimidylthio)acetic acid, (4-carboxybutyl)triphenyl-phosphonium bromide, (4-chlorophenylthio)acetic acid, (4-methylphenoxy)acetic acid, (α,α,α-trifluoro-m-tolyl)acetic acid, (E)-2-((4-hydroxyphenyl)diazenyl)benzoic acid, (E)-2-methyl-3-(2,4,5-trimethoxyphenyl)acrylic acid, (methylthio)acetic acid, (R )-(-)-2-Hydroxy-4-phenylbutyric acid, (R)-(-)-3-chloromandelic acid, (R)-(-)-hexahydromandelic acid, (R)-(+)-2-pyrrolidone-5-carboxylic acid, (R)-(+)-citronellic acid, (R)-2-(1-phenylethylcarbamoyl)benzoic acid, (R)-2-hydroxy-2-phenylacetic acid, (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid, (R)-6-hydroxy-2,5,7,8-Tetramethylchroman-2-carboxylic acid, (S)-(-)-indoline-2-carboxylic acid, (S)-(+)-2-oxo-4-phenyl-3-oxazolidineacetic acid, (S)-(+)-5-oxo-2-tetrahydro-furancarboxylic acid, (S)-(+)-hexahydromandelic acid, (S)-(+)-N-[1-(1-naphthyl)-ethyl]-phthalamic acid, (S)-(+)-O-acetylmandelic acid, (S)-2-(1-phenylethylcarbamoyl)benzoic acid, (S)-2-(4-isobutylphenyl)propanoic acid, (S)-2-(phenyl (S)-3-(benzyloxycarbonyl)-2-oxoimidazolidine-4-carboxylic acid, (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid, (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid, (S)-6-methoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, (trimethylsilyl)acetic acid, (Z)-2-cyano-3-(3-hydroxyphenyl)acrylic acid, 1-(4-chlorophenyl)-1-cyclopentanecarboxylic acid, 1-(te rt-butyl) hydrocinnamic acid, 1,2-phenylenedioxydiacetic acid, 1,4-dihydro-2-methylbenzoic acid, 1,4-dihydroxy-2-naphthoic acid, 10-hydroxydecanoic acid, 10-undecynoic acid, 1-admantanecarboxylic acid, 1-cyano-1-cyclopropanecarboxylic acid, 1-hydroxy-2-naphthoic acid, 1-isoquinolinecarboxylic acid, 1-methyl-(1S,2R)-(+)-cis-1,2,3,6-tetrahydrophthalate, 1-methyl-1-cyclohexanecarboxylic acid, 1-methyl-1H-indole-2-carboxylic acid, 1-Methyl-2-pyrrolecarboxylic acid, 1-methylcyclopropanecarboxylic acid, 1-naphthoic acid, 1-phenyl-1-cyclopentanecarboxylic acid, 1-phenyl-1-cyclopropanecarboxylic acid, 1-pyreneacetic acid, 1-pyrenebutyric acid, 1-pyrenecarboxylic acid, 2-((1R,2R,3R,4S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)acetic acid, 2-((benzyloxycarbonyl)(methyl)amino)-2-methylpropanoic acid, 2-(2-(trifluoromethyl)phenyl)acetic acid, 2-(2,4,5-trichlorophenoxy)-propionic acid, 2-(2,4-dichlorophenoxy)-propionic acid, 2-(3,5-dinitrobenzamido)-2-phenylacetic acid, 2-(3,5-dinitrobenzamido)-4-methylpentanoic acid, 2-(3-chlorophenoxy)propionic acid, 2-(4-(trifluoromethyl)phenyl)acetic acid, 2-(4-chloro-3-nitrobenzoyl)-benzoic acid, 2-(4-chlorophenoxy)-2-methyl-propionic acid, 2-(4-chlorophenoxy)propionic acid, 2-(4-fluorobenzoyl)benzoic acid, 2-(4- Hydroxy-3-methoxyphenyl)acetic acid, 2-(4-hydroxyphenoxy)-propionic acid, 2-(4-isobutylphenyl)propanoic acid, 2-(4-nitrophenyl)propionic acid, 2-(benzyloxycarbonylamino)-3-(1H-indol-3-yl)propanoic acid, 2-(trifluoromethyl)acrylic acid, 2-(trifluoromethyl)benzoic acid, 2-(trifluoromethyl)cinnamic acid, 2,2,3,3-tetramethyl-cyclopropanecarboxylic acid, 2,2-bis(hydroxymethyl)-propionic acid, 2,3,4,5,6-pentafluoropropane Fluoro-cinnamic acid, 2,3,4,5,6-pentafluorophenoxyacetic acid, 2,3,4,5,6-pentafluorophenyl-acetic acid, 2,3,4,5-tetrafluorobenzoic acid, 2,3,4-trifluorocinnamic acid, 2,3,4-trihydroxybenzoic acid, 2,3,4-trimethoxybenzoic acid, 2,3,5,6-tetrafluoro-4-hydroxy-benzoic acid hydrate, 2,3,5,6-tetrafluorobenzoic acid, 2,3,5,6-tetrafluoro-p-toluic acid, 2,3,5-triiodobenzoic acid, 2,3,6-trifluorobenzoic acid, 2,3-dichlorobenzoic acid Benzoic acid, 2,3-difluorobenzoic acid, 2,3-dihydroxybenzoic acid, 2,3-dimethylbenzoic acid, 2,4,5-trichlorophenoxyacetic acid, 2,4,5-trimethoxybenzoic acid, 2,4,6-trichlorobenzoic acid, 2,4,6-trifluorobenzoic acid, 2,4,6-trihydroxybenzoic acid monohydrate, 2,4,6-trimethylbenzoic acid, 2,4-bis(trifluoromethyl)-benzoic acid, 2,4-dichloro-5-fluorobenzoic acid, 2,4-dichloro-5-sulfamoyl-benzoic acid, 2,4-dichlorobenzoic acid, 2,4-dichlorophenylacetic acid, 2,4-Difluorobenzoic acid, 2,4-difluorophenylacetic acid, 2,4-dihydroxybenzoic acid, 2,4-dimethylbenzoic acid, 2,4-dinitrobenzoic acid, 2,4-dinitrophenylacetic acid, 2,4-hexadienoic acid, 2,5-bis(trifluoromethyl)-benzoic acid, 2,5-dichlorobenzoic acid, 2,5-difluorobenzoic acid, 2,5-difluorophenylacetic acid, 2,5-dihydroxybenzoic acid, 2,5-dihydroxyphenylacetic acid, 2,5-Dimethoxybenzoic acid, 2,5-dimethoxycinnamic acid, 2,6-dichloro-3-nitrobenzoic acid, 2,6-difluorobenzoic acid, 2,6-difluorophenylacetic acid, 2,6-dihydroxybenzoic acid, 2,6-dimethoxynicotinic acid, 2,6-dimethylbenzoic acid, 2,6-heptadienoic acid, 2-[4-(dibutylamino)-2-hydroxybenzoyl]benzoic acid, 2-bibenzylcarboxylic acid, 2-biphenylcarboxylic acid, 2-butanol Bromo-3-nitrobenzoic acid, 2-bromo-4,5-dimethoxybenzoic acid, 2-bromo-5-methoxybenzoic acid, 2-bromo-5-nitrobenzoic acid, 2-bromoacrylic acid, 2-bromophenylacetic acid, 2-chloro-3-nitrobenzoic acid, 2-chloro-4,5-difluorobenzoic acid, 2-chloro-4-fluorobenzoic acid, 2-chloro-5-(methylthio)-benzoic acid, 2-chloro-5-(trifluoro-methyl)benzoic acid, 2-chloro- 5-Nitrobenzoic acid, 2-chloro-5-nitrocinnamic acid, 2-chloro-6-fluorobenzoic acid, 2-chloro-6-fluorophenylacetic acid, 2-chloro-6-methylnicotinic acid, 2-chlorobenzoic acid, 2-chloronicotinic acid, 2-chlorophenylacetic acid, 2-chloropropionic acid, 2-ethoxy-1-naphthoic acid, 2-ethoxybenzoic acid, 2-ethyl-2-hydroxybutyric acid, 2-ethylbutyric acid, 2-ethylhexanoic acid, 2-ethylthio-2,2-Diphenyl-acetic acid, 2-fluoro-3-(trifluoromethyl)-benzoic acid, 2-fluoro-4-(trifluoromethyl)-benzoic acid, 2-fluoro-5-methylbenzoic acid, 2-fluoro-5-nitrobenzoic acid, 2-fluoro-6-(trifluoromethyl)-benzoic acid, 2-fluorobenzoic acid, 2-fluorocinnamic acid, 2-fluorophenylacetic acid, 2-hydroxy-3-isopropyl-6-methylbenzoic acid, 2-hydroxy-3-isopropylbenzoic acid, 2-hydroxy-3-methylbutyric acid, 2 -Hydroxy-6-isopropyl-3-methylbenzoic acid, 2-hydroxycaproic acid, 2-hydroxyhippuric acid, 2-hydroxyisobutyric acid, 2-hydroxynicotinic acid, 2-hydroxyphenylacetic acid, 2-iodobenzoic acid, 2-mercaptonicotinic acid, 2-methoxy-2-phenylacetic acid, 2-methoxy-4-(methylthio)-benzoic acid, 2-methoxy-4-nitrobenzoic acid, 2-methoxyphenylacetic acid, 2-methyl-1-cyclohexane-carboxylic acid (cis and trans), 2-methyl-3-nitrobenzoic acid Torobenzoic acid, 2-methyl-3-phenylpropanoic acid, 2-methyl-4-oxo-4-phenylbutyric acid, 2-methyl-6-nitrobenzoic acid, 2-methylbutyric acid, 2-methylcinnamic acid, 2-methylcyclopropane-carboxylic acid (cis and trans), 2-methylhexanoic acid, 2-methylhippuric acid, 2-methylhydrocinnamic acid, 2-methylvaleric acid, 2-naphthoic acid, 2-naphthylacetic acid, 2-nitro-4-(trifluoromethyl)benzoic acid, 2-nitrobenzoic acid, 2-norbornaneacetic acid, 2-oxo-6 -pentyl-2H-pyran-3-carboxylic acid, 2-phenoxybenzoic acid, 2-phenoxybutyric acid, 2-phenoxypropionic acid, 2-propylpentanoic acid, 2-quinoxalinecarboxylic acid, 2-thiopheneacetic acid, 2-thiopheneglyoxylic acid, 3-(2-hydroxyphenyl)propionic acid, 3-(2-thienyl)acrylic acid, 3-(3,4,5-trimethoxyphenyl)-propionic acid, 3-(3,4-dimethoxyphenyl)-propionic acid, 3-(3-hydroxy-2,4,6-Triiodophenyl)pentanoic acid, 3-(3-hydroxyphenyl)-propionic acid, 3-(3-methoxyphenyl)propionic acid, 3-(4-chlorobenzoyl)propionic acid, 3-(4-fluorobenzoyl)propionic acid, 3-(4-hydroxyphenyl)propionic acid, 3-(phenylsulfonyl)propionic acid, 3-(trifluoromethyl)cinnamic acid, 3-(trimethylsilyl)propynoic acid, 3,3,3-triphenylpropionic acid, 3,4-(methylenedioxy)cinnamic acid, 3,4-(methylenedioxy)phenyl-acetic acid, 3,4-dichlorobenzoic acid, 3,4-dichlorophenoxyacetic acid, 3,4-diethoxybenzoic acid, 3,4-difluorobenzoic acid, 3,4-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid Dorocinnamic acid, 3,4-dihydroxyphenylacetic acid, 3,5,6-trichlorosalicylic acid, 3,5-bis(trifluoromethyl)-phenylacetic acid, 3,5-dibromobenzoic acid, 3,5-dichlorosalicylic acid, 3,5-difluorocinnamic acid, 3,5-dihydroxy-2-naphthoic acid, 3,5-dinitrobenzoic acid, 3,5-dinitro-o-toluic acid, 3,5-dinitro-p-toluic acid, 3,5-dinitrosalicylic acid, 3,5-di-tert-butyl-4-hydroxy-benzoic acid, 3,5-di-tert-butylbenzoic acid, 3,7-dihydroxy-2-naphthoic acid, 3-thiopheneacetic acid, 3-benzoyl-2-pyridine-carboxylic acid, 3-benzoylbenzoic acid, 3-bromo-4-fluorobenzoic acid (95%), 3-bromo-4, -methylbenzoic acid, 3-bromo-5-iodobenzoic acid, 3-bromobenzoic acid, 3-bromocinnamic acid, 3-carboxy-proxyl, 3-chloro-2-nitrobenzoic acid, 3-chloro-4-fluorobenzoic acid, 3-chloro-4-hydroxyphenyl-acetic acid, 3-chlorosalicylic acid, 3-cyanobenzoic acid, 3-fluoro-2-methylbenzoic acid, 3-fluoro-4-hydroxy-phenylacetic acid, 3-fluoro-4-methoxybenzoic acid, 3-fluoro phenylacetic acid, 3-furoic acid, 3-hydroxy-2-naphthoic acid, 3-hydroxy-2-quinoxaline-carboxylic acid, 3-hydroxy-4-methoxybenzoic acid, 3-hydroxy-4-methoxy-cinnamic acid, 3-hydroxy-4-nitrobenzoic acid, 3-hydroxybenzoic acid, 3-hydroxybutyric acid, 3-hydroxyphenylacetic acid, 3-indolebutyric acid, 3-indoleglyoxylic acid, 3-indolepropionic acid, 3-iodo-4-methyl Benzoic acid, 3-iodobenzoic acid, 3-isoquinolinecarboxylic acid hydrate, 3-methoxy-4-nitrobenzoic acid, 3-methoxycyclohexane-carboxylic acid (cis and trans), 3-methyl-2-phenylvaleric acid, 3-methylhippuric acid, 3-methylindene-2-carboxylic acid, 3-methylsalicylic acid, 3-methylvaleric acid, 3-nitrobenzoic acid, 3-nitrophenylacetic acid, 3-nitropropionic acid, 3-noradamantanecarboxylic acid, 3- Oxo-1-indancarboxylic acid, 3-phenoxybenzoic acid, 3-phenylbutyric acid, 3-p-tolylpropanoic acid, 3-thiophenecarboxylic acid, 4-(1,3-dioxoisoindolin-2-yl)-2-hydroxybutanoic acid, 4-(2,4,5-trichlorophenoxy)-butyric acid, 4-(2,4-dichlorophenoxy)-butyric acid, 4-(2,4-di-tert-pentylphenoxy)butyric acid, 4-(2-phenoxyethoxy)benzoic acid, 4-(3,4-Dimethoxyphenyl)-butyric acid, 4-(4-methoxyphenyl)butyric acid, 4-(4-nitrophenyl)butyric acid, A-(diethylamino)benzoic acid, 4-(dimethylamino)cinnamic acid, 4-(dimethylamino)phenyl-acetic acid, 4-(ethylthio)benzoic acid, 4-(hydroxymethyl)benzoic acid, 4-(methylsulfonyl)benzoic acid, 4-(methylthio)benzoic acid, 4-(methylthio)phenylacetic acid, 4-(trifluoromethoxy)benzoic acid, 4'-(trifluoromethyl)biphenyl-2 -carboxylic acid, α-(trifluoromethyl)mandelic acid, 4,4,4-trifluoro-3-methyl-2-butenoic acid, 4,4-bis(4-hydroxyphenyl)-valeric acid, 4,5-dimethoxy-2-nitrobenzoic acid, 4,6-dioxoheptanoic acid, 4-[4-(2-carboxybenzoyl)-phenyl]butyric acid, 4-acetamidobenzoic acid, α-acetylbenzoic acid, 4-acetylphenoxyacetic acid, 4-benzyloxy-3-methoxyphenyl-acetic acid, 4-biphenylacetic acid, 4-bromo-3,5 -Dihydroxybenzoic acid, 4-bromobenzoic acid, 4-bromocinnamic acid, 4-bromophenylacetic acid, 4-butoxybenzoic acid, A-butoxyphenylacetic acid, 4-butylbenzoic acid, 4-chloro-2,5-difluorobenzoic acid, 4-chloro-3-sulfamoylbenzoic acid, 4-chlorobenzoic acid, 4-chloro-o-tolyloxyacetic acid, A-chlorophenylacetic acid, 4-chlorosalicylic acid, 4-ethoxycarbonyloxy-3,5-dimethoxybenzoic acid, 4-ethoxyphenylacetic acid, 4-ethylbenzo Acid, 4'-ethylbiphenyl-4-carboxylic acid, 4-fluorenecarboxylic acid, 4-fluoro-1-naphthoic acid, α-fluoro-2-(trifluoromethyl)-benzoic acid, 4-fluoro-3-nitrobenzoic acid, 4-fluorobenzoic acid, 4-fluorobenzoic acid, 4-fluorocinnamic acid, 4-fluorophenoxyacetic acid, α-heptyloxybenzoic acid, 4-hexylbenzoic acid, 4-hexyloxybenzoic acid, 4-hydroxy-3-(morpholino-methyl)benzoic acid hydrate, 4-hydroxy-3,5-Dinitrobenzoic acid, 4-hydroxy-3-methoxy-benzoic acid, 4-hydroxy-3-methoxy-mandelic acid, 4-hydroxy-3-nitrobenzoic acid, 4-hydroxy-3-nitrophenylacetic acid, 4-hydroxybenzoic acid, 4'-hydroxybiphenyl-4-carboxylic acid, 4-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid, α-hydroxyphenylpyruvic acid, 4-iodobenzoic acid, 4-isopropoxybenzoic acid, 4-methoxy-3-nitrobenzoic acid, 4-methoxycyclohexane-carboxylic acid, 4-methoxy Cisalicylic acid, α-methyl-1-cyclohexane-carboxylic acid (cis and trans), 4-methyl-3-nitrobenzoic acid, α-methylhippuric acid, 4-methylsalicylic acid, 4-methylvaleric acid, 4-nitro-3-pyrazolecarboxylic acid, 4-nitrohippuric acid, 4-nonyloxybenzoic acid, 4-octylbenoic acid, 4-oxo-4H-1-benzopyran-2-carboxylic acid, 4-oxo-6-phenyl-5-hexenoic acid, α-pentenoic acid, 4-pentylbenzoic acid, 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid, α- Pentyloxybenzoic acid, 4-pentynoic acid, 4-phenylbutyric acid, 4-propoxybenzoic acid, 4-propylbenzoic acid, 4-pyrazolecarboxylic acid, 4-tert-butylbenzoic acid, 4-tert-butylcyclohexanecarboxylic acid, 4-vinylbenzoic acid, 5-(4-chlorophenyl)-2-furoic acid, 5,6-dichloronicotinic acid, 5-bromo-2,4-dihydroxybenzoic acid, 5-fluoro-2-methylbenzoic acid, 5-fluoroindole-2-carboxylic acid, 5-fluorosalicylic acid, 5-hydantoinacetic acid, 5-hydroxy- 2-Indole-carboxylic acid, 5-methoxy-1-indanone-3-acetic acid, 5-methoxy-2-methyl-3-indoleacetic acid, 5-methoxy-2-nitrobenzoic acid, 5-methoxysalicylic acid, 5-methyl-2-nitrobenzoic acid, 5-methyl-2-pyrazine-carboxylic acid, 5-nitro-2-furoic acid, 5-nitro-3-pyrazolecarboxylic acid, 5-phenylvaleric acid, 6-(carbobenzyloxyamino)-caproic acid, 6-acetamidohexanoic acid, 6-bromohexanoic acid, 6-chloronicotinic acid, 6-hydroxy-2,5,7,8-Tetramethylchroman-2-carboxylic acid, 6-methylchromone-2-carboxylic acid, 6-methylnicotinic acid, 6-nitrocaproic acid, 6-oxoheptaoic acid, 6-phenylhexanoic acid, 7-(carboxymethyoxy)-4-methylcoumarin, 7-hydroxycoumarin-4-acetic acid, 7-methoxy-2-benzofuran-carboxylic acid, 7-methoxycoumarin-4-acetic acid, 7-oxooctanoic acid, 9-anthracenecarboxylic acid, 9-fluoreneacetic acid, 9-fluorenone-1-carboxylic acid, α,α,α-trifluoro-m-toluic acid, α-acetamidocinnamic acid, abietic acid, acetic acid, acetyl-L-asparagine, acetylsalicylic acid, α-cyano-4-hydroxycinnamic acid, adipic acid monoethyl ester, α-hydroxyhippuric acid, anthranilic acid, anti-3-oxotricyclo[2.2.1.0, 2,6]Heptane-7-carboxylic acid, α-phenylcyclopentaneacetic acid, α-phenyl-o-toluic acid, atrolactic acid, benzilic acid, benzotriazole-5-carboxylic acid, benzoylformic acid, bis(4-chlorophenyl)acetic acid, carbobenzyloxy-DL-alanine, carbobenzyloxy-L-alanine, carbobenzyloxy-l-glutamine, carbobenzyloxy-L-valine, cis-2-methoxycinnamic acid, crotonic acid, cyclohexanebutyric acid, cyclohexanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanepropionic acid Acid, Cyclopentylacetic acid, D,L-3,4-dihydroxymandelic acid, D-3-phenyllactic acid, Decanoic acid, Dicyclohexylacetic acid, Diethylphosphonoacetic acid, Dikeglac hydrate, Diphenylacetic acid, Fumaric acid monoethyl ester, Fusaric acid, Gallic acid, Gelanic acid, Glycolic acid, Heptadecafluorononanoic acid, Heptanoic acid, Hexanoic acid, Hippuric acid, Hydrocinnamic acid, Indole-3-carboxylic acid, Indole-4-carboxylic acid, Isovaleric acid, L-3-phenyllactic acid, Lauric acid, L-Lactic acid (85%), Maleamic acid, Methoxyacetic acid, Phthalic acid mono- (1R)-(-)-Menthyl, mono-(1S)-(+)-menthyl phthalate, monomethyl cis-5-norbornene-endo-2,3-dicarboxylate, monomethyl phthalate, monomethyl terephthalate, N-(2-furoyl)glycine, N-(3,5-dinitrobenzoyl)-DL-α-phenylglycine, N-(3-indolylacetyl)-L-alanine, N-(3-indolylacetyl)-L-isoleucine, N-(3-indolylacetyl)-L-leucine, N-(3-indolylacetyl)-L-phenylalanine, N-(3-indolylacetyl)-L-phenylalanine, N-(3-indolylacetyl)-L-isoleucine, N-(3-indolylacetyl)-L-leucine, N-(3-indolylacetyl)-L-phenylalanine, N-acetyl)-L-valine, N-(carbobenzyloxy)-1-phenylalanine, N,N-diethyl-3,6-difluorophthalamic acid, N-[(R)-1-(1-naphthyl)ethyl]-phthalamic acid, N-[5-(trifluoromethyl)-2-pyridyl]-L-valine, n-acetyl-4-fluoro-DL-phenylalanine, N-acetyl-DL-tryptophan, N-acetyl-1-leucine, N-acetyl-L-methionine, N-acetyl-L-phenylalanine, N-acetyl-1-tyrosine, N-benzoyl-(2R,3S)-3-Phenyl-isoserine, N-benzoyl-L-threonine, N-carbobenzyloxy-2-methyl-alanine, N-carbobenzyloxy-L-glutamic acid 1-methyl ester, N-carbobenzyloxy-L-isoleucine, N-carbobenzyloxy-L-leucine, N-carbobenzyloxy-1-threonine, N-ethoxycarbonyl-1-phenylalanine, nonanoic acid, Np-tosylglycine, Np-tosyl-L-phenylalanine, o-anisic acid, p-anisic acid, pentafluorobenzoic acid, phenoxy Acetic acid, phenylacetic acid, podocarpic acid, pyruvic acid, rhodanine-3-acetic acid, S-(thiobenzoyl)thioglycolic acid, S-benzyl-n-carbobenzyloxy-1-cysteine, sebacic acid monomethyl ester, succinamic acid, succinic acid 2,2-dimethylhydrazide, tetrahydro-2-furoic acid, trans-1-acetyl-4-hydroxy-L-proline, trans-2,3-dimethoxycinnamic acid, trans-2,4-dichlorocinnamic acid, trans-2,4-difluorocinnamic acid, trans-2,5-difluoro trans-2,6-difluorocinnamic acid, trans-2-chloro-6-fluoro-cinnamic acid, trans-2-hexenoic acid, trans-3-(2,3,5,6-tetramethyl-benzoyl)acrylic acid, trans-3-(2,5-dimethylbenzoyl)acrylic acid, trans-3-(4-ethoxy-benzoyl)acrylic acid, trans-3-(4-methoxybenzoyl)acrylic acid, trans-3-(4-methylbenzoyl)acrylic acid, trans-3,4-difluorocinnamic acid, trans The hydroxybenzoic acid is selected from the group consisting of trans-3-fluorocinnamic acid, trans-3-furanacrylic acid, trans-3-hexenoic acid, trans-4-chloro-3-nitrocinnamic acid, trans-4-hydroxy-3-methoxy-cinnamic acid, trans-4-methyl-1-cyclohexanecarboxylic acid, trans-4-pentylcyclohexanecarboxylic acid, trans-5-bromo-2-methoxycinnamic acid, trans-styrylacetic acid, tridecafluoroheptanoic acid, trimethylacetic acid, triphenylacetic acid, valeric acid, and yohimbic acid monohydrate.

[0110] In some embodiments, the compound of formula (III) is

[0111] [Table 4-1]

[0112] [Table 4-2]

[0113] [Table 4-3]

[0114] [Table 4-4]

[0115] [Table 4-5]

[0116] [Table 4-6]

[0117] [Table 4-7]

[0118] [Table 4-8]

[0119] [Table 4-9]

[0120] [Table 4-10]

[0121] Table 4-11

[0122] Table 4-12

[0123] Table 4-13

[0124] Table 4-14

[0125] Table 4-15

[0126] Table 4-16

[0127] Table 4-17

[0128] Table 4-18

[0129] Table 4-19

[0130] Table 4-20

[0131] [Table 4-21]

[0132] or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof is.

[0133] The compounds of Formulas (I), (II), and (III), and the intermediates used in their preparation, are enantiomerically enriched, e.g., the enantiomeric excess or "ee" of the compounds is about 5% or greater, as measured by chiral HPLC.

[0134] In some embodiments, the ee is about 10%. In some embodiments, the ee is about 20%. In some embodiments, the ee is about 30%. In some embodiments, the ee is about 40%. In some embodiments, the ee is about 50%. In some embodiments, the ee is about 60%. In some embodiments, the ee is about 70%. In some embodiments, the ee is about 80%. In some embodiments, the ee is about 85%. In some embodiments, the ee is about 90%. In some embodiments, the ee is about 91%. In some embodiments, the ee is about 92%. In some embodiments, the ee is about 93%. In some embodiments, the ee is about 94%. In some embodiments, the ee is about 95%. In some embodiments, the ee is about 96%. In some embodiments, the ee is about 97%. In some embodiments, the ee is about 98%. In some embodiments, the ee is about 99%.

[0135] In some embodiments, B is an E3 ligase-binding portion of the molecule, which may be enantiomerically enriched. In an exemplary embodiment, the E3 ligase-binding portion of the molecule is racemic. The present disclosure encompasses all possible stereoisomeric compounds, e.g., diastereomers, forms of the compounds of Formulas (I), (II), and (III).

[0136] Pharmaceutically acceptable salts of the compounds described above, as well as their preparation and use, are provided. The salts may be prepared during the final isolation and purification of the compounds, or separately by reacting the compounds with a suitable acid.

[0137] In some embodiments, the salt may be an acid addition salt formed with a pharmaceutically acceptable acid. Examples of inorganic acids that can be used to form pharmaceutically acceptable salts include, but are not limited to, nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, oxalic acid, maleic acid, succinic acid, and citric acid.

[0138] Examples of salts of the compounds described herein include hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, 2-hydroxyethanesulfonate, phosphate, hydrogenphosphate, acetate, adipate, alginate, aspartate, benzoate, hydrogensulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, and the like. Salts include, but are not limited to, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate, and p-toluenesulfonate salts.

[0139] The amino groups in the compounds may be quaternized with methyl chloride, ethyl chloride, propyl chloride, butyl chloride; methyl bromide, ethyl bromide, propyl bromide, butyl bromide; methyl iodide, ethyl iodide, propyl iodide, butyl iodide; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, diamyl sulfate; decyl chloride, lauryl chloride, myristyl chloride, steryl chloride; decyl bromide, lauryl bromide, myristyl bromide, steryl bromide; decyl iodide, lauryl iodide, myristyl iodide, steryl iodide; and benzyl bromide or phenethyl bromide.

[0140] Solvates of the compounds described above, as well as their preparation and use, are provided. Solvates typically do not significantly alter the biological activity or toxicity of the compounds and as such may function as pharmacological equivalents.

[0141] The term "solvate" refers to a combination, physical association, and / or solvation of a compound described herein with solvent molecules, such as a disolvate, monosolvate, or hemisolvate, in which the ratio of solvent molecules to the described compound is about 2:1, about 1:1, or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates.

[0142] Solvated forms of compounds can be prepared with pharmaceutically acceptable solvents. Examples of solvents include, but are not limited to, water, methanol, and ethanol, and it is intended that the present disclosure encompass both solvated and unsolvated forms of the compounds described above. One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecule is water. Solvates can generally function as pharmacological equivalents. The preparation of solvates is known in the art. For example, M. Caira et al., J. Pharmaceut. Sci., 2004, 93(3): 601-611, describes the preparation of a solvate of fluconazole with ethyl acetate and water. Similar preparations of solvates, hemisolvates, hydrates, and the like are described by EC van Tonder et al., AAPS Pharm. Sci. Tech., 2004, 5(1): Article 12, and AL Bingham et al., 200, Chem. Commun., 603-604. A typical, non-limiting method for preparing a solvate involves dissolving the compound in a desired solvent (organic, aqueous, or a mixture thereof) at a temperature above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, for example, filtration. Analytical techniques, such as infrared spectroscopy, can be used to confirm the presence of the solvate in the solvate crystals.

[0143] The term "pharmaceutically acceptable salts" refers to salts or zwitterionic forms of the compounds described herein.

[0144] Any reference to a compound of the present disclosure appearing herein is intended to include the compound of the present disclosure, and its pharmaceutically acceptable salts or hydrates.

[0145] The term "alkyl" refers to alkyl groups containing 1 to about 20 carbon atoms (C1 to C 20 ), 1 to 12 carbon atoms (C1 to C 12"Alkyl" refers to substituted or unsubstituted straight-chain and branched alkyl and cycloalkyl groups having 1 to 8 carbon atoms (C1-C8), or, in some embodiments, 1 to 6 carbon atoms (C1-C6). Examples of straight-chain alkyl groups include, but are not limited to, those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. 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, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0146] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent group derived from alkyl, exemplified but not limited by -CHCHCHCH-. Typically, alkyl (or alkylene) groups have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in various embodiments.

[0147] The term "cycloalkyl" refers to substituted or unsubstituted cyclic alkyl groups, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. 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. In some embodiments, cycloalkyl groups can have 3 to 6 carbon atoms (C3-C6). Cycloalkyl groups further include polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, as well as fused rings, such as, but not limited to, decalinyl and the like.

[0148] The term "alkenyl" refers to an alkyl group having 2 to 20 carbon atoms (C 20 ), 2 to 12 carbon atoms (C2 to C 12 (C-C), or, in some embodiments, 2 to 4 carbon atoms (C-C), and at least one carbon-carbon double bond. Examples of straight-chain alkenyl groups include those having 2 to 8 carbon atoms, such as -CH=CH-, -CH=CHCH-, and the like. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH)-, and the like.

[0149] The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. An alkylene group may be described, for example, as a 1- to 6-membered alkylene, where the term "member" refers to a non-hydrogen atom in the moiety.

[0150] The term "alkynyl" refers to an unsaturated, monovalent chain of carbon atoms containing at least one triple bond, which may be optionally branched. In various embodiments containing alkynyl, illustrative examples include smaller alkynyls, e.g., C2-C6, C2-C4 alkynyl, and the like.

[0151] The term "alkoxy" refers to an oxygen atom bonded to an alkyl group, including a cycloalkyl group, 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 may further contain double or triple bonds and may also contain heteroatoms. For example, an aryloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, and similarly, a methylenedioxy group is also an alkoxy group within the meaning herein when two adjacent atoms of the structure are replaced thereby.

[0152] The term "halogen" is used to describe compounds that contain one or more halogen atoms, such as fluorine, chlorine, bromine, and iodine.

[0153] It is understood that each of the alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkylene, and heterocycle may be optionally substituted with independently selected groups, such as alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxylic acid and derivatives thereof including esters, amides, and nitrites, hydroxy, alkoxy, acyloxy, amino, alkyl and dialkylamino, acylamino, thio, and the like, and combinations thereof.

[0154] The term "heterocyclyl" refers to substituted or unsubstituted aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which is a heteroatom, such as, but not limited to, B, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or heteroaryl, or any combination thereof, provided it is polycyclic. In some embodiments, heterocyclyl groups contain from 3 to about 20 ring members, while other such groups have from 3 to about 15 ring members. In some embodiments, a heterocyclyl group can contain from 3 to 8 carbon atoms (C3-C8), from 3 to 6 carbon atoms (C3-C6), or from 6 to 8 carbon atoms (C6-C8).

[0155] The term "substituted" refers to a functional group in which one or more hydrogen atoms are replaced with one or more non-hydrogen atoms. The term "functional group" or "substituent" refers to a group that can be substituted or has been substituted on a molecule. Examples of substituents or functional groups include, but are not limited to, halo (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxylic acids, carboxylates, and carboxylic acid esters; sulfur atoms in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in groups such as amine, azide, hydroxylamine, cyano, nitro groups, N-oxides, hydrazides, and enamines; and other heteroatoms in various other groups.

[0156] Non-limiting examples of substituents that can be attached to a substituted carbon atom (or other atom, e.g., nitrogen) 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, R, SO, N(R), SO, R, (CH). 0~2P(O)OR2, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)C(O)OR, (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, wherein R may be hydrogen or a carbon-based moiety, which may itself be further substituted, e.g., R may be hydrogen, alkyl, alkylphenyl, alkylsulfonyl, alkylsulfonyl, alkylphenyl ... R may be any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, where R may be independently mono- or polysubstituted; or, if two R groups attached to a nitrogen atom or adjacent nitrogen atoms can form a heterocyclyl together with the nitrogen atom or atoms to which they are attached, the heterocycle may be mono- or independently polysubstituted.

[0157] The terms "optionally substituted" and "optional substituents" indicate that the group in question is unsubstituted or substituted with one or more of the specified substituents. When the group in question is substituted with more than one substituent, the substituents may be the same or different. When used in conjunction with the terms "independently," "independently is," and "independently selected from," the groups in question may be the same or different. Certain of the terms defined herein may appear more than once in the structures, and upon such appearance, each term shall be defined independently of the other.

[0158] The term "amine" refers to primary, secondary, and tertiary amines, e.g., having the formula N(group), where each group can independently be H or non-H, e.g., alkyl, aryl, and the like. Amines include, but are not limited to, R-NH, e.g., alkylamines, arylamines, alkylarylamines; RNH where each R is independently selected, e.g., dialkylamines, diarylamines, aralkylamines, heterocyclylamines, and the like; and RN where each R is independently selected, e.g., trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions.

[0159] The term "amino group" refers to a substituent in each protonated form, excluding the forms -NH, -NHR, -NR, -NR, and -NR, where each R is independently selected, and -NR, which cannot be protonated. Thus, any compound substituted with an amino group may be considered an amine. An "amino group" may be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0160] The compounds may contain one or more chiral centers and may otherwise be capable of existing as multiple stereoisomers. In various embodiments, the compounds are not limited to any particular stereochemical requirement, and the compounds, as well as compositions, methods, uses, and medicaments comprising them, may be optically pure or may be any of a variety of stereoisomeric mixtures, including racemates and other mixtures of enantiomers, other mixtures of diastereomers, and the like. Such mixtures of stereoisomers may contain a single stereochemical configuration at one or more chiral centers, but may also contain a mixture of stereochemical configurations at one or more other chiral centers.

[0161] Similarly, the compounds described herein may contain geometric centers, such as cis, trans, E, and Z double bonds. In various embodiments, the compounds are not limited to any particular geometric isomer, and the compounds, as well as compositions, methods, uses, and medicaments comprising them, may be pure or any of various geometric isomeric mixtures. Such mixtures of geometric isomers may contain a single configuration at one or more double bonds, but may contain a mixture of geometries at one or more other double bonds.

[0162] The term "compound," as used herein, is intended to include all stereoisomers, geometric isomers, and tautomers of the structures depicted.

[0163] In some embodiments, the compound may inhibit PTP1B and TC-PTP to the same extent. In other embodiments, the compound inhibits PTP1B to a greater extent than it inhibits TC-PTP. In still other embodiments, the compound inhibits TC-PTP to a greater extent than it inhibits PTP1B. If there is a difference in inhibition between PTP1B and TC-PTP, the difference in inhibition may range from as little as about 1% (e.g., 1%) to as much as about 80% (e.g., 80%). It may be preferred, or even desirable, in various embodiments, for the compound to inhibit PTP1B and TC-PTP to at least approximately the same extent.

[0164] In some embodiments, a pharmaceutical composition is provided that includes one or more compounds of formula (I), (II), or (III), or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. The carrier or excipient may vary based on the specific route of administration (see, for example, Remington's The Science and Practice of Pharmacy, 23rd ed. (2020)).

[0165] In some embodiments, the pharmaceutical composition further comprises at least one additional pharmaceutically active agent. The pharmaceutical composition can be prepared by combining one or more compounds of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer of any of the foregoing, with a pharmaceutically acceptable carrier or excipient, and, optionally, one or more additional pharmaceutically active agents.

[0166] Provided are pharmaceutical compositions comprising (i) one or more compounds of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer of any of the foregoing, and (ii) one or more other prophylactic or therapeutic agents, and a pharmaceutically acceptable carrier or excipient.

[0167] The compound and one or more other prophylactic or therapeutic agents may be administered as two separate compositions simultaneously or sequentially, in either order, by the same or different routes.

[0168] The compounds of formula (I), (II), and (III), or pharmaceutically acceptable salts, hydrates, tautomers, or stereoisomers of any of the foregoing, can inhibit or degrade both PTP1B and TC-PTP. Thus, they can treat or prevent various diseases and conditions associated with PTP1B and TC-PTP. In particular, the compounds are useful in treating or preventing diseases or conditions in which the inhibition or degradation of both PTP1B and TC-PTP is beneficial.

[0169] Methods for treating or preventing cancer in a patient are provided, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer of any of the foregoing, optionally as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing cancer in the patient.

[0170] Further provided is a method for treating or preventing cancer in a patient. The method comprises administering to a patient in need thereof an effective amount of (i) a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer of any of the foregoing, and (ii) one or more other prophylactic or therapeutic agents, optionally as a pharmaceutical composition comprising (i) and (ii) and a pharmaceutically acceptable carrier or excipient. The other prophylactic or therapeutic agent may be selected from drugs known to prevent or treat cancer, for example, monoclonal antibodies useful in treating specific cancers.

[0171] Examples of cancer include, but are not limited to, colon cancer, lung adenocarcinoma, squamous cell carcinoma, and melanoma.

[0172] In some embodiments, compounds of the present disclosure can promote weight loss and improve glucose metabolism.

[0173] Further provided is a method for treating or preventing type II diabetes. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer of any of the foregoing, optionally as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing type II diabetes in the patient. The effective amount of the compound may optionally be administered together with one or more other prophylactic or therapeutic agents. The other prophylactic or therapeutic agents may be selected from drugs known to prevent or treat type II diabetes.

[0174] Further provided is a method for treating or preventing obesity. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer of any of the foregoing, optionally as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing obesity in the patient. The effective amount of the compound may optionally be administered together with one or more other prophylactic or therapeutic agents. The other prophylactic or therapeutic agents may be selected from drugs known to prevent or treat obesity.

[0175] Because the compounds described herein are inhibitors or degraders of PTP1B and TC-PTP proteins, multiple diseases and conditions mediated by PTP1B and / or TC-PTP can be treated (e.g., prophylactically or therapeutically) using these compounds.

[0176] Furthermore, methods for treating or preventing diseases or conditions responsive to PTP1B / TC-PTP inhibition or degradation are further provided. The methods comprise administering to a patient in need thereof an effective amount of the compound described above, or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, optionally as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient. The effective amount of the compound may optionally be administered together with one or more other prophylactic or therapeutic agents. The other prophylactic or therapeutic agents may be selected from drugs known to prevent or treat diseases or conditions.

[0177] Further provided is a method for inhibiting or degrading dual PTP1B and TC-PTP in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound described herein above, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, such that dual PTP1B and TC-PTP are inhibited or degraded in the patient. In some embodiments, the patient has colon cancer, lung adenocarcinoma, squamous cell carcinoma, or melanoma. In some embodiments, the patient has type II diabetes. In some embodiments, the patient is obese.

[0178] The method includes administering an effective amount of the compound described above as a neat compound or a pharmaceutical composition. The compound or pharmaceutical composition may be administered during or after the onset of the disease or condition. Typically, the pharmaceutical composition is sterile and does not contain any toxic, carcinogenic, or mutagenic compounds that may cause adverse reactions when administered.

[0179] Further provided is the use of the compounds described hereinabove in the treatment of a disease or condition treatable by inhibiting or degrading dual PTP1B or TC-PTP proteins. In some embodiments, the disease or condition is cancer, type II diabetes, or obesity.

[0180] Additionally, kits are provided that include the compounds described above, and optionally, separately or together packaged, one or more other prophylactic or therapeutic agents, and an appendix with instructions for using these active agents.

[0181] Other therapeutic agents may be administered simultaneously or sequentially, by the same or different routes, to achieve the desired effect. The compounds described herein and one or more other prophylactic or therapeutic agents may be administered from a single composition or two separate compositions, for example, by the same or different routes. The prophylactic or therapeutic agent may be administered in an amount that produces the desired prophylactic or therapeutic effect. The effective dosage range for each prophylactic or therapeutic agent is well known in the art or can be determined according to dosage range determination methods known to those skilled in the art, and the therapeutic agent may be administered to a patient in need thereof within such established range. The compounds described herein and one or more other prophylactic or therapeutic agents may be administered together as a single unit dose or separately as multiple unit doses, and the compound may be administered before the other prophylactic or therapeutic agent, or vice versa. One or more doses of the compound and / or one or more doses of the second prophylactic or therapeutic agent may be administered.

[0182] The term "effective amount" or "effective dose" refers to the amount of active ingredient that is sufficient to effectively deliver the active ingredient for the treatment of the disease or condition in question to a subject in need thereof when administered. The prophylactically or therapeutically effective amount of such a compound varies depending on the patient and the disease or condition being treated, the patient's weight and age, the severity of the disease or condition, the mode of administration, and the like, and can be easily determined by those skilled in the art. In the case of cancer or other proliferative disorders, a prophylactically or therapeutically effective amount of an agent can reduce (i.e., inhibit or stop to some extent) unwanted cell proliferation; reduce the number of cancer cells; reduce tumor size; inhibit (or stop) cancer cell invasion into peripheral organs; inhibit (or stop) tumor metastasis; for example, inhibit tumor growth to some extent; and / or alleviate to some extent one or more signs or symptoms associated with cancer. To the extent that the administered compound or composition prevents the proliferation and / or kills existing cancer cells, the administered compound or composition can be cytostatic and / or cytotoxic.

[0183] The compounds are typically administered in admixture with a pharmaceutical carrier to provide a pharmaceutical composition selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, including excipients and / or adjuvants that facilitate processing of the compound. Pharmaceutical compositions may be prepared, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. The appropriate formulation depends on the route of administration selected. When a therapeutically effective amount of a compound described herein is administered orally, the composition is typically in the form of a tablet, capsule, powder, liquid, or elixir. When administered in tablet form, the composition may further contain a solid carrier, such as gelatin or an adjuvant. Tablets, capsules, and powders may contain from about 0.01% to about 95%, preferably from about 1% to about 50%, of the compound. When administered in liquid form, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, may be added. Liquid forms of the composition may further contain saline solution, dextrose or other sugar solution, or glycols. When administered in liquid form, the composition contains from about 0.1% to about 90% by weight of the compound, preferably from about 1% to about 50% by weight.

[0184] The compounds may be administered by any suitable route, for example, orally, bucally, by inhalation, sublingually, rectally, vaginally, intracisternally, intrathecally via lumbar puncture, transurethrally, nasally, percutaneously, i.e., transdermal, or parenterally, including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection, and / or by surgical implantation at a specific site of administration. Parenteral administration may be performed using a needle and syringe or using high pressure techniques.

[0185] For oral administration, the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers, excipients, or diluents well known in the art that enable the compounds to be formulated as tablets, pills, powders, dragees, capsules, liquids, gels, syrups, slurries, suspensions, solutions, and the like, for oral ingestion by a subject to be treated.

[0186] The exact formulation, route of administration, and dosage of a pharmaceutical composition containing an effective amount of the compound will be determined by the individual physician in light of the diagnosed condition or disease. Dosage amount and interval may be adjusted individually to provide sufficient levels of the compound to maintain prophylactic or therapeutic effect.

[0187] The toxicity and therapeutic efficacy of a compound can be determined by standard pharmaceutical procedures, for example, in cell cultures or experimental animals to determine the maximum tolerated dose (MTD) of a compound, which is defined as the maximum dose that does not cause toxicity in animals.Therapeutic index is the dose ratio between the maximum tolerated dose and therapeutic effect (for example, tumor growth inhibition).Dosage can vary within this range depending on the dosage form and administration route used.Determining a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0188] The effective amount of compound required for use in therapy varies with the nature of the condition being treated, the length of time that activity is required, and the age and condition of the patient, and is ultimately determined by the attending physician.Dosage and interval can be individually adjusted to achieve a plasma level of PTP1B / TC-PTP dual inhibitor or decomposer sufficient to maintain the desired preventive or therapeutic effect.The desired dose can be administered as a single dose or multiple doses administered at suitable intervals, for example, as divided doses once, twice, three times, four times, or more per day.Multiple doses are often desirable or necessary.For example, the compound can be administered at a frequency of four doses (q4dx4), delivered as one dose per day at four-day intervals. 4 doses delivered as one dose per day, 3 days apart (q3dx4); 1 dose delivered per day, 5 days apart (qdx5); 1 dose per week for 3 weeks (qwk3); 5 days daily, 2 days off, and 5 more days daily (5 / 2 / 5); or any dosing regimen determined to be appropriate for the situation.

[0189] The compound may be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose. For example, the compound may be administered in an amount of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 milligrams per dose, including all doses between 0.005 and 500 milligrams.

[0190] The compositions containing the compounds may be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient.

[0191] Dosages of compositions containing the compounds described herein may range from about 1 mg / kg to about 200 mg / kg, about 1 mg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg. The above dosages are exemplary of average cases, but there may be individual instances in which higher or lower dosages are appropriate, and such are within the scope of the present disclosure. In practice, a physician will determine the actual dosing regimen most suitable for an individual patient, which may vary with the age, weight, and response of the particular patient.

[0192] As previously stated, the compounds described herein may be administered in combination with one or more other prophylactically or therapeutically active agents. In some embodiments, the other therapeutically active agent is an immune checkpoint inhibitor. Immune checkpoint inhibitors are a type of drug that blocks proteins called checkpoints produced by several immune system cells, such as T cells and some cancer cells. These checkpoints help prevent the immune response from becoming too strong and may also prevent T cells from killing cancer cells. When these checkpoints are blocked, T cells are better able to kill cancer cells. Examples of immune checkpoint inhibitors include, but are not limited to, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, CD47 inhibitors, and B7-H1 inhibitors.

[0193] In some embodiments, the immune checkpoint inhibitor is a programmed cell death (PD-1) inhibitor. PD-1 is a T cell co-inhibitory receptor that plays a central role in the ability of tumor cells to evade the host immune system. Blocking the interaction between PD-1 and its ligand, PD-L1, enhances immune function and mediates anti-tumor activity. Examples of PD-1 inhibitors include, but are not limited to, antibodies that specifically bind to PD-1. The anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, STI-A1014, and pidilizumab. The availability, methods of production, mechanism of action, and clinical trials of anti-PD-1 antibodies are described in U.S. Patent Application Publication No. 2013 / 0309250, U.S. Patent No. 7,595,048, U.S. Patent No. 8,728,474, U.S. Patent No. 8,779,105, U.S. Patent No. 8,952,136, U.S. Patent No. 8,900,587, U.S. Patent No. 9,073,994, and U.S. Patent No. 9,084,776, all of which are specifically incorporated by reference herein for their teachings.

[0194] In some embodiments, the immune checkpoint inhibitor is a PD-L1 (also known as B7-H1 or CD274) inhibitor. PD-L1 inhibitors include antibodies that specifically bind to PD-L1. Examples of anti-PD-L1 antibodies include, but are not limited to, avelumab, atezolizumab, durvalumab, and BMS-936559. The availability, methods of production, mechanisms of action, and clinical trials of anti-PD-L1 antibodies are described in U.S. Patent No. 8,217,149, U.S. Patent Application Publication No. 2014 / 0341917, U.S. Patent Application Publication No. 2013 / 0071403, International Patent Application Publication No. 2015036499, and Naido et al., British Journal of Cancer 2014, 777 2214-19, all of which are specifically incorporated herein by reference for their teachings.

[0195] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor. CTLA-4, also known as cytotoxic T-lymphocyte antigen 4, is a protein receptor that downregulates the immune system. CTLA-4 is characterized as a "brake" that binds to costimulatory molecules on antigen-presenting cells, preventing their interaction with CD28 on T cells and generating a distinct inhibitory signal that blocks T cell activation. Examples of CTLA-4 inhibitors include antibodies that specifically bind to CTLA-4. Particular anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. The availability, production methods, mechanism of action, and clinical trials of CTLA-4 antibodies are described in U.S. Patent No. 6,984,720, U.S. Patent No. 6,207,156, and Naido et al., British Journal of Cancer 2014, 777 2214-19, all of which are specifically incorporated herein by reference for their teachings.

[0196] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor. LAG-3, lymphocyte activation gene 3, is a negative costimulatory receptor that regulates T cell homeostasis, proliferation, and activation. Furthermore, LAG-3 has been reported to be involved in the suppressive function of regulatory T cells (Tregs). Most LAG-3 molecules are maintained near microtubule-organizing centers within cells and are only induced after antigen-specific T cell activation (see U.S. Patent Application Publication No. 2014 / 0286935). LAG-3 inhibitors include antibodies that specifically bind to LAG-3. Examples of anti-LAG-3 antibodies include, but are not limited to, GSK2831781. For a general discussion of availability, methods of production, mechanism of action, and research, see U.S. Patent Application Publication No. 2011 / 0150892, U.S. Patent Application Publication No. 2014 / 0093511, U.S. Patent Application Publication No. 2015 / 0259420, and Huang et al., Immunity, 2004, 21, 503-13, all of which are specifically incorporated by reference herein for their teachings regarding the same.

[0197] In some embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor. TIM-3, T-cell immunoglobulin and mucin domain 3, is an immune checkpoint receptor that functions to limit the duration and magnitude of TH1 and TC1 T cell responses. The TIM-3 pathway inhibits dysfunctional CD8+, two reported immune cell populations that constitute immunosuppression in tumor tissues. + Due to its expression in T cells and Tregs, it is considered a target for anti-cancer immunotherapy (Anderson, Cancer Immunology Research 2014, 2, 393-98). Examples of TIM3 inhibitors include antibodies that specifically bind to TIM-3. For a general discussion of the availability, production methods, mechanism of action, and research of TIM-3 inhibitors, see US Patent Application Publication No. 2015 / 0225457, US Patent Application Publication No. 2013 / 0022623, US Patent No. 8,522,156, Ngiow et al., Cancer Res 201, 7, 6567-71, Ngiow, et al., Cancer Res 201, 7, 3540-51, and Anderson, Cancer Immunology Res., 2014, 2, 393-98, all of which are specifically incorporated herein by reference for their teachings.

[0198] In some embodiments, the immune checkpoint inhibitor is a CD47 inhibitor (see Unanue, ER, PNAS 2013,110:10886-87, which is specifically incorporated by reference herein for its teachings therein).

[0199] The term "antibody" refers to whole monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two whole antibodies, and antibody fragments so long as they exhibit the desired biological activity. In some embodiments, "antibody" refers to a soluble receptor that does not have the Fc portion of an antibody. In some embodiments, the antibody is a humanized monoclonal antibody and fragments thereof produced by recombinant genetic engineering.

[0200] Another class of immune checkpoint inhibitors includes polypeptides that bind to and block the PD-1 receptor on T cells without triggering inhibitor signaling. U.S. Patent No. 8,114,845 (specifically incorporated herein by reference for its teachings) describes such peptides, including B7-DC polypeptides, B7-H1 polypeptides, B7-1 polypeptides, and B7-2 polypeptides, and soluble fragments thereof.

[0201] Another class of immune checkpoint inhibitors includes compounds having a peptide moiety that inhibits PD-1 signaling, as disclosed in U.S. Pat. No. 8,907,053, which is specifically incorporated herein by reference for its teachings in this regard.

[0202] Another class of immune checkpoint inhibitors includes inhibitors of specific metabolic enzymes expressed by infiltrating myeloid cells and tumor cells, such as indoleamine 2,3 dioxygenase (IDO). The IDO enzyme inhibits immune responses by depriving T cells of amino acids necessary for anabolic function or through the synthesis of specific natural ligands for cytoplasmic receptors that can alter lymphocyte function (Lob, Cancer Immunol Immunother, 2009, 58.T53-57). Specific IDO blockers include, but are not limited to, levo-1-methyltryptophan (L-1MT) and 1-methyl-tryptophan (1MT) (Lob et al., Cancer Immunol Immunother 2009, 58.T53-7; the teachings of which are specifically incorporated herein by reference).

[0203] In some embodiments, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, STI-A1110, avelumab, atezolizumab, durvalumab, STI-A1014, ipilimumab, tremelimumab, GSK2831781, BMS-936559, or MED14736.

[0204] Other prophylactically or therapeutically active agents described above, one or more of which may be used in combination with compounds of Formula (I), (II), or (III), are prepared and administered as described in the art.

[0205] The term "diseases or conditions in which inhibition or degradation of PTP1B / TC-PTP would be beneficial" and the like relate to diseases or conditions in which PTP1B / TC-PTP is important or necessary, for example, for the onset, progression, or manifestation of the disease or condition, or diseases or conditions known to be treated with PTP1B / TC-PTP inhibitors or degraders.

[0206] The term "additional prophylactic or therapeutic agent" refers to a prophylactic or therapeutic agent known to treat the disease or condition in question that is different from the compounds of the present disclosure.

[0207] The term "disease" or "condition" refers to a disorder and / or abnormality that is typically considered to be a pathological state or function and may manifest itself as specific signs, symptoms, and / or forms of dysfunction.

[0208] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition and / or its associated symptoms. Although not intended, treating a disease or condition does not require the complete elimination of the disease, condition, or its associated symptoms. The term "treat" and cognate terms contemplate administering a prophylactically or therapeutically effective amount of a compound described herein to a subject in need of such treatment. Treatment may be symptomatic, e.g., aimed at suppressing symptoms. This may be short-term, medium-term, or in the context of long-term treatment, e.g., maintenance therapy.

[0209] The terms "prevent," "preventing," and "prevention" refer to a method of preventing the onset of a disease or condition and / or its associated symptoms or barring a subject from contracting the disease. As used herein, "prevent," "preventing," and "prevention" also include delaying the onset of a disease and / or its associated symptoms, as well as reducing a subject's risk of contracting the disease. The terms "prevent," "preventing," and "prevention" may include "prophylactic treatment," which refers to reducing the likelihood of a disease or condition reoccurring, or the recurrence of a disease or condition that was once controlled, in a subject who does not have the disease or condition but who is at risk or susceptible to reoccurring the disease or condition or experiencing a recurrence of the disease or condition.

[0210] It will be understood by those skilled in the art that the present disclosure is not limited by what has been particularly shown and described hereinabove. Rather, the scope of the present disclosure includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that would occur to one skilled in the art upon reading the present specification and that are not in the prior art. [Example]

[0211] Unless otherwise noted, all reagents were purchased from commercial suppliers and used without further purification. The protected, non-hydrolyzable phosphotyrosine mimetic 4-(difluorophosphonomethyl)-N-(9-fluorenylmethyloxycarbonyl)-L-phenylalanine (FmocF2Pmp-OH), which served as the starting point for inhibitor development, was prepared using procedures well known in the art (M. F. Gordeev et al., Tetrahedron Letters, 1994, 35, 7585-7588), the teachings of which are specifically incorporated herein by reference.

[0212] Thin-layer chromatography was performed using glass pre-coated Merck silica gel 60 F254 plates. Column chromatography was performed using KP-SIL silica gel (Biotage, USA). Flash column chromatography was performed on Biotage prepacked columns using the automated Biotage Isolera One flash chromatography system.

[0213] on a Bruker AVANCE 500 MHz spectrometer using dimethyl sulfoxide (DMSO-d6) as the solvent. 1 H- and 13 C NMR spectra were recorded. Chemical shifts are expressed as ppm (δ scale) and are referenced to residual protonated solvent. Peak multiplicities are reported using the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broad singlet).

[0214] Mass spectra and purity data were obtained using an Agilent Technologies 6470 Series Triple Quadrupole LC-MS. The purity of all final compounds tested was determined to be greater than 95% (UV, λ=254 nm). High-resolution mass analysis was performed on an Agilent 6550 iFunnel Q-TOF Mass LC-MS.

[0215] Recombinant mouse IFN-γ was purchased from PeproTech Inc. Anti-ERK1 / 2 (catalog #4696), anti-phospho-ERK1 / 2 (catalog #9101), anti-p38 (catalog #9212), anti-phospho-p38 (catalog #9211s), anti-AKT (catalog #2920s), and anti-phospho-Akt473 (catalog #9271s) antibodies were purchased from Cell Signaling. Anti-HA (catalog #SC-7392) and anti-GAPDH (catalog #SC-59541) antibodies were purchased from Santa Cruz. pNPP was purchased from Thermo Scientific (catalog #PI34045).

[0216] Abbreviations used rt - room temperature; HPLC - high performance liquid chromatography; LC / MS - liquid chromatography-mass spectrometry; DCM - dichloromethane; DMF - dimethylformamide; NMM - N-methylmorpholine; DIPEA - N,N-diisopropylethylamine; EDTA - ethylenediaminetetraacetic acid; DTT - dithiothreitol; BSA - bis(trimethylsilyl)acetamide; HBTU - (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate); HOBt - hydroxybenzotriazole; TFA - trifluoroacetic acid; TIS - triisopropylsilane; DMSO - dimethyl sulfoxide; AcOH - acetic acid; 5(6)-FAM SE - 5-(and -6)-carboxyfluorescein, succinimidyl ester mixed isomers; JAK - Janus kinase; STAT - signal transduction and activator of transcription.

[0217] [Example 1] General methods for solid-phase peptide synthesis. General Procedure A: Rink Amide Resin Activation. Rink amide resin was mixed with DCM (1 mL per 100 mg of resin) and then shaken for 30 minutes. After activation, the resin was washed three times with DMF (1 mL per 100 mg of resin).

[0218] General Procedure B for the removal of the Fmoc group from Rink amide resin. Rink amide resin was mixed with 30% piperidine in DMF, shaken for 30 min, and then washed sequentially with DMF (1 mL per 100 mg of resin, 3 times), isopropanol (1 mL per 100 mg of resin, 3 times), and DCM (1 mL per 100 mg of resin, 3 times). Removal of the Fmoc group was confirmed by the ninhydrin test.

[0219] General Procedure C for the Removal of Alloc Groups from Rink Amide Resin. The resin was washed with DCM (1 mL per 100 mg of resin, 5x) and shaken overnight under N with a solution of tetrakis(triphenylphosphine)-palladium(0) (10 mg), AcOH (0.5 mL), and NMM (0.2 mL) in DCM (10 mL). The resin was then washed with DMF (1 mL per 100 mg of resin, 3 times), isopropanol (1 mL per 100 mg of resin, 3 times), and DCM (1 mL per 100 mg of resin, 3 times). Removal of the Alloc group was confirmed by the ninhydrin test.

[0220] General Procedure D for coupling carboxylic acids to Rink amide resin. First, carboxylic acid (5 equiv., 0.5 M in DMF) was mixed with HBTU (5 equiv., 0.5 M in DMF), HOBt (5 equiv., 0.5 M in DMF), and NMM (15 equiv., 1.5 M in DMF). The mixed solution was then added to the resin and shaken for 2 hours. The resin was then washed with DMF (1 mL per 100 mg of resin, 3 times), isopropanol (1 mL per 100 mg of resin, 3 times), and DCM (1 mL per 100 mg of resin, 3 times). Completion of the coupling reaction was confirmed by the ninhydrin test.

[0221] General procedure for peptide cleavage from Rink amide resin. The resin was washed with DCM (1 mL per 100 mg of resin, 5 times) followed by shaking with 95% TFA, 2.5% TIS, and 2.5% HO (1 mL per 100 mg of resin). The resin was removed by filtration, and the TFA was evaporated under vacuum. The crude peptide was obtained after trituration with diethyl ether (2 times 5 mL per 100 mg of resin).

[0222] [Example 2] Library Construction Libraries were prepared on a Freedom EVO workstation (Tecan) using a 96-channel MCA chip block with disposable tips. The detailed procedure is as follows: Five hundred and seventy-six different carboxylic acids (40 mM, 10 μL) in DMF were placed in six 96-well microplates. HBTU (35 mM, 10 μL), HOBt (50 mM, 10 μL), and NMM (200 mM, 10 μL) were sequentially added to each well of these plates. Library precursor 1, 2, or 3 (2 mM, 10 μL in DMF for library generations 1, 2, and 3, respectively) was then added to each well. After 1 h, the reaction was quenched with cyclohexylamine (87 mM, 10 μL in DMF). Finally, 190 μL of DMSO was added to each well to create a ready-to-screen format. The library was stored in a -20°C freezer.

[0223] For each generation of the library, fluorescein-labeled precursors were synthesized by solid-phase peptide synthesis as indicated.

[0224] Synthesis of intermediate 1 for the first generation library

[0225] [ka] Synthesis of Intermediate 1. (a) 30% piperidine / DMF; (b) Fmoc-Lys(Boc)-OH / HBTU / HOBt / NMM; (c) Fmoc-Ala-OH / HBTU / HOBt / NMM; (d) Fmoc-Lys(Alloc)-OH / HBTU / HOBt / NMM; (e) Fmoc-FPmp-OH / HBTU / HOBt / NMM; (f) AcOH / HBTU / HOBt / NMM; (g) tetrakis(triphenylphosphine)-palladium(0), AcOH / NMM / CHCl; (h) Fmoc-Cl / NMM; (i) TFA / HO / TIS (95:2.5:2.5); (j) 5-(and -6) carboxyfluorescein succinimidyl ester / NMM.

[0226] Synthesis of compound 1a Compound 1a was synthesized on Rink amide resin using standard Fmoc chemistry. First, the resin (200 mg, 0.5 mmol / g loading) was activated using General Procedure A. The Fmoc group was removed with 30% piperidine in DMF using General Procedure B. The resin was then coupled with Fmoc-Lys(Boc)-OH using General Procedure D, followed by removal of the Fmoc group using General Procedure B. The resin was then sequentially coupled with Fmoc-Ala-OH, Fmoc-Lys(Alloc)-OH, Fmoc-FPmp-OH, and AcOH. The Alloc group was then removed using General Procedure C. The resin was shaken with FmocCl (0.2 M in DMF, 2.5 mL) and NMM (1.5 M in DMF, 0.5 mL) for 2 h. Compound 1a was cleaved from the resin using General Procedure E. The crude peptide was purified by HPLC to give compound 1a (31.5 mg, 35% yield). Mass calculated for [M] 884.36, found [M+H] + 885.41.

[0227] Synthesis of compound 1b Compound 1a (31.5 mg) was treated with 5(6)-FAM SE (20 mg) and NMM (0.1 mL) in DMF (5 mL) overnight. After evaporation of the solvent, the crude product was purified by reverse-phase HPLC to give 1b (16.39 mg, 37% yield). Calculated mass for [M]: 1243.41, detected [M+H]. + 1244.39.

[0228] Synthesis of intermediate 1 Compound 1b (16.39 mg) was treated with 30% piperidine in DMF (10 mL) for 30 minutes. After evaporation of the solvent, the crude product was purified by reverse-phase HPLC to give intermediate 1 (6.9 mg, 51% yield). Calculated mass for [M]: 1021.34, found [M+H]: 1022.37.

[0229] [Example 3] Synthesis of intermediate 2 for the second generation library

[0230] [ka] Synthesis of Intermediate 2. (a) 30% piperidine / DMF; (b) Fmoc-Lys(Boc)-OH / HBTU / HOBt / NMM; (c) Fmoc-Ala-OH / HBTU / HOBt / NMM; (d) Fmoc-Lys(Alloc)-OH / HBTU / HOBt / NMM; (e) tetrakis(triphenylphosphine)-palladium(0), AcOH / NMM / CHCl; (f) 3-bromo-4-methylbenzoic acid / HBTU / HOBt / NMM; (g) Fmoc-FPmp-OH / HBTU / HOBt / NMM; (h) TFA / HO / TIS (95:2.5:2.5); (i) 5-(and-6)-carboxyfluorescein succinimidyl ester / NMM.

[0231] Synthesis of compound 2a Compound 2a was synthesized on Rink amide resin using standard Fmoc chemistry. First, the resin (200 mg, 0.5 mmol / g loading) was activated (General Procedure A), followed by removal of the Fmoc group (General Procedure B). The resin was sequentially coupled with Fmoc-Lys(Boc)-OH, Fmoc-Ala-OH, and Fmoc-Lys(Alloc)-OH (General Procedure D). The Alloc group was then removed (General Procedure C), and the exposed amine was coupled with 3-bromo-4-methylbenzoic acid. The Fmoc group was removed, and the exposed amine was coupled with Fmoc-FPmp-OH. Compound 2a was then cleaved from the resin (General Procedure E). The crude product was purified by HPLC to give compound 2a (33.3 mg, 34% yield). Calculated mass for [M] 1039.31, found [M+H]+ 1040.32.

[0232] Synthesis of compound 2b Compound 2a (33.3 mg) was treated with 5(6)-FAM SE (20 mg) and NMM (0.1 mL) in DMF (5 mL) overnight. After evaporation of the solvent, the crude product was purified by reverse-phase HPLC to give compound 2b (13.9 mg, 31% yield). Calculated mass for [M]: 1397.35, detected [M+H]: 1398.31.

[0233] Synthesis of intermediate 2 Compound 2b (13.9 mg) was treated with 30% piperidine in DMF (10 mL) for 30 minutes. After evaporation of the solvent, the crude product was purified by reverse-phase HPLC to give intermediate 2 (6.4 mg, 55% yield). Calculated mass for [M]: 1175.29, found [M+H]: 1176.33.

[0234] [Example 4] Synthesis of intermediate 3 for the third generation library

[0235] [ka] Synthesis of intermediate 3. (a) 30% piperidine / DMF; (b) Fmoc-Lys(Boc)-OH / HBTU / HOBt / NMM; (c) Fmoc-Ala-OH / HBTU / HOBt / NMM; (d) Fmoc-Lys(Alloc)-OH / HBTU / HOBt / NMM; (e) tetrakis(triphenylphosphine)-palladium(0), AcOH / NMM / CHCl; (f) 3-bromo-4-methylbenzoic acid / HBTU / HOBt / NMM; (g) Fmoc-FPmp-OH / HBTU / HOBt / NMM; (h) Fmoc-Phe-OH / HBTU / HOBt / NMM; (i) TFA / HO / TIS (95:2.5:2.5); (j) 5-(and-6)-carboxyfluorescein succinimidyl ester / NMM.

[0236] Synthesis of compound 3a. Compound 3a was synthesized on Rink amide resin using standard Fmoc chemistry. First, the resin (200 mg, 0.5 mmol / g loading) was activated (General Procedure A), followed by removal of the Fmoc group (General Procedure B). The exposed amine was sequentially coupled with Fmoc-Lys(Boc)-OH, Fmoc-Ala-OH, and Fmoc-Lys(Alloc)OH. The Alloc group was removed (General Procedure C), and the exposed amine was coupled with 3-bromo-4-methylbenzoic acid. The Fmoc group was then removed, and the resin was sequentially coupled with Fmoc-FPmp-OH and Fmoc-Phe-OH. Compound 3a was then cleaved from the resin (General Procedure E). The crude product was purified by HPLC to give compound 3a (43.6 mg, 39% yield). Calculated mass for [M]: 1186.37, detected [M+H]: 1187.34.

[0237] Synthesis of compound 3b. Compound 3a (43.6 mg) was treated with 5(6)-FAM SE (20 mg) and NMM (0.1 mL) in DMF (5 mL) overnight. After evaporation of the solvent, the crude product was purified by reverse-phase HPLC to give compound 3b (17.6 mg, 31% yield). Calculated mass for [M]: 1544.42, detected [M+H]: 1545.40.

[0238] Synthesis of intermediate 3. Compound 3b (17.6 mg) was treated with 30% piperidine in DMF (10 mL) for 30 minutes. After evaporation of the solvent, the crude product was purified by reverse-phase HPLC to give intermediate 3 (9.5 mg, 63% yield). Calculated mass for [M]: 1322.35, found [M+H]: 1323.39.

[0239] [Example 5] Synthesis of ((4-((S)-2-acetamido-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid ((4-((S)-2-acetamido-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid was synthesized on Rink amide resin using standard Fmoc chemistry. The resin (200 mg, 0.5 mmol / g loading) was first activated (General Procedure A), followed by treatment with 30% piperidine to remove the Fmoc group (General Procedure B). The exposed amine was coupled with Fmoc-Lys(Alloc)-OH (General Procedure D). The Alloc group was removed (General Procedure C), and the exposed amine was coupled with 3-bromo-4-methylbenzoic acid. After removal of the Fmoc group, the resin was sequentially coupled with Fmoc-FPmp-OH and AcOH. ((4-((S)-2-acetamido-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid was then cleaved from the resin (General Procedure E). The crude product was purified by HPLC to give ((4-((S)-2-acetamido-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid (23.1 mg, 35% yield). Mass calculated for [M] 660.12, found [M+H]+ 661.17. 1H NMR (500 MHz, DMSO) δ 8.49 (t, J = 5.5 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.74 (dd, J = 7.9, 1.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 2H), 7.42- 7.38 (m, 3H), 7.24 (s, 1H), 7.05 (s, 1H), 4.55 - 4.47 (m, 1H), 4.15 (m, 1H), 3.20 (q, J = 6.6 Hz, 2H), 3.00 (dd, J = 13.8, 4.8 Hz, 1H), 2.78 (dd, J = 13.9, 9.7 Hz, 1H), 2.35 (s, 3H), 1.75 (s, 3H), 1.67 (ddt, J = 15.2, 11.0, 5.5 Hz, 1H), 1.57 - 1.43 (m, 3H), 1.34 - 1.24 (m, 2H).

[0240] [ka] Synthesis of ((4-((S)-2-acetamido-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid. (a) 30% piperidine / DMF; (b) Fmoc-Lys(Alloc)-OH / HBTU / HOBt / NMM; (c) tetrakis(triphenylphosphine)-palladium(0), AcOH / NMM / CHCl; (d) 3-bromo-4-methylbenzoic acid / HBTU / HOBt / NMM; (e) Fmoc-FPmp-OH / HBTU / HOBt / NMM; (f) AcOH / HBTU / HOBt / NMM; (g) TFA / HO / TIS (95:2.5:2.5).

[0241] [Example 6] Synthesis of ((4-((S)-2-((S)-2-acetamido-3-phenylpropanamido)-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid ((4-((S)-2-((S)-2-acetamido-3-phenylpropanamido)-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid was synthesized on Rink amide resin using standard Fmoc chemistry. The resin (200 mg, 0.5 mmol / g loading) was activated (General Procedure A) and treated with 30% piperidine to remove the Fmoc group (General Procedure B). The exposed amine was coupled with Fmoc-Lys(Alloc)-OH (General Procedure D). The Alloc group was removed (General Procedure C), and the exposed amine was coupled with 3-bromo-4-methylbenzoic acid. The Fmoc group was removed, and the resin was sequentially coupled with Fmoc-FPmp-OH, Fmoc-PheOH, and AcOH. ((4-((S)-2-((S)-2-acetamido-3-phenylpropanamido)-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid was then cleaved from the resin (General Procedure E). The crude product was purified by HPLC to give ((4-((S)-2-((S)-2-acetamido-3-phenylpropanamido)-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid (22.6 mg, 28% yield). Calculated mass for [M] 807.18, found [M+H]+ 808.17. 11H NMR (500 MHz, DMSO) δ 8.49 (t, J = 5.5 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.73 (dd, J = 7.9, 1.8 Hz, 1H), 7.42 - 7.38 (m, 3H), 7.34 - 7.25 (m, 3H), 7.25 - 7.16 (m, 4H), 7.16 - 7.10 (m, 1H), 7.07 (s, 1H), 4.53 (td, J = 8.4, 4.8 Hz, 1H), 4.44 (ddd, J = 10.2, 8.3, 4.2 Hz, 1H), 4.18 (td, J = 8.3, 5.2 Hz, 1H), 3.21 (q, J = 6.7 Hz, 2H), 3.07 (dd, J = 13.9, 4.8 Hz, 1H), 2.94 (dd, J = 14.0, 4.2 Hz, 1H), 2.90 - 2.81 (m, 1H), 2.73 - 2.62 (m, 1H), 2.35 (s, 3H), 1.70 (s, 3H), 1.70 - 1.63 (m, 1H), 1.59 - 1.45 (m, 3H), 1.35 - 1.25 (m, 2H).

[0242]

Chem.

[0243] [Example 7] Synthesis of ((4-((S)-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid ((4-((S)-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid was synthesized on Rink amide resin using standard Fmoc chemistry. The resin (200 mg, 0.5 mmol / g loading) was activated (General Procedure A), followed by treatment with 30% piperidine to remove the Fmoc group (General Procedure B). The exposed amine was coupled with Fmoc-Lys(Alloc)-OH (General Procedure D). The Alloc group was removed (General Procedure C), and the exposed amine was coupled with 3-bromo-4-methylbenzoic acid. The Fmoc group was removed, and the resin was sequentially coupled with Fmoc-FPmp-OH, Fmoc-Phe-OH, and homovanillic acid. ((4-((S)-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid was then cleaved from the resin (General Procedure E). The crude product was purified by HPLC to give ((4-((S)-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid (13.0 mg, 14% yield). Mass calculated for [M] 929.22, found [M+H]+ 930.24. 11H NMR (500 MHz, DMSO) δ 8.49 (t, J = 5.6 Hz, 1H), 8.21 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.06 - 7.97 (m, 2H), 7.73 (dd, J = 7.9, 1.8 Hz, 1H), 7.39 (dd, J = 8.1, 3.0 Hz, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.25 (s, 1H), 7.17 - 7.08 (m, 6H), 6.67 (d, J = 2.0 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.41 (dd, J = 8.0, 2.0 Hz, 1H), 4.57 - 4.52 (m, 1H), 4.48 - 4.43 (m, 1H), 4.21 - 4.13 (m, 1H), 3.65 (s, 3H), 3.29 - 3.20 (m, 3H), 3.18 (d, J = 14.0 Hz, 2H), 3.03 (dd, J = 13.9, 5.3 Hz, 1H), 2.96 (dd, J = 14.0, 4.0 Hz, 1H), 2.90 - 2.82 (m, 1H), 2.74 - 2.66 (m, 1H), 2.35 (s, 3H), 1.74 - 1.61 (m, 1H), 1.57 - 1.44 (m, 3H), 1.37 - 1.21 (m, 2H).

[0244] [Chemical formula] Synthesis of ((4-((S)-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid. (a) 30% piperidine / DMF; (b) Fmoc-Lys(Alloc)-OH / HBTU / HOBt / NMM; (c) tetrakis(triphenylphosphine)-palladium(0), AcOH / NMM / CHCl; (d) 3-bromo-4-ethylbenzoic acid / HBTU / HOBt / NMM; (e) Fmoc-FPmp-OH / HBTU / HOBt / NMM; (f) Fmoc-Phe-OH / HBTU / HOBt / NMM; (g) homovanillic acid / HBTU / HOBt / NMM; (h) TFA / HO / TIS (95:2.5:2.5).

[0245] [Example 8] Synthesis of intermediate 6 Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl)propanoate (Intermediate 4) To a stirred mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl)propanoic acid (10.00 g, 25.6 mmol, 1.0 eq) and K2CO3 (5.31 g, 38.4 mmol, 1.5 eq) in DMF (100 mL) was added benzyl bromide (6.57 g, 38.4 mmol, 1.5 eq). The mixture was then stirred at room temperature (rt) for 4 h. After completion, the reaction mixture was diluted with EtOAc (500 ml) and washed with brine (3 x 500 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. The product was then purified by flash chromatography (EtOAc / n-hexane, 0% to 10%). Yield: 8.80 g (72%). 1H NMR (500 MHz, DMSO) δ 7.63 - 7.57 (m, 2H), 7.37 - 7.29 (m, 4H), 7.29 - 7.22 (m, 2H), 7.07 - 7.02 (m, 2H), 5.11 - 5.00 (m, 2H), 4.18 LC / MS m / z calculated value [M+H] + 482.08, actual value 482.18.

[0246] Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((diethoxyphosphoryl)difluoromethyl)phenyl)propanoate (Intermediate 5) Intermediate 4 (10.00 g, 20.8 mmol, 1.0 eq) was dissolved in anhydrous DMF (100 mL), followed by dropwise addition of CuBr (5.97 g, 41.6 mmol, 2 eq) and half of the supernatant solution of Cd reagent 7 (approximately 1.7 eq, prepared according to the method described in C. Meyer, M. Kohn, New York, 2011, 6). After 3 h, additional CuBr (2.98 g, 20.8 mmol, 1 eq) and the remaining half of the Cd reagent solution were added. The reaction was allowed to stir at rt for a total of 19 h. The reaction progress was monitored by LC-MS. Upon completion, the reaction mixture was diluted with EtOAc (500 mL), filtered through Celite, and extracted with aqueous NH4Cl (2 x 500 mL) and brine (500 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. The product was then purified by flash chromatography (EtOAc / n-hexane, 0% to 10%). Yield 11.86 g (57%). 1H NMR (500 MHz, DMSO) δ 7.45 (d, J = 7.9 Hz, 2H), 7.41 - 7.26 (m, 8H), 5.09 (s, 2H), 4.26 (ddd, J = 9.8, 8.1, 5.3 Hz, 1H), 4.16 - 3.99 (m, LC / MS m / z calculated value [M+H] + 542.21, actual value 542.28.

[0247] (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((diethoxyphosphoryl)difluoromethyl)phenyl)propanoic acid (Intermediate 6) To a solution of intermediate 5 (8.98 g, 16.6 mmol, 1.0 eq) in 50 mL of EtOAc was added Pd / C (10 wt.% loading, 750.0 mg). The reaction mixture was evacuated and filled with H2 three times. The mixture was then stirred at room temperature for 12 h. Upon completion, the reaction mixture was concentrated in vacuo. The product was then purified by flash chromatography (MeOH / DCM, 0% to 5%). Yield 6.66 g (89%). 1 H NMR (500 MHz, DMSO) δ 7.45 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.5 Hz, 1H), 4.17 - 3.98 (m, 4H), 3.07 (dd, J = 13.8, LC / MS m / z calculated value [M+H] + 452.16, actual value 452.23.

[0248] [ka] Synthesis of intermediate 6.

[0249] [Example 9] Synthesis of intermediate 10 Benzyl N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysinate (Intermediate 8) To a mixture of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysine (10.00 g, 21.34 mmol, 1.0 eq) and K2CO3 (4.42 g, 32.01 mmol, 1.5 eq) in DMF (100 ml) was added benzyl bromide (5.47 g, 32.01 mmol, 1.5 eq). The mixture was then stirred at rt for 4 h. After completion, the reaction mixture was diluted with EtOAc (500 ml) and washed with brine (3 x 500 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. The product was then purified by flash chromatography (EtOAc / n-hexane, 0% to 30%). Yield 9.06 g (76%). 1 H NMR (500 MHz, DMSO) δ 7.90 - 7.82 (m, 2H), 7.78 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 7.5 Hz, 2H), 7.43 - 7.36 (m, 2H), 7.35 - 7.26 (m, 7H), 6.74 (t, J = 5.8 Hz, 1H), 5.10 (d, J = 1.3 Hz, 2H), 4.33 - 4.23 (m, 2H), 4.23 - 4.17 (m, 1H), 4.06 - 3.99 (m, 1H), 2.88 - 2.81 (m, 2H), 1.74 - 1.57 (m, 2H), 1.36 - 1.27 (m, 13H). LC / MS m / z calculated value [M+H] + 559.28, actual value 559.39.

[0250] Benzyl N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(3-bromo-4-methylbenzoyl)-L-lysinate (Intermediate 9) To a solution of intermediate 8 (7.50 g, 13.42 mmol, 1.0 eq) in DCM (80 mL) was added trifluoroacetic acid (20 mL) and stirred at rt for 4 h. The excess reagents and solvent were then evaporated under reduced pressure to give the deprotected amine, which was used in the next step without further purification.

[0251] The deprotected amine, 3-bromo-4-methylbenzoic acid (3.17 g, 14.76 mmol, 1.1 eq), HOAt (2.19 g, 16.10 mmol, 1.2 eq), and DIPEA (12.14 g, 93.94 mmol, 7.0 eq) were then dissolved in DMF (100 ml) and stirred at 0 °C. HATU (7.65 g, 20.13 mmol, 1.5 eq) was slowly added to the stirred solution. After 15 min, the reaction mixture was diluted with EtOAc (800 ml) and washed with brine (3 × 500 ml). The organic layer was dried over anhydrous NaSO and evaporated in vacuo. The product was then purified by flash chromatography (EtOAc / n-hexane, 0% → 40%). The two-step yield was 7.21 g (82%). 1 H NMR (500 MHz, DMSO) δ 8.50 (t, J = 5.6 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 7.6 Hz, 2H), 7.81 (d, J = 7.8 Hz, 1H), 7.74 (dd, J = 7.8, 1.8 Hz, 1H), 7.68 (d, J = 7.5 Hz, 2H), 7.44 - 7.36 (m, 3H), 7.36 - 7.23 (m, 7H), 5.11 (s, 2H), 4.33 - 4.15 (m, 3H), 4.12 - 3.93 (m, 1H), 3.22 (q, J = 6.6 Hz, 2H), 2.34 (s, 3H), 1.80 - 1.61 (m, 2H), 1.55 - 1.44 (m, 6.7 Hz, 2H), 1.41 - 1.27 (m, 2H). LC / MS m / z calculated value [M+H] + 655.18, actual value 655.22.

[0252] Benzyl N6-(3-bromo-4-methylbenzoyl)-N2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-((diethoxyphosphoryl)difluoromethyl)phenyl)propanoyl)-L-lysinate (Intermediate 10) To a solution of intermediate 9 (7.10 g, 10.82 mmol, 1.0 eq) in DCM (80 mL) was added diethylamine (20 mL) and stirred at rt for 4 h. Excess reagents and solvents were then evaporated under reduced pressure to give the crude deprotected amine, which was then purified by flash chromatography (MeOH / DCM, 0% to 10%).

[0253] The deprotected amine, intermediate 6 (5.37 g, 11.90 mmol, 1.1 eq), HOAt (1.77 g, 12.98 mmol, 1.2 eq), and DIPEA (5.59, 43.28 mmol, 4.0 eq) were then dissolved in DMF (100 ml) and stirred at 0 °C. HATU (6.17 g, 16.23 mmol, 1.5 eq) was slowly added to the stirred solution. After 15 min, the reaction mixture was diluted with EtOAc (800 ml) and washed with brine (3 × 500 ml). The organic layer was dried over anhydrous NaSO and evaporated in vacuo. The product was then purified by flash chromatography (cyclohexane-EtOAc, 6:1 → 2:1). The two-step yield was 7.22 g (77%). 1H NMR (500 MHz, DMSO) δ 8.51- 8.46 (m, J = 5.5 Hz, 1H), 8.35 (d, J = 7.4 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.73 (dd, J = 7.8, 1.8 Hz, 1H), 7.47 - 7.34 (m, 6H), 7.34 - 7.25 (m, 4H), 6.92 (d, J = 8.7 Hz, 1H), 5.10 (s, 2H), 4.34 - 4.27 (m, 1H), 4.23 (ddd, J = 10.7, 8.7, 3.8 Hz, 1H), 4.14 - 3.98 (m, 4H), 3.21 (q, J = 6.5 Hz, 2H), 2.95 (dd, J = 13.9, 3.7 Hz, 1H), 2.71 (dd, J = 13.9, 10.9 Hz, 1H), 2.35 (s, 3H), 1.82- 1.72 (m, 1H), 1.72- 1.62 (m, 1H), 1.55- 1.34 (m, 2H), 1.39- 1.30 (m, 2H), 1.24 (s, 9H), 1.20- 1.17 (m, 6H). LC / MS m / z calculated value [M+H] + 866.26, actual value 866.28.

[0254] [ka] Synthesis of intermediate 10

[0255] [Example 10] Synthesis of intermediate 12 Methyl (2-(4-hydroxy-3-methoxyphenyl)acetyl)-L-phenylalaninate (Intermediate 11) Then, methyl L-phenylalaninate (5.00 g, 27.90 mmol, 1.0 eq), 2-(4-hydroxy-3-methoxyphenyl)acetic acid (5.59 g, 30.69 mmol, 1.1 eq), HOAt (4.56 g, 33.48 mmol, 1.2 eq), and DIPEA (14.42 g, 111.60 mmol, 4.0 eq) were dissolved in DMF (100 ml) and stirred at 0 °C. HATU (15.91 g, 41.85 mmol, 1.5 eq) was slowly added to the stirred solution. After 15 min, the reaction mixture was diluted with EtOAc (600 ml) and washed with brine (3 × 500 ml). The organic layer was dried over anhydrous NaSO and evaporated in vacuo. The product was then purified by flash chromatography (cyclohexane-EtOAc, 6:1 → 2:1). Yield: 7.76 g (81%). 1 H NMR (500 MHz, DMSO) δ 8.76 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.26 - 7.12 (m, 5H), 6.73 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 6.50 (dd, J = 8.0, 2.0 Hz, 1H), 4.45 (ddd, J = 9.3, 7.8, 5.3 Hz, 1H), 3.68 (s, 3H), 3.58 (s, 3H), 3.28 (s, 2H), 3.16 (d, J = 4.7 Hz, 1H), 3.03 - 2.97 (m, 1H), 2.92 - 2.85 (m, 1H). LC / MS m / z calculated value [M+H] + 344.15, actual value 344.24.

[0256] (2-(4-hydroxy-3-methoxyphenyl)acetyl)-L-phenylalanine (Intermediate 12) To a solution of intermediate 11 (5.22 g, 15.20 mmol) in THF (50 mL) was added 0.5 M LiOH (aq.). The mixture was stirred at rt for 4 h. Then 50 ml of 1.0 M HCl (aq.) was added to the reaction mixture. The mixture was extracted with EtOAc (3 x 250 ml) and washed with brine (2 x 250 ml). The organic layers were combined, dried over anhydrous NaSO, and evaporated in vacuo to give crude intermediate 8. This crude product was used in the following synthesis without further purification.

[0257] [ka] Synthesis of intermediate 12

[0258] [Example 11] Synthesis of intermediate 14 (PTP1B / TC-PTP dual ligand) Benzyl N6-(3-bromo-4-methylbenzoyl)-N2-((S)-3-(4-((diethoxyphosphoryl)difluoromethyl)phenyl)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)propanoyl)-L-lysinate (Intermediate 13) To a solution of intermediate 10 (5.79 g, 6.68 mmol, 1.0 eq) in DCM (80 mL) was added trifluoroacetic acid (20 mL) and stirred at rt for 6 h. Excess reagents and solvents were then evaporated under reduced pressure to give the crude deprotected amine, which was used in the next step without further purification.

[0259] The deprotected amine, Intermediate 12 (2.42 g, 7.35 mmol, 1.1 eq), HOAt (1.09 g, 8.02 mmol, 1.2 eq), and DIPEA (6.04 g, 46.76 mmol, 7.0 eq) were then dissolved in DMF (50 ml) and stirred at 0 °C. HATU (3.81 g, 10.02 mmol, 1.5 eq) was slowly added to the stirred solution. After 15 min, the reaction mixture was diluted with EtOAc (300 ml) and washed with brine (3 × 300 ml). The organic layer was dried over anhydrous NaSO and evaporated in vacuo. The product was then purified by flash chromatography (EtOAc / n-hexane, 50% → 100%). The two-step yield was 4.89 g (69%). 1H NMR (500 MHz, DMSO) δ 8.70 (s, 1H), 8.54 - 8.44 (m, 2H), 8.15 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.73 (dd, J = 7.8, 1.8 Hz, 1H), 7.44 - 7.37 (m, 3H), 7.37 - 7.32 (m, 5H), 7.32 - 7.25 (m, 1H), 7.18 - 7.07 (m, 5H), 6.66 (d, J = 2.0 Hz, 1H), 6.61 - 6.53 (m, 1H), 6.44 - 6.37 (m, 1H), 5.11 (s, 2H), 4.60 (td, J = 8.7, 4.3 Hz, 1H), 4.43 (ddd, J = 9.8, 8.3, 4.1 Hz, 1H), 4.29 (ddd, J = 8.8, 7.2, 5.3 Hz, 1H), 4.13 - 3.95 (m, 4H), 3.64 (s, 3H), 3.29 - 3.13 (m, 4H), 3.02 (dd, J = 14.0, 4.3 Hz, 1H), 2.89 (dd, J = 14.0, 4.1 Hz, 1H), 2.80 (dd, J = 14.0, 9.3 Hz, 1H), 2.67 (dd, J = 14.0, 9.9 Hz, 1H), 2.35 (s, 3H), 1.82 - 1.72 (m, 1H), 1.71 - 1.61 (m, 1H), 1.50 (p, J = 7.3 Hz, 2H), 1.35 (q, J = 7.3 Hz, 2H), 1.24 - 1.09 (m, 6H). LC / MS m / z calculated value [M+H] + 1077.32, actual value 1077.38.

[0260] N6-(3-Bromo-4-methylbenzoyl)-N2-((S)-3-(4-(difluoro(phosphono)methyl)phenyl)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)propanoyl)-L-lysine (Intermediate 14) To a solution of intermediate 13 (2.50 g, 2.32 mmol, 1.0 eq) in EtOAc (50 mL) was added Pd / C (10 wt.% loading, 250.0 mg). The reaction mixture was evacuated and filled with H three times. The mixture was then stirred at rt for 12 h. Upon completion, the reaction mixture was concentrated in vacuo to give the crude deprotected carboxylic acid, which was used directly in the next step without further purification.

[0261] A solution of the deprotected carboxylic acid in anhydrous DCM (25 ml) was cooled to 0 °C and stirred vigorously. Iodotrimethylsilane (3.25 g, 16.24 mmol, 7.0 eq) was then added dropwise to the solution. The reaction was kept at 0 °C and monitored by LC-MS. Upon completion, the reaction mixture was added dropwise to a 50% MeCN / HO mixture and stirred at rt for 30 min. The water and organic solvent were then evaporated in vacuo to give crude intermediate 10, which was further purified by prep HPLC (MeOH / HO, 50% to 90%). The two-step yield was 1.09 g (47%). 1H NMR (500 MHz, DMSO) δ 8.52 (t, J = 5.5 Hz, 1H), 8.29 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 8.10 - 7.98 (m, 2H), 7.74 (dd, J = 8.0, 1.8 Hz, 1H), 7.44 - 7.37 (m, 3H), 7.35 (d, J = 8.0 Hz, 2H), 7.17 - 7.08 (m, 5H), 6.67 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.43 - 6.38 (dd, J = 8.0, 1.9 Hz, 1H), 4.65 - 4.55 (m, 1H), 4.50 - 4.41 (m, 1H), 4.25 - 4.14 (m, 1H), 3.65 (s, 3H), 3.30 - 3.15 (m, 4H), 3.09 (dd, J = 14.2, 4.4 Hz, 1H), 2.96 (dd, J = 14.1, 4.0 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.70 (dd, J = 13.9, 10.0 Hz, 1H), 2.35 (s, 3H), 1.84 - 1.72 (m, 1H), 1.68 - 1.58 (m, 1H), 1.57 - 1.45 (m, 2H), 1.42 - 1.33 (m, 2H). LC / MS m / z calculated value [MH] - 931.20, measured value 931.35.

[0262]

change

[0263] [Example 12] General synthesis method of リンカー-VHL リガンドのための Linker-VHL ligand tethering was performed according to known methods (Q. Zhao et al., J. Med. Chem. 2019, 62, 9281-9298; X. Han, et al., J. Med. Chem. 2019, 62, 941-964). Specifically, to a DMF solution of Boc-protected linker (0.50 mmol, 1.0 eq, commercially available), (S,R,S)-APLC / (S,R,S)-AHPC-Me (0.55 mmol, 1.1 eq, synthesized by known methods (X. Han, et al., J. Med. Chem. 2019, 62, 941-964; K. Raina et al., Proc Natl Acad Sci USA 2016, 113, 7124-7129)), HOAt (0.60 mmol, 1.2 eq), and DIPEA (2.00 mmol, 4.0 eq) was added HATU (0.75 mmol, 1.5 eq). After 15 min, the reaction was quenched with DI water, and the mixture was purified by reverse-phase flash column chromatography to give the product shown (MeOH / HO, 40% → 100%). Yields ranging from 75% to 90%.

[0264] [ka] General synthetic method for linker-VHL ligand tethering for the synthesis of intermediates 15-22.

[0265] Synthesis of intermediate 15

[0266] [ka] tert-Butyl (2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethyl)carbamate (Intermediate 15). 1H NMR (500 MHz, DMSO) δ 8.96 (s, 1H), 8.54 (t, J = 6.1 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.45 - 7.34 (m, 4H), 6.68 (t, J = 5.8 Hz, 1H), 5.11 (d, J = 3.5 Hz, 1H), 4.54 (d, J = 9.4 Hz, 1H), 4.46 - 4.38 (m, 2H), 4.37 - 4.30 (m, 1H), 4.20 (dd, J = 15.8, 5.4 Hz, 1H), 3.69 - 3.50 (m, 4H), 3.37 - 3.27 (m, 2H), 3.03 (q, J = 6.1 Hz, 2H), 2.57 - 2.45 (m, 1H), 2.43 (s, 3H), 2.36 - 2.28 (m, 1H), 2.06 - 1.99 (m, 1H), 1.89 (ddd, J = 12.9, 8.6, 4.6 Hz, 1H), 1.35 (s, 9H), 0.92 (s, 9H). LC / MS m / z calculated value [M+H] + 646.31, actual value 646.47.

[0267] Synthesis of intermediate 16

[0268] [ka] tert-Butyl (2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethyl)carbamate (Intermediate 16). 1H NMR (500 MHz, DMSO) δ 8.96 (s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 9.3 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.39 - 7.31 (m, 2H), 6.69 (t, J = 5.8 Hz, 1H), 5.09 (d, J = 3.6 Hz, 1H), 4.96 - 4.86 (m, 1H), 4.52 (d, J = 9.4 Hz, 1H), 4.41 (t, J = 8.0 Hz, 1H), 4.28 - 4.24 (m, 1H), 3.62 - 3.51 (m, 4H), 3.39 - 3.27 (m, 3H), 3.04 (p, J = 6.0 Hz, 2H), 2.44 (s, 3H), 2.33 (dt, J = 14.6, 6.0 Hz, 1H), 2.03 - 1.96 (m, 1H), 1.78 (ddd, J = 12.9, 8.5, 4.7 Hz, 1H), 1.39 - 1.33 (m, 12H), 0.92 (s, 9H). LC / MS m / z calculated value [M+H] + 660.31, actual value 660.44.

[0269] Synthesis of intermediate 17

[0270] [ka] tert-Butyl (2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropyl)benzyl)carbamate (Intermediate 17). 1H NMR (500 MHz, DMSO) δ 8.96 (s, 1H), 8.55 (t, J = 6.1 Hz, 1H), 7.93 (d, J = 9.3 Hz, 1H), 7.46 - 7.34 (m, 4H), 7.27 (t, J = 6.1 Hz, 1H), 7.21 - 7.09 (m, 4H), 5.14 (d, J = 3.5 Hz, 1H), 4.54 (d, J = 9.4 Hz, 1H), 4.42 (ddd, J = 10.7, 6.7, 3.2 Hz, 2H), 4.35 (s, 1H), 4.24 - 4.13 (m, 3H), 3.70 - 3.61 (m, 2H), 2.81 (dddd, J = 23.2, 19.9, 9.0, 6.2 Hz, 2H), 2.54 (ddd, J = 14.3, 9.2, 7.2 Hz, 1H), 2.43 (s, 3H), 2.45 - 2.33 (m, 1H), 2.08 - 1.97 (m, 2H), 1.37 (s, 9H), 0.88 (s, 9H). LC / MS m / z calculated value [M+H] + 646.33, actual value 646.39.

[0271] Synthesis of intermediate 18

[0272] [ka] tert-Butyl (3-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)benzyl)carbamate (Intermediate 18). 1H NMR (500 MHz, DMSO) δ 8.97 (s, 1H), 8.56 (t, J = 6.1 Hz, 1H), 8.09 (d, J = 9.3 Hz, 1H), 7.44 - 7.29 (m, 5H), 7.20 (t, J = 7.5 Hz, 1H), 7.14 - 7.08 (m, 2H), 7.05 (d, J = 7.4, 1H), 5.10 (d, J = 3.5 Hz, 1H), 4.50 (d, J = 9.3 Hz, 1H), 4.45 - 4.39 (m, 2H), 4.35 - 4.30 (m, 1H), 4.20 (dd, J = 15.8, 5.4 Hz, 1H), 4.08 (d, J = 6.2 Hz, 2H), 3.68 - 3.56 (m, 3H), 3.41 (d, J = 13.9 Hz, 1H), 2.43 (s, 3H), 2.04 - 1.98 (m, 1H), 1.88 (ddd, J = 12.9, 8.6, 4.6 Hz, 1H), 1.37 (s, 9H), 0.91 (s, 9H). LC / MS m / z calculated value [M+H] + 678.33, actual value 678.42.

[0273] Synthesis of intermediate 19

[0274] [ka] tert-Butyl (4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)benzyl)carbamate (Intermediate 19). 1H NMR (500 MHz, DMSO) δ 8.96 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.45 - 7.34 (m, 5H), 7.29 (d, J = 8.0 Hz, 2H), 5.15 (d, J = 3.6 Hz, 1H), 4.75 (d, J = 9.1 Hz, 1H), 4.48 - 4.33 (m, 3H), 4.22 (dd, J = 15.8, 5.5 Hz, 1H), 4.15 (d, J = 6.2 Hz, 2H), 3.71 (d, LC / MS m / z calculated value [M+H] + 664.32, actual value 664.48.

[0275] Synthesis of intermediate 20

[0276] [ka] tert-Butyl 4-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropyl)piperidine-1-carboxylate (Intermediate 20). 1H NMR (500 MHz, DMSO) δ 8.96 (s, 1H), 8.54 (t, J = 6.1 Hz, 1H), 7.87 (d, J = 9.3 Hz, 1H), 7.45 - 7.34 (m, 4H), 5.11 (d, J = 3.6 Hz, 1H), 4.52 (d, J = 9.4 Hz, 1H), 4.46 - 4.37 (m, 2H), 4.33 (s, 1H), 4.20 (dd, J = 15.9, 5.5 Hz, 1H), 3.88 (d, J = 12.5 Hz, 2H), 3.69 - 3.59 (m, 2H), 3.40 - 3.35 (m, 2H), 2.42 (s, 3H), 2.32 - 2.20 (m, 1H), 2.14 (ddd, J = 14.3, 8.6, 6.1 Hz, 1H), 2.08 - 1.97 (m, 2H), 1.88 (ddd, J = 12.9, 8.6, 4.6 Hz, 1H), 1.64 - 1.55 (m, 2H), 1.48 - 1.27 (m, 4H), 1.36 (s, 9H), 0.91 (s, 9H). LC / MS m / z calculated value [M+H] + 670.36, actual value 670.43.

[0277] Synthesis of intermediate 21

[0278] [ka] tert-Butyl 4-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropyl)piperazine-1-carboxylate (Intermediate 21). 1H NMR (500 MHz, DMSO) δ δ 8.95 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.53 (d, J = 9.5 Hz, 1H), 7.45 - 7.32 (m, 4H), 5.13 (s, 1H), 4.53 (d, J = 9.5 Hz, 1H), 4.42 (dt, J = 12.1, 7.3 Hz, 2H), 4.34 (s, 1H), 4.19 (dd, J = 15.9, 5.4 Hz, 1H), 3.68 - 3.56 (m, 2H), 3.34 - 3.24 (m, 6H, 2.42 (s, 3H), 2.40 - 2.35 (m, 2H), 2.32 - 2.21 (m, 3H), 2.08 - 1.98 (m, 2H), 1.88 (ddd, J = 13.0, 8.7, 4.6 Hz, 1H), 1.32 (s, 9H), 0.92 (s, 9H). LC / MS m / z calculated value [M+H] + 671.36, actual value 671.45.

[0279] Synthesis of intermediate 22

[0280] [ka] tert-Butyl (3-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)benzyl)carbamate (Intermediate 22). 1H NMR (500 MHz, DMSO) δ 8.96 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.39 - 7.27 (m, 3H), 7.21 (t, J = 7.5 Hz, 1H), 7.14 - 7.09 (m, 2H), 7.06 (dt, J = 7.6, 1.5 Hz, 1H), 5.07 (d, J = 3.5 Hz, 1H), 4.95 - 4.87 (m, 1H), 4.48 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 - 4.22 (m, 1H), 4.08 (d, J = 6.2 Hz, 2H), 3.64 - 3.53 (m, 3H), 3.41 (d, J = 13.9 Hz, 1H), 2.44 (s, 3H), 2.03 - 1.95 (m, 1H), 1.77 (ddd, J = 12.9, 8.5, 4.6 Hz, 1H), 1.41 - 1.34 (m, 12H), 0.91 (s, 9H). LC / MS m / z calculated value [M+H] + 692.35, actual value 692.46.

[0281] [Example 13] General synthetic methods for PROTAC molecules

[0282] [ka]

[0283] To a solution of the Boc-protected linker-E3 ligase ligand complex (1.0 eq) in DCM (4 mL) was added trifluoroacetic acid (1 mL) and stirred at rt for 4 h. Excess reagents and solvent were then evaporated under reduced pressure to give the crude deprotected amine, which was used in the next step without further purification.

[0284] The deprotected amine, Intermediate 10 (1 eq), HOAt (1.2 eq), and DIPEA (7.0 eq) were then dissolved in DMF (50 ml) and stirred at 0 °C. HATU (1.5 eq) was slowly added to the stirred solution. After 15 min, the reaction mixture was quenched with DI water. The mixture was then purified by prep HPLC to give the indicated products (MeOH / HO, 50% to 90%). Yields ranged from 55% to 70%.

[0285] The linker-E3 ligand conjugates of Examples 14 to 27 were synthesized by known methods (see, e.g., X. Han, et al., J. Med. Chem. 2019, 62, 941-964, which is specifically incorporated herein by reference for its teachings therein).

[0286] Synthesis of PROTAC compound 6

[0287] [ka] ((4-((S)-3-(((S)-6-(3-bromo-4-methylbenzamido)-1-((5-(((R)-1-((2R,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentyl)amino)-1-oxohexan-2-yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid (compound 6).

[0288] The linker-E3 ligand conjugate was synthesized by a known method (X. Han, et al., J. Med. Chem. 2019, 62, 941-964). NMR characterization is consistent with reported results. 1H NMR (500 MHz, DMSO) δ 8.98 - 8.93 (m, 1H), 8.60 - 8.54 (m, 2H), 8.13 - 8.00 (m, 3H), 7.99 - 7.68 (m, 4H), 7.46 - 7.34 (m, 8H), 7.25 - 7.07 (m, 6H), 6.66 (d, J = 2.0 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.44 - 6.38 (m, 1H), 4.57 - 4.47 (m, 2H), 4.47 - 4.35 (m, 3H), 4.35 - 4.29 (m, 1H), 4.23 - 4.13 (m, 2H), 3.67 - 3.54 (m, 5H), 3.28 - 3.13 (m, 4H), 3.08 - 2.98 (m, 2H), 2.98 - 2.90 (m, 2H), 2.88 - 2.78 (m, 1H), 2.73- 2.66 (m, 1H), 2.42 (s, 3H), 2.35 (s, 3H), 2.27 - 2.18 (m, 1H), 2.14 - 1.97 (m, 3H), 1.89 (ddd, J = 13.0, 8.5, 4.6 Hz, 1H), 1.67 - 1.58 (m, 1H), 1.57 - 1.28 (m, 8H), 0.91 (s 9H). LC / MS m / z calculated value [MH] - 1442.46, measured value 1442.58.

[0289] [Example 14] Synthesis of PROTAC compound 8

[0290]

change

[0291] The linker-E3 ligand conjugate was synthesized by a known method (X. Han, et al., J. Med. Chem. 2019, 62, 941-964). NMR characterization is consistent with reported results. 1H NMR (500 MHz, DMSO) δ 8.97 (s, 1H), 8.57 - 8.45 (m, 2H), 8.19 (d, J = 8.1 Hz, 1H), 8.12 - 7.98 (m, 3H), 7.86 - 7.80 (m, 2H), 7.76 - 7.70 (m, 1H), 7.42 - 7.27 (m, 9H), 7.17 - 7.08 (m, 5H), 6.65 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.43 - 6.37 (m, 1H), 4.58 - 4.48 (m, 2H), 4.47 - 4.35 (m, 3H), 4.35 - 4.29 (m, 1H), 4.23 - 4.13 (m, 2H), 3.67 - 3.54 (m, 5H), 3.29 - 3.13 (m, 4H), 3.09 - 2.99 (m, 2H), 2.99 - 2.91 (m, 2H), 2.89 - 2.79 (m, 1H), 2.69 (dd, J = 13.5, 9.6 Hz, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 2.26 - 2.15 (m, 1H), 2.13 - 1.98 (m, 3H), 1.88 (ddd, J = 13.0, 8.6, 4.6 Hz, 1H), 1.68 - 1.59 (m, 1H), 1.56 - 1.25 (m, 10H), 0.90 (s, 9H). LC / MS m / z calculated value [MH] - 1456.47, measured value 1456.60.

[0292] [Example 15] Synthesis of PROTAC compound 10

[0293]

change

[0294] The linker-E3 ligand conjugate was synthesized by a known method (X. Han, et al., J. Med. Chem. 2019, 62, 941-964). NMR characterization is consistent with reported results. 1H NMR (500 MHz, DMSO) δ 8.96 (d, J = 3.7 Hz, 1H), 8.62 - 8.51 (m, 2H), 8.12 - 8.00 (m, 4H), 7.88 - 7.70 (m, 3H), 7.45 - 7.32 (m, 8H), 7.16 - 7.08 (m, 6H), 6.67 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.41 (dd, J = 8.2, 2.1 Hz, 1H), 4.55 - 4.48 (m, 2H), 4.47 - 4.35 (m, 3H), 4.35 - 4.28 (m, 1H), 4.23 - 4.13 (m, 2H), 3.69 - 3.53 (m, 5H), 3.29 - 3.13 (m, 4H), 3.03- 2.90 (m, 4H), 2.89 - 2.78 (m, 1H), 2.75 - 2.67 (m, 1H), 2.42 (s, 3H), 2.35 (s, 3H), 2.26 - 2.17 (m, 1H), 2.13 - 1.98 (m, 3H), 1.91 - 1.84 (m, 1H), 1.67 - 1.57 (m, 1H), 1.57 - 1.26 (m, 12H), 0.90 (s, 9H). LC / MS m / z Calculated value [MH] - 1470.49, measured value 1470.61.

[0295] [Example 16] Synthesis of PROTAC compound 83

[0296]

change

[0297] The linker-E3 ligand conjugate was synthesized by a known method (X. Han, et al., J. Med. Chem. 2019, 62, 941-964). NMR characterization is consistent with reported results. 1H NMR (500 MHz, DMSO) δ 8.97 (d, J = 3.7 Hz, 1H), 8.63 - 8.52 (m, 2H), 8.13 - 8.01 (m, 4H), 7.89 - 7.71 (m, 3H), 7.45 - 7.30 (m, 8H), 7.18 - 7.09 (m, 6H), 6.68 (d, J = 2.0 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.42 (dd, J = 8.2, 2.1 Hz, 1H), 4.56 - 4.49 (m, 2H), 4.48 - 4.36 (m, 3H), 4.35 - 4.29 (m, 1H), 4.24 - 4.14 (m, 2H), 3.69 - 3.54 (m, 5H), 3.30 - 3.14 (m, 4H), 3.04- 2.91 (m, 4H), 2.89 - 2.79 (m, 1H), 2.76 - 2.68 (m, 1H), 2.42 (s, 3H), 2.35 (s, 3H), 2.27 - 2.17 (m, 1H), 2.13 - 1.98 (m, 3H), 1.91 - 1.84 (m, 1H), 1.67 - 1.57 (m, 1H), 1.58 - 1.25 (m, 14H), 0.90 (s, 9H). LC / MS m / z Calculated value [MH] - 1484.50, measured value 1485.60.

[0298] [Example 17] Synthesis of PROTAC compound 14

[0299]

change

[0300] The linker-E3 ligand conjugate was synthesized by a known method (X. Han, et al., J. Med. Chem. 2019, 62, 941-964). NMR characterization is consistent with reported results. 1H NMR (500 MHz, DMSO) δ 8.99 (s, 1H), 8.54 (t, J = 6.1 Hz, 1H), 8.47 (t, J = 5.6 Hz, 1H), 8.11 - 7.94 (m, 3H), 7.91 - 7.76 (m, 3H), 7.73 (d, J = 8.0 Hz, 1H), 7.45 - 7.23 (m, 8H), 7.20 - 7.03 (m, 6H), 6.69 - 6.49 (m, 2H), 6.44 - 6.37 (m, 1H), 4.59 - 4.48 (m, 2H), 4.48 - 4.36 (m, 3H), 4.35 - 4.29 (m, 1H), 4.24 - 4.13 (m, 2H), 3.69 - 3.53 (m, 5H), 3.30 - 3.12 (m, 4H), 3.10 - 2.78 (m, 5H), 2.75 - 2.65 (m, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 2.23 (dt, J = 14.7, 7.7 Hz, 1H), 2.13 - 1.94 (m, 3H), 1.88 (ddd, J = 12.9, 8.6, 4.6 Hz, 1H), 1.68 - 1.58 (m, 1H), 1.58 - 1.16 (m, 18H), 0.91 (s, 9H). LC / MS m / z calculated value [MH] - 1512.54, measured value 1512.61.

[0301] [Example 18] Synthesis of PROTAC compound 18

[0302]

change

[0303] The linker-E3 ligand conjugate was synthesized by a known method (X. Han, et al., J. Med. Chem. 2019, 62, 941-964). NMR characterization is consistent with reported results. 1 H NMR (500 MHz, DMSO) δ 8.97 (s, 1H), 8.77 - 8.67 (m, 1H), 8.58 - 8.43 (m, 2H), 8.12 - 7.94 (m, 3H), 7.92 - 7.76 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.51 - 7.25 (m, 8H), 7.24 - 6.99 (m, 6H), 6.67 - 6.47 (m, 2H), 6.42 - 6.35 (m, 1H), 4.59 - 4.49 (m, 2H), 4.48 - 4.36 (m, 3H), 4.35 - 4.29 (m, 1H), 4.27 - 4.13 (m, 2H), 3.66 - 3.49 (m, 5H), 3.28 - 3.11 (m, 4H), 3.10 - 2.78 (m, 5H), 2.73 - 2.64 (m, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 2.28 - 2.20 (m, 1H), 2.10 - 1.85 (m, 3H), 1.92 - 1.84 (m, 1H), 1.67 - 1.58 (m, 1H), 1.58 - 1.09 (m, 22H), 0.91 (s, 9H). LC / MS m / z calculated value [MH]- 1540.57, actual value 1540.70.

[0304] [Example 19] Synthesis of PROTAC compound 28

[0305] [ka] ((4-((2S,5S,15S)-5-(4-(3-bromo-4-methylbenzamido)butyl)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-16,16-dimethyl-3,6,13-trioxo-10-oxa-4,7,14-triazaheptadecyl)phenyl)difluoromethyl)phosphonic acid (compound 28). 1H NMR (500 MHz, DMSO) δ 9.01 (s, 1H), 8.58 - 8.53 (m, 1H), 8.52 - 8.46 (m, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.10 - 8.02 (m, 2H), 8.02 (d, J = 1.8 Hz, 1H), 8.00 - 7.91 (m, 2H), 7.73 (dd, J = 7.8, 1.9 Hz, 1H), 7.44 - 7.29 (m, 9H), 7.20 - 7.08 (m, 5H), 6.65 (d, J = 2.0 Hz, 1H), 6.60 - 6.54 (m, 1H), 6.44 - 6.36 (m, 1H), 4.60 - 4.51 (m, 2H), 4.48 - 4.36 (m, 3H), 4.35 - 4.30 (m, 1H), 4.26 - 4.16 (m, 2H), 3.68 - 3.51 (m, 7H), 3.40 - 3.29 (m, 2H), 3.28 - 3.10 (m, 6H), 3.06 (dd, J = 14.2, 4.4 Hz, 1H), 2.95 (dd, J = 14.0, 3.9 Hz, 1H), 2.89 - 2.78 (m, 1H), 2.73 - 2.65 (m, 1H), 2.57 - 2.50 (m, 1H), 2.42 (s, 3H), 2.38 - 2.28 (m, 4H), 2.05 - 1.98 (m, 1H), 1.88 (ddd, J = 12.9, 8.7, 4.6 Hz, 1H), 1.69 - 1.42 (m, 4H), 1.37 - 1.19 (m, 2H), 0.91 (s, 9H). LC / MS m / z calculated value [MH] - 1458.45, measured value 1458.54.

[0306] [Example 20] Synthesis of PROTAC compound 27

[0307]

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[0308] [Example 21] Synthesis of PROTAC compound 40

[0309]

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[0310] [Example 22] Synthesis of PROTAC compound 48

[0311]

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[0312] [Example 23] Synthesis of PROTAC compound 54

[0313]

change

[0314] [Example 24] Synthesis of PROTAC compound 58

[0315] [ka] ((4-((S)-3-(((S)-6-(3-bromo-4-methylbenzamido)-1-(4-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropyl)piperidin-1-yl)-1-oxohexan-2-yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid (compound 58). 1H NMR (500 MHz, DMSO) δ 8.99 (s, 1H), 8.55 (t, J = 6.1 Hz, 1H), 8.49 (p, J = 4.5 Hz, 1H), 8.24 - 8.17 (m, 2H), 8.07 (dd, J = 8.4, 3.0 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.95 - 7.86 (m, 2H), 7.73 (dt, J = 8.1, 2.2 Hz, 1H), 7.40 (d, J = 7.9 Hz, 4H), 7.38 - 7.32 (m, 3H), 7.31 (dd, J = 8.3, 3.2 Hz, 1H), 7.19 - 7.08 (m, 5H), 6.69 - 6.63 (m, 1H), 6.56 (dd, J = 8.0, 2.9 Hz, 1H), 6.39 (dd, J = 8.2, 2.2 Hz, 1H), 4.75 - 4.62 (m, 1H), 4.58 - 4.49 (m, 2H), 4.48 - 4.37 (m, 3H), 4.37 - 4.27 (m, 2H), 4.20 (dd, J = 15.9, 5.5 Hz, 1H), 3.88 (dd, J = 29.1, 12.5 Hz, 1H), 3.68 - 3.54 (m, 5H), 3.28 - 3.13 (m, 4H), 3.07 - 2.91 (m, 2H), 2.87 - 2.77 (m, 1H), 2.72 - 2.64 (m, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 2.32 - 2.20 (m, 1H), 2.18 - 2.05 (m, 3H), 2.05 - 1.97 (m, 1H), 1.88 (ddd, J = 12.9, 8.6, 4.5 Hz, 1H), 1.73 - 1.58 (m, 3H), 1.53 - 1.19 (m, 9H), 0.91 (m, 9H). LC / MS m / z calculated value [MH] - 1482.49, measured value 1482.61.

[0316] [Example 25] Synthesis of PROTAC compound 56

[0317] [ka] ((4-((S)-3-(((S)-6-(3-bromo-4-methylbenzamido)-1-(4-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropyl)piperazin-1-yl)-1-oxohexan-2-yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid (compound 56). 1H NMR (500 MHz, DMSO) δ 8.97 (s, 1H), 8.61 (s, 1H), 8.50 - 8.42 (m, 1H), 8.36 - 8.26 (m, 2H), 8.09 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.47 - 7.32 (m, 8H), 7.25 - 7.19 (m, 2H), 7.19 - 7.09 (m, 5H), 6.72 - 6.67 (m, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.44 (d, J = 8.1 Hz, 1H), 4.66 - 4.38 (m, 7H), 4.37 - 4.31 (m, 1H), 4.22 (dd, J = 16.1, 5.4 Hz, 1H), 3.71 - 3.56 (m, 6H), 3.30 - 3.13 (m, 9H), 3.02 - 2.97 (m, 1H), 2.94 (dd, J = 13.8, 4.1 Hz, 1H), 2.86 (s, 1H), 2.74 (m, 1H), 2.48 - 1.44 (m, 2H), 2.42 (s, 3H), 2.40 (m, 2H), 2.35 (s, 3H), 2.12 - 1.99 (m, 3H), 1.93 - 1.84 (m, 1H), 1.70 - 1.59 (m, 1H), 1.55 - 1.41 (m, 3H), 1.27 - 1.18 (m, 2H), 0.94 (s, 9H). LC / MS m / z calculated value [MH] - 1483.48, measured value 1483.62.

[0318] [Example 26] Synthesis of PROTAC cis compound 47

[0319]

change

[0320] [Example 27] Synthesis of PROTAC compound 47

[0321]

change

[0322] [Example 28] FP-based library screening Library 1 screening Library screening assays were performed on a Tecan Genesis workstation using a 96-channel chip block with fixed chips. Prior to screening, library compounds were diluted from DMSO stock solutions into 3,3-dimethylglutaric acid buffer (50 mM 3,3-dimethylglutaric acid buffer, pH 7.0, containing 1 mM EDTA, with an ionic strength of 0.15 M adjusted by adding NaCl), resulting in a series of six daughter plates with each compound at a concentration of approximately 75 nM per well. In the first screening, 50 μL of PTP1B or TCPTP (2 μM in 50 mM 3,3-dimethylglutaric acid buffer, pH 7.0, containing 1 mM EDTA, with an ionic strength of 0.15 M adjusted by adding NaCl) was dispensed into each well of a 384-well plate, and then 2 μL of fluorescein-labeled library compounds were transferred from the four 96-well intermediate plates to the 384-well plate (final compound concentration of approximately 3 nM). Fluorescence polarization values ​​(A1) were recorded using an Envision 2021 multilabel microplate reader (Perkin-Elmer). In the second screening, 50 μL of a mixture of 2 μM PTP1B or TCPTP and 500 μM Fmoc-F2Pmp-OH (as a competitive ligand) in 3,3-dimethylglutaric acid buffer (50 mM 3,3-dimethylglutaric acid buffer, pH 7.0, containing 1 mM EDTA, with an ionic strength of 0.15 M adjusted by the addition of NaCl) was dispensed into each well of another 384-well plate, followed by the addition of 2 μL of fluorescein-labeled library compound (75 nM in 3,3-dimethylglutaric acid buffer, pH 7.0, containing 1 mM EDTA, with an ionic strength of 0.15 M adjusted by the addition of NaCl). Fluorescence polarization values ​​(A2) were measured again. The substitution percentage was calculated for each library compound as (A1-A2) / (A1-A0) × 100%, where A1 and A2 are the fluorescence anisotropy values ​​for each listed sample, and A0 is the fluorescence anisotropy of the free library compound in 3,3-dimethylglutaric acid buffer. For simplicity of calculation, A0 was set to 30.The binding affinity ranking of each compound was determined relative to the substitution percentage: the smaller the substitution percentage, the greater the binding affinity. The best hits were selected based on affinity and are listed in Table 1. Table 1 shows the top 5 hits from Library 1 (compounds showing equally high binding affinity to PTP1B and TC-PTP were selected). a

[0323] [ka]

[0324] [Table 5]

[0325] a The substitution percentage was calculated for each library compound as (A1-A2) / (A1-A0) x 100%. In this formula, A1 and A2 are the fluorescence polarization values ​​generated by binding between the library compound and the target enzyme in the absence and presence of the competitive ligand (Fmoc-F2Pmp-OH), respectively. A0 is the fluorescence anisotropy of the free library compound. The binding affinity ranking of each compound was determined relative to the substitution percentage: the smaller the substitution percentage, the greater the binding affinity.

[0326] Screening of library 2. The library was screened using the same protocol as Library 1, except that 0.5 μM PTP1B / TC-PTP and 1.5 mM competitive ligand Fmoc-F2Pmp-OH were used. The best hits were selected based on affinity and are listed in Table 2.

[0327] Table 2 shows the top 5 hits from Library 2 (compounds showing equally high binding affinity to PTP1B and TC-PTP were selected). a

[0328] [ka]

[0329] [Table 6]

[0330] a The substitution percentage was calculated for each library compound as (A1-A2) / (A1-A0) x 100%. In this formula, A1 and A2 are the fluorescence polarization values ​​generated by binding between the library compound and the target enzyme in the absence and presence of the competitive ligand (Fmoc-F2Pmp-OH), respectively. A0 is the fluorescence anisotropy of the free library compound. The binding affinity ranking of each compound was determined relative to the substitution percentage: the smaller the substitution percentage, the greater the binding affinity.

[0331] Library 3 screening The library was screened using the same protocol as Library 1, except that 0.5 μM PTP1B / TC-PTP and 5 μM ((4-((S)-2-((S)-2-acetamido-3-phenylpropanamido)-3-(((S)-1-amino-6-(3-bromo-4-methylbenzamido)-1-oxohexan-2-yl)amino)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid (as competitor) were used. The best hits were selected based on affinity and are listed in Table 3.

[0332] Table 3 shows the top 5 hits from Library 3 (compounds showing equally high binding affinity to PTP1B and TC-PTP were selected). a

[0333] [ka]

[0334] [Table 7]

[0335] a The substitution percentage was calculated for each library compound as (A1-A2) / (A1-A0) x 100%. In this formula, A1 and A2 are the fluorescence polarization values ​​generated by binding between the library compound and the target enzyme in the absence and presence of the competitive ligand (Fmoc-F2Pmp-OH), respectively. A0 is the fluorescence anisotropy of the free library compound. The binding affinity ranking of each compound was determined relative to the substitution percentage: the smaller the substitution percentage, the greater the binding affinity.

[0336] [Example 29] Inhibition constant (K i ) and IC 50 Determining Values PTP activity was assayed at 25°C using p-nitrophenyl phosphate (pNPP) as a substrate in DMG buffer (50 mM DMG, pH 7.0, 1 mM EDTA, 150 mM NaCl, 2 mM DTT, 0.1 mg / mL BSA). Assays were performed in 96-well plates. Typically, IC 50To determine K values, reactions were initiated by the addition of enzyme (final concentration 0.4 nM for PTP1B and TCPTP, final concentration 10 nM for other PTPs) to reaction mixtures (0.2 mL) containing 2 mM (Km of substrate) pNPP with various concentrations of inhibitor (see Figure 1). Reaction rates were measured using a SpectraMax Plus 384 microplate spectrophotometer (Molecular Devices). Data were fitted using SigmaPlot Enzyme Kinetics Module (Systat Software, Inc.). To determine the mode of inhibition, reactions were initiated by the addition of enzyme (final concentration 0.4 nM for TC-PTP and PTP1B) to reaction mixtures (0.2 mL) containing various concentrations of pNPP with various concentrations of inhibitor. Data were fitted using SigmaPlot Enzyme Kinetics Module (Systat Software, Inc.).

[0337] [Example 30] cell culture HEK293, MIAPaCa-2, HepG2, U2OS, H116, MEF, B16F10, and MC38 cells were grown in DMEM, and Jurkat and H358 cells were grown in RPMI 1640 supplemented with 10% fetal bovine serum, penicillin (50 units / mL), and streptomycin (50 μg / mL) in a 37°C incubator containing 5% CO. JAK / STAT pathway stimulation was performed with 20 ng / mL human (Biolegend #713906) or mouse (Biolegend #714006) interferon-γ.

[0338] Immunoblotting Tissues or cultured cells were lysed in ice-cold lysis buffer (50 mM Tris (pH 8.0), 150 mM NaCl, 10% glycerol, 1% Triton-X-100) supplemented with phosphatase inhibitors (Bimake) and a protease inhibitor mixture (Roche Applied Science). Equal amounts of protein were separated by SDS-PAGE, transferred to nitrocellulose membranes, and immunoblotted. Antibodies used in this study included anti-pSTAT1; ... Tyr701 (Cell Signaling Technology#9167, 1:3000), GAPDH(Cell Signaling Technology#97166, 1:5000), pJAK1 Tyr1034 / 1035 (Cell Signaling Technology#74129, 1:1000), pJAK2 Tyr1007 / 1008 (Cell Signaling Technology#3776, 1:1000), TC-PTP (Abcam#ab180764, 1:3000), PTP1B (Abcam#ab244207, 1:1500).

[0339] Evaluation of degradation efficiency.

[0340] [ka]

[0341] Table 4 shows the structures and degradation results for an initial set of degraders. Degradation assays were performed in HEK293 cells using 1 μM degrader and 24 hour incubation.

[0342] [Table 8]

[0343] Table 5 shows the structures and degradation results for the second set of degraders. Degradation assays were performed in HEK293 cells using 0.2 μM degraders and 16 hours of incubation.

[0344] [ka]

[0345] [Table 9]

[0346] Verification of decomposition mechanism PROTAC-mediated protein degradation requires the essential formation of a functional ternary complex of target protein-PROTAC-E3 ligase to enable ubiquitination of the target protein by the E3 ligase and subsequent proteasomal degradation. The VHL E3 ligase dependency of compound 47-induced PTP1B and TC-PTP degradation was confirmed by preparing a cis-isomer of compound 47 (cis-47), in which the VHL E3 ligand was replaced with (S,S,S)-AHPC-Me, an epimer of (S,R,S)-AHPC-Me, which has weaker affinity for VHL. The IC of cis-47 for PTP1B and TC-PTP was 50 The IC values ​​(25.1 ± 1.6 and 29.7 ± 2.1 nM) were the IC values ​​for compound 47. 50The results demonstrated that the values ​​were comparable to those of the VHL-dependent degradation of PTP1B and TC-PTP. Consistent with the inability of (S,S,S)-AHPC-Me to bind to VHL, cis-47 did not degrade either PTP1B or TC-PTP in HEK293 cells (Figure 6A). Furthermore, addition of the VHL ligand (S,R,S)-AHPC-Me reduced compound 47-mediated degradation of the two proteins (Figure 6A). In contrast, pretreatment of cells with lenalidomide, a ligand for cereblon (another E3 ligase commonly utilized in PROTAC development), had no effect on compound 47-mediated degradation of PTP1B and TC-PTP (Figure 6A). These observations suggest that compound 47-induced degradation of PTP1B and TC-PTP is VHL-dependent. The ubiquitination and proteasome dependence of compound 47-induced PTP1B and TC-PTP degradation was demonstrated by determining the effects of MLN-4924, an inhibitor of E1 ubiquitin-activating enzyme, and MG-132, a proteasome inhibitor. Pretreatment of cells with these inhibitors for 30 minutes significantly reduced the extent of compound 47-induced PTP1B and TC-PTP degradation, indicating that E1 ubiquitin-activating enzyme and the 26S proteasome are indeed required for compound 47-induced PTP1B and TC-PTP degradation (Figure 6A). Compound 47-mediated PTP1B and TC-PTP degradation and proteasome dependence were also verified by immunofluorescence imaging (Figures 6B and 6C). Taken together, the data demonstrated that compound 47 is a highly potent and selective PTP1B and TC-PTP dual PROTAC degrader.

[0347] Proteomic analysis of selectivity Quantitative mass spectrometry-based proteomics experiments were performed to assess the proteome-wide degradation selectivity of compound 47 and determine the range of targets degraded by compound 47 in HEK293 cells. As shown in Figure 7, PTP1B was the only protein whose levels were significantly reduced by 100 nM compound 47. Mass spectrometry measurements under the given conditions did not detect TC-PTP. Taken together, the above results indicated that compound 47 is a potent PTP1B and TC-PTP dual degrader with remarkably high selectivity.

[0348] Flow cytometry After incubation, MC38 cells were trypsinized, washed in PBS + 2% FBS, stained with Alexa Fluor® 647 anti-mouse H-2Kb / H-2Db antibody against the mouse MHC-I complex, and then analyzed on a BD Fortessa LSR flow cytometry cell analyzer. MC38 cells treated with Compound 47 exhibited increased expression of MHC-I (Figure 4).

[0349] In vivo antitumor studies All in vivo studies were conducted under animal protocols approved by the Purdue University Institutional Animal Care and Use Committee (1511001324) and in accordance with the recommendations in the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

[0350] Pharmacokinetic studies For the PK study, C57BL6 female mice (25–30 g body weight) were intraperitoneally injected with 25 or 50 mg / kg of compound 47 dissolved in 0.4 ml of saline. Blood samples were collected from the tail vein at the indicated time points after injection. Isoflurane was used as the anesthetic. All blood samples were centrifuged at 1,500 g for 5 minutes, and plasma was separated and stored at -80°C until analysis by a validated method based on reversed-phase liquid chromatography coupled with mass spectrometry detection (LC / MS) using a reported procedure (Journal of Clinical Investigation, 2018, 128, 816–825), which is specifically incorporated herein by reference for its teachings (Figure 5A).

[0351] In the MC38 syngeneic tumor study, 12-week-old C57BL6 female mice were given 10 6 MC38 cells were injected subcutaneously. Tumors grew to an average volume of 200 mm 3 Once the tumor size reached 100 mm, the mice were randomly assigned to various experimental groups, matched by tumor size, for the experiments. Mice were intraperitoneally injected daily with saline or 25 or 50 mg / kg of Compound 47. Tumor size and animal weight were measured twice weekly (Figures 5B-5C). Tumor volume (mm 3 )=(length x width 2 ) / 2. At the end of the experiment, the mice were euthanized and the tumors were collected for analysis.

[0352] To improve the PK properties, saline was replaced with PBS buffer in the treatment of compound 47 in mice (Figure 10). max Both the serotonin concentration and area under the curve (AUC) were increased compared to the saline method. No significant improvement was observed with the addition of the solubilizer Kolliphor.

[0353] Compound 47 enhances IFN-γ-induced JAK1 / 2-STAT1 pathway activation and promotes MHC-I expression in tumor cells. Compound 47 enhances STAT1 and STAT5 phosphorylation, thereby inhibiting CD8 +Importantly, compound 47 induces PTP1B and TC-PTP degradation in vivo and activates CD8 T cells. + Suppresses MC38 syngeneic tumor growth by enhancing T cell-mediated immune responses (Figures 5D-5F).

[0354] Biochemical IC of dual PROTACs 50 are listed in Table 6. The compound of Example 7 was included as a control compound.

[0355] [Table 10]

[0356] TC-PTP / PTP1B KO MEF cells for pJAK1 / 2 elevation and 1B / TC degradation. We confirmed target binding by compound 47 in cells. As negative regulators of IFN-γ signaling, PTP1B and TC-PTP dephosphorylate JAK2 at Y1007 / Y1008 and JAK1 at Y1034 / Y1035, respectively. Furthermore, TC-PTP can also directly dephosphorylate STAT family members, including STAT1 and STAT3, in the nucleus, globally attenuating IFN signaling. Treatment of MEF cells with 500 nM compound 47 for 16 h led to complete removal of both PTP1B and TC-PTP and enhanced IFN-γ-stimulated JAK2 Y1007 / Y1008 and JAK1 Y1034 / Y1035 phosphorylation (Figure 8). The increase in pJAK1 / Y1034 / Y1035 and pJAK2 / Y1007 / Y1008 caused by PTP1B / TC-PTP degradation was demonstrated by utilizing MEF cells lacking either PTP1B or TC-PTP as negative controls. As shown in Figure 8, TC-PTP - / - Compound 47 treatment of MEF cells further increased IFN-γ-mediated phosphorylation of the PTP1B substrate JAK2 / Y1007 / Y1008, but had no effect on the levels of the TC-PTP substrate pJAK1 / Y1034 / Y1035. In contrast, PTP1B - / -Addition of compound 47 to MEF cells further increased IFN-γ-mediated levels of the TC-PTP substrate pJAK1 / Y1034 / Y1035, but did not alter phosphorylation of the PTP1B substrate JAK2 / Y1007 / Y1008. These results indicate that compound 47 can block both PTP1B- and TC-PTP-catalyzed substrate dephosphorylation.

[0357] Compound 47 is a CD8 + Induces PTP1B and TC-PTP degradation, enhances STAT1 and STAT5 phosphorylation, and upregulates CD8 in naive T cells. + Promotes T cell activation. In addition to attenuating JAK / STAT signaling in tumor cells, PTP1B and TC-PTP also play fundamental roles in T cells, and deficiency of either TC-PTP or PTP1B in T cells can significantly enhance antitumor immunity. TC-PTP attenuates T cell receptor (TCR) signaling by dephosphorylating and activating the Src family kinase LCK. TC-PTP attenuates JAK / STAT1 / 5 signaling in response to cytokines, such as IFN and IL-2, required for T cell activation, clonal proliferation, and differentiation. Deficiency of TC-PTP in T cells enhances immune surveillance and inhibits the growth of syngeneic tumors in mice and the antitumor efficacy of adoptively transferred T cells. PTP1B also negatively regulates IL-2-induced JAK / STAT5 signaling in T cells, and its deficiency or inhibition in vivo can enhance the antitumor activity of T cells. Therefore, the impact of targeting PTP1B and TC-PTP by compound 47 on JAK / STAT signaling and T cell activation following TCR crosslinking was evaluated. The effects of compound 47 were assessed by genetic deletion of TC-PTP (encoded by Ptpn2) in T cells (Lck-Cre;Ptpn2 fl / fl) were compared. The effect of Compound 47 on TC-PTP and PTP1B protein levels was first assessed by flow cytometry using validated antibodies. 48 hr after treatment, TC-PTP and PTP1B were effectively degraded in T cells (Figure 9A). Degradation of TC-PTP and PTP1B was accompanied by a more than three-fold increase in STAT1 Y701 phosphorylation and a two-fold increase in STAT5 Y694 phosphorylation, detected after T cell activation by crosslinking the TCR with α-CD3 / α-CD28 (Figure 9B). Importantly, the promotion of pSTAT1 / Y701 and pSTAT5 / Y694 by Compound 47 treatment exceeded that achieved by genetic deletion of TC-PTP, consistent with targeting of both TC-PTP and PTP1B by Compound 47 to enhance signaling. Furthermore, compound 47 treatment also enhanced TCR-induced activation of T cells, as assessed by monitoring cell size and expression of cell surface activation markers, including CD44, CD25 (IL-2 receptor α), and CD69 (Figure 9C). In this example, compound 47 enhanced T cell activation above that achieved by deficiency of TC-PTP, but only moderately, not significantly. This suggests that TC-PTP enhances naive CD8 + This is not necessarily surprising, as compound 47 attenuates TCR signaling, but not PTP1B, in T cells. Nevertheless, these results suggest that the combined targeting of PTP1B and TC-PTP with compound 47 may mediate JAK / STAT signaling and CD8 signaling, which may be useful in antiviral and antitumor immunity. + It has been shown that it can enhance T cell activation.

[0358] Blood Glucose Level Studies---Implications for Diabetes and Obesity PTP1B and TC-PTP are known to function cooperatively in regulating both insulin- and leptin-mediated cellular processes. Inhibition of PTP1B and TC-PTP has been reported to improve insulin sensitivity and glucose homeostasis in diet-induced obese mice. The effect of compound 47 on glucose levels in mice was evaluated. Results showed that 15 mg / kg of compound 47 was sufficient to reduce blood glucose levels in high-fat-fed (HFD) mice to those of normal-fat-fed (NFD) mice, and treatment with 50 mg / kg of compound 47 led to further reductions in glucose levels (Figure 11). In an MC38 synergistic tumor mouse model, 25 mg / kg of compound 47 did not significantly reduce blood glucose levels, while 50 mg / kg slightly reduced blood glucose levels (Figure 11), suggesting that the reduction in glucose levels by compound 47 was minimal in mice with healthy blood glucose levels.

[0359] Comparison of Compound 47 to the TC-PTP inhibitor ABBV-CLS-484 on STAT1 phosphorylation Abbvie and Calico have developed a potent PTP1B / TC-PTP inhibitor, ABBV-CLS-484 (disclosed in International PCT Application WO 2019246513), which is currently being evaluated as a treatment for locally advanced or metastatic tumors (NCT04777994). The efficacy of compound 47 was demonstrated by comparing its efficiency in activating STAT1 phosphorylation with that of ABBV-CLS-484 (Figure 12A). In HEK293 cells, compound 47 induced the degradation of TC-PTP in a dose-dependent manner and upregulated pSTAT1 in EC 50 It was active at 9.1 nM, which is superior to ABBV-CLS-484 (79.7 nM).

[0360] As used herein, the following terms and phrases shall have the meanings indicated below: Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0361] The term "about" allows a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of the stated value or the limits of the stated range.

[0362] The term "substantially" refers to the degree of variability of a value or range, for example, within 90%, within 95%, or within 99% of a stated value or the limits of a stated range.

[0363] The terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a non-exclusive "or" unless otherwise indicated. Furthermore, any phraseology or terminology employed herein and not otherwise defined is for purposes of description only and not of limitation. Any use of section headings is intended to aid in the reading and comprehension of the document and should not be construed as limiting. Furthermore, information associated with a section heading may appear within or outside of that particular section. The terms "including" and "having" are defined as compris- ing (i.e., open phraseology).

[0364] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All such publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof: 【Chemistry 1】 (In the formula, R １ and R ２ are each independently a residue of a carboxylic acid or a pharmaceutically acceptable salt thereof; R １ and R ２ may be the same or different, R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ are each independently hydrogen, deuterium, halogen, hydroxy, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, —C １ ~C ６ Alkylene, 4- to 6-membered heterocyclyl, and —C １ ~C ６ alkylene-4- to 6-membered heterocyclyl; １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, and C １ ~C ６ The alkylene-4 to 6-membered heterocyclyl group is substituted with deuterium, halogen, hydroxy, C═O, C １ ~C ６ Alkyl, C ３ ~C ６ Alkenyl, C ３ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, —C １ ~C ６ -Alkylene-C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkyl-S(O) ２ -, C ３ ~C ６ Cycloalkyl-S(O) ２ -, C １ ~C ６ Alkyl-C(O)-, C １ ~C ６ Alkoxy-C(O)-, -NH-C(O)-R ａ and —C(O)—NH—R ａ and optionally substituted on one or more available carbons with one or more substituents each independently selected from R ａ is deuterium, halogen, hydroxy, C=O, C １ ~C ６ Alkyl, C ３ ~C ６ Alkenyl, C ３ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, —C １ ~C ６ -Alkylene-C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkyl-S(O) ２ -, C １ ~C ６ Cycloalkyl-S(O) ２ -, C １ ~C ６ Alkyl-C(O)-, C １ ~C ６ Alkoxy-C(O)-, -NH-C(O)-R ｂ and —C(O)—NH—R ｂ C optionally substituted on one or more available carbons with one or more substituents each independently selected from １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C １ ~C ６ alkylene-4- to 6-membered heterocyclyl, and R ｂ is deuterium, halogen, hydroxy, C=O, C １ ~C ６ Alkyl, C ３ ~C ６ Alkenyl, C ３ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, —C １ ~C ６ -Alkylene-C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkyl-S(O) ２ -, C ３ ~C ６ Cycloalkyl-S(O) ２ -, C １ ~C ６ Alkyl-C(O)-, and C １ ~C ６ alkoxy-C(O)—; t is 0 to 6; R ９ is H or a group represented by the formula LB, and L is Table 1 is a linker selected from the group consisting of w is 1 to 5, x is 1 to 15, a and b are each independently 0 to 3, 【Chemistry 2】 The bond indicated by is attached to B and ＊ The bond indicated by " is R ９ represents the point of attachment of B is group B １ , B ２ , and B ３ B is selected from １ is the structure: 【Transformation 3】 is represented by R ３ａ is fluoro, hydrogen, or deuterium, B ２ is the structure: 【Chemistry 4】 is represented by R ３ｂ is fluoro, hydrogen, or deuterium, B ３ is the structure: 【Transformation 5】 is represented by R ４ is methyl, hydrogen, or deuterium).

2. The carboxylic acid is represented by the formula RCOOH, wherein R is selected from the group consisting of hydrogen, an aliphatic group, or an aromatic group, the aliphatic group being saturated or unsaturated, and the aliphatic group or the aromatic group being selected from the group consisting of C １ ~C ２４ Alkyl, C １ ~C ２４ Alkenyl, C １ ~C ２４ substituted with alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl; １ ~C ２４ Alkyl, hydroxy, alkoxy, cyano, halo, nitro, aryl, amino, C １ ~C ２４ Alkenyl, C １ ~C ２４ 2. The compound of claim 1, optionally substituted with at least one of the group selected from alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl.

3. The carboxylic acid may be 3-dimethylaminobenzoic acid, 2-(2-cyanophenylthio)benzoic acid, 2-(4-chlorobenzoyl)benzoic acid, (-)-2-oxo-4-thiazolidine-carboxylic acid, (-)-N-acetylneuraminic acid, (+)-6-methoxy-α-methyl-2-naphthaleneacetic acid, (+)-carbobenzyloxy-D-proline, (+)-menthoxyacetic acid, (±)-2-(2-chlorophenoxy)propionic acid, (±)-1-methyl-2 -Cyclohexene-1-carboxylic acid, (1-naphthoxy)acetic acid, (1R)-(1a,2b,3a)-(+)-3-methyl-2-nitromethyl-5-oxocyclopentaneacetic acid, (1R,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylic acid, (1S)-(+)-camphanic acid, (1S,3R,4S,5R)-1,3,4,5-tetrahydroxycyclohexanecarboxylic acid, (2,4-di-tert-pentyl phthalate (phenoxyl)acetic acid, (2-naphthoxy)acetic acid, (2-pyrimidylthio)acetic acid, (4-carboxybutyl)triphenyl-phosphonium bromide, (4-chlorophenylthio)acetic acid, (4-methylphenoxy)acetic acid, (α,α,α-trifluoro-m-tolyl)acetic acid, (E)-2-((4-hydroxyphenyl)diazenyl)benzoic acid, (E)-2-methyl-3-(2,4,5-trimethoxyphenyl)acrylic acid, (methylthio)acetic acid, (R)-( -)-2-Hydroxy-4-phenylbutyric acid, (R)-(-)-3-chloromandelic acid, (R)-(-)-hexahydromandelic acid, (R)-(+)-2-pyrrolidone-5-carboxylic acid, (R)-(+)-citronellic acid, (R)-2-(1-phenylethylcarbamoyl)benzoic acid, (R)-2-hydroxy-2-phenylacetic acid, (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid, (R)-6-hydroxy-2,5,7,8-Tetramethylchroman-2-carboxylic acid, (S)-(-)-indoline-2-carboxylic acid, (S)-(+)-2-oxo-4-phenyl-3-oxazolidineacetic acid, (S)-(+)-5-oxo-2-tetrahydro-furancarboxylic acid, (S)-(+)-hexahydromandelic acid, (S)-(+)-N-[1-(1-naphthyl)-ethyl]-phthalamic acid, (S)-(+)-O-acetylmandelic acid, (S)-2-(1-phenylethylcarbamoyl)benzoic acid, (S)-2-(4-isobutylphenyl)propanoic acid, (S)-2-(phenylethyl)benzoic acid (S)-3-(benzyloxycarbonyl)-2-oxoimidazolidine-4-carboxylic acid, (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid, (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid, (S)-6-methoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, (trimethylsilyl)acetic acid, (Z)-2-cyano-3-(3-hydroxyphenyl)acrylic acid, 1-(4-chlorophenyl)-1-cyclopentanecarboxylic acid, 1-(te rt-butyl)hydrocinnamic acid, 1,2-phenylenedioxydiacetic acid, 1,4-dihydro-2-methylbenzoic acid, 1,4-dihydroxy-2-naphthoic acid, 10-hydroxydecanoic acid, 10-undecynoic acid, 1-admantanecarboxylic acid, 1-cyano-1-cyclopropanecarboxylic acid, 1-hydroxy-2-naphthoic acid, 1-isoquinolinecarboxylic acid, 1-methyl-(1S,2R)-(+)-cis-1,2,3,6-tetrahydrophthalate, 1-methyl-1-cyclohexanecarboxylic acid, 1-methyl-1H-indole-2-carboxylic acid, 1-Methyl-2-pyrrolecarboxylic acid, 1-methylcyclopropanecarboxylic acid, 1-naphthoic acid, 1-phenyl-1-cyclopentanecarboxylic acid, 1-phenyl-1-cyclopropanecarboxylic acid, 1-pyreneacetic acid, 1-pyrenebutyric acid, 1-pyrenecarboxylic acid, 2-((1R,2R,3R,4S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)acetic acid, 2-((benzyloxycarbonyl)(methyl)amino)-2-methylpropanoic acid, 2-(2-(trifluoromethyl)phenyl)acetic acid, 2-(2,4,5-trichlorophenoxy)-propionic acid, 2-(2,4-dichlorophenoxy)-propionic acid, 2-(3,5-dinitrobenzamido)-2-phenylacetic acid, 2-(3,5-dinitrobenzamido)-4-methylpentanoic acid, 2-(3-chlorophenoxy)propionic acid, 2-(4-(trifluoromethyl)phenyl)acetic acid, 2-(4-chloro-3-nitrobenzoyl)-benzoic acid, 2-(4-chlorophenoxy)-2-methyl-propionic acid, 2-(4-chlorophenoxy)propionic acid, 2-(4-fluorobenzoyl)benzoic acid, 2-(4- Hydroxy-3-methoxyphenyl)acetic acid, 2-(4-hydroxyphenoxy)-propionic acid, 2-(4-isobutylphenyl)propanoic acid, 2-(4-nitrophenyl)propionic acid, 2-(benzyloxycarbonylamino)-3-(1H-indol-3-yl)propanoic acid, 2-(trifluoromethyl)acrylic acid, 2-(trifluoromethyl)benzoic acid, 2-(trifluoromethyl)cinnamic acid, 2,2,3,3-tetramethyl-cyclopropanecarboxylic acid, 2,2-bis(hydroxymethyl)-propionic acid, 2,3,4,5,6-pentafluorophenyl Fluoro-cinnamic acid, 2,3,4,5,6-pentafluorophenoxyacetic acid, 2,3,4,5,6-pentafluorophenyl-acetic acid, 2,3,4,5-tetrafluorobenzoic acid, 2,3,4-trifluorocinnamic acid, 2,3,4-trihydroxybenzoic acid, 2,3,4-trimethoxybenzoic acid, 2,3,5,6-tetrafluoro-4-hydroxy-benzoic acid hydrate, 2,3,5,6-tetrafluorobenzoic acid, 2,3,5,6-tetrafluoro-p-toluic acid, 2,3,5-triiodobenzoic acid, 2,3,6-trifluorobenzoic acid, 2,3-dichlorobenzoic acid Benzoic acid, 2,3-difluorobenzoic acid, 2,3-dihydroxybenzoic acid, 2,3-dimethylbenzoic acid, 2,4,5-trichlorophenoxyacetic acid, 2,4,5-trimethoxybenzoic acid, 2,4,6-trichlorobenzoic acid, 2,4,6-trifluorobenzoic acid, 2,4,6-trihydroxybenzoic acid monohydrate, 2,4,6-trimethylbenzoic acid, 2,4-bis(trifluoromethyl)-benzoic acid, 2,4-dichloro-5-fluorobenzoic acid, 2,4-dichloro-5-sulfamoyl-benzoic acid, 2,4-dichlorobenzoic acid, 2,4-dichlorophenylacetic acid, 2,4-difluorobenzoic acid, 2,4-difluorophenylacetic acid, 2,4-dihydroxybenzoic acid, 2,4-dimethylbenzoic acid, 2,4-dinitrobenzoic acid, 2,4-dinitrophenylacetic acid, 2,4-hexadienoic acid, 2,5-bis(trifluoromethyl)-benzoic acid, 2,5-dichlorobenzoic acid, 2,5-difluorobenzoic acid, 2,5-difluorophenylacetic acid, 2,5-dihydroxybenzoic acid, 2,5-dihydroxyphenylacetic acid, 2,5-Dimethoxybenzoic acid, 2,5-dimethoxycinnamic acid, 2,6-dichloro-3-nitrobenzoic acid, 2,6-difluorobenzoic acid, 2,6-difluorophenylacetic acid, 2,6-dihydroxybenzoic acid, 2,6-dimethoxynicotinic acid, 2,6-dimethylbenzoic acid, 2,6-heptadienoic acid, 2-[4-(dibutylamino)-2-hydroxybenzoyl]benzoic acid, 2-bibenzylcarboxylic acid, 2-biphenylcarboxylic acid, 2-butylbenzoic acid, 2-bromo-3-nitrobenzoic acid, 2-bromo-4,5-dimethoxybenzoic acid, 2-bromo-5-methoxybenzoic acid, 2-bromo-5-nitrobenzoic acid, 2-bromoacrylic acid, 2-bromophenylacetic acid, 2-chloro-3-nitrobenzoic acid, 2-chloro-4,5-difluorobenzoic acid, 2-chloro-4-fluorobenzoic acid, 2-chloro-5-(methylthio)-benzoic acid, 2-chloro-5-(trifluoro-methyl)benzoic acid, 2-chloro- 5-Nitrobenzoic acid, 2-chloro-5-nitrocinnamic acid, 2-chloro-6-fluorobenzoic acid, 2-chloro-6-fluorophenylacetic acid, 2-chloro-6-methylnicotinic acid, 2-chlorobenzoic acid, 2-chloronicotinic acid, 2-chlorophenylacetic acid, 2-chloropropionic acid, 2-ethoxy-1-naphthoic acid, 2-ethoxybenzoic acid, 2-ethyl-2-hydroxybutyric acid, 2-ethylbutyric acid, 2-ethylhexanoic acid, 2-ethylthio-2,2-Diphenyl-acetic acid, 2-fluoro-3-(trifluoromethyl)-benzoic acid, 2-fluoro-4-(trifluoromethyl)-benzoic acid, 2-fluoro-5-methylbenzoic acid, 2-fluoro-5-nitrobenzoic acid, 2-fluoro-6-(trifluoromethyl)-benzoic acid, 2-fluorobenzoic acid, 2-fluorocinnamic acid, 2-fluorophenylacetic acid, 2-hydroxy-3-isopropyl-6-methylbenzoic acid, 2-hydroxy-3-isopropylbenzoic acid, 2-hydroxy-3-methylbutyric acid, 2-hydroxy 2-hydroxy-6-isopropyl-3-methylbenzoic acid, 2-hydroxycaproic acid, 2-hydroxyhippuric acid, 2-hydroxyisobutyric acid, 2-hydroxyisobutyric acid, 2-hydroxynicotinic acid, 2-hydroxyphenylacetic acid, 2-iodobenzoic acid, 2-mercaptonicotinic acid, 2-methoxy-2-phenylacetic acid, 2-methoxy-4-(methylthio)-benzoic acid, 2-methoxy-4-nitrobenzoic acid, 2-methoxyphenylacetic acid, 2-methyl-1-cyclohexane-carboxylic acid (cis and trans), 2-methyl- 2-methyl-3-nitrobenzoic acid, 2-methyl-3-phenylpropanoic acid, 2-methyl-4-oxo-4-phenylbutyric acid, 2-methyl-6-nitrobenzoic acid, 2-methylbutyric acid, 2-methylcinnamic acid, 2-methylcyclopropane-carboxylic acid (cis and trans), 2-methylhexanoic acid, 2-methylhippuric acid, 2-methylhydrocinnamic acid, 2-methylvaleric acid, 2-naphthoic acid, 2-naphthylacetic acid, 2-nitro-4-(trifluoromethyl)benzoic acid, 2-nitrobenzoic acid, 2-norbornaneacetic acid, 2-oxo so-6-pentyl-2H-pyran-3-carboxylic acid, 2-phenoxybenzoic acid, 2-phenoxybutyric acid, 2-phenoxypropionic acid, 2-propylpentanoic acid, 2-quinoxalinecarboxylic acid, 2-thiopheneacetic acid, 2-thiopheneglyoxylic acid, 3-(2-hydroxyphenyl)propionic acid, 3-(2-thienyl)acrylic acid, 3-(3,4,5-trimethoxyphenyl)-propionic acid, 3-(3,4-dimethoxyphenyl)-propionic acid, 3-(3-hydroxy-2,4,6-triiodophenyl)pentanoic acid, 3-(3-hydroxyphenyl)-propionic acid, 3-(3-methoxyphenyl)propionic acid, 3-(4-chlorobenzoyl)propionic acid, 3-(4-fluorobenzoyl)propionic acid, 3-(4-hydroxyphenyl)propionic acid, 3-(phenylsulfonyl)propionic acid, 3-(trifluoromethyl)cinnamic acid, 3-(trimethylsilyl)propynoic acid, 3,3,3-triphenylpropionic acid, 3,4-(methylenedioxy)cinnamic acid, 3,4-(methylenedioxy)phenyl-acetic acid, 3,4-dichlorobenzoic acid, 3,4-dichlorophenoxyacetic acid, 3,4-diethoxybenzoic acid, 3,4-difluorobenzoic acid, 3,4-dihydroxybenzoic acid, 3,4-dihydroxy Hydrocinnamic acid, 3,4-dihydroxyphenylacetic acid, 3,5,6-trichlorosalicylic acid, 3,5-bis(trifluoromethyl)-phenylacetic acid, 3,5-dibromobenzoic acid, 3,5-dichlorosalicylic acid, 3,5-difluorocinnamic acid, 3,5-dihydroxy-2-naphthoic acid, 3,5-dinitrobenzoic acid, 3,5-dinitro-o-toluic acid, 3,5-dinitro-p-toluic acid, 3,5-dinitrosalicylic acid, 3,5-di-tert-butyl-4-hydroxy-benzoic acid, 3,5-di-tert-butylbenzoic acid, 3,7-dihydroxy-2-naphthoic acid, 3-thiopheneacetic acid, 3-benzoyl-2-pyridine-carboxylic acid, 3-benzoylbenzoic acid, 3-bromo-4-fluorobenzoic acid (95%), 3-bromo, 4-methylbenzoic acid, 3-bromo-5-iodobenzoic acid, 3-bromobenzoic acid, 3-bromocinnamic acid, 3-carboxy-proxyl, 3-chloro-2-nitrobenzoic acid, 3-chloro-4-fluorobenzoic acid, 3-chloro-4-hydroxyphenyl-acetic acid, 3-chlorosalicylic acid, 3-cyanobenzoic acid, 3-fluoro-2-methylbenzoic acid, 3-fluoro-4-hydroxy-phenylacetic acid, 3-fluoro-4-methoxybenzoic acid, 3-fluoro Fluorophenylacetic acid, 3-furoic acid, 3-hydroxy-2-naphthoic acid, 3-hydroxy-2-quinoxaline-carboxylic acid, 3-hydroxy-4-methoxybenzoic acid, 3-hydroxy-4-methoxy-cinnamic acid, 3-hydroxy-4-nitrobenzoic acid, 3-hydroxybenzoic acid, 3-hydroxybutyric acid, 3-hydroxyphenylacetic acid, 3-indolebutyric acid, 3-indoleglyoxylic acid, 3-indolepropionic acid, 3-iodo-4-methyl 3-aminobenzoic acid, 3-iodobenzoic acid, 3-isoquinolinecarboxylic acid hydrate, 3-methoxy-4-nitrobenzoic acid, 3-methoxycyclohexane-carboxylic acid (cis and trans), 3-methyl-2-phenylvaleric acid, 3-methylhippuric acid, 3-methylindene-2-carboxylic acid, 3-methylsalicylic acid, 3-methylvaleric acid, 3-nitrobenzoic acid, 3-nitrophenylacetic acid, 3-nitropropionic acid, 3-noradamantanecarboxylic acid, 3- Oxo-1-indancarboxylic acid, 3-phenoxybenzoic acid, 3-phenylbutyric acid, 3-p-tolylpropanoic acid, 3-thiophenecarboxylic acid, 4-(1,3-dioxoisoindolin-2-yl)-2-hydroxybutanoic acid, 4-(2,4,5-trichlorophenoxy)-butyric acid, 4-(2,4-dichlorophenoxy)-butyric acid, 4-(2,4-di-tert-pentylphenoxy)butyric acid, 4-(2-phenoxyethoxy)benzoic acid, 4-(3,4-dimethoxyphenyl)-butyric acid, 4-(4-methoxyphenyl)butyric acid, 4-(4-nitrophenyl)butyric acid, 4-(diethylamino)benzoic acid, 4-(dimethylamino)cinnamic acid, 4-(dimethylamino)phenyl-acetic acid, 4-(ethylthio)benzoic acid, 4-(hydroxymethyl)benzoic acid, 4-(methylsulfonyl)benzoic acid, 4-(methylthio)benzoic acid, 4-(methylthio)phenylacetic acid, 4-(trifluoromethoxy)benzoic acid, 4'-(trifluoromethyl)biphenyl-2 -carboxylic acid, 4-(trifluoromethyl)mandelic acid, 4,4,4-trifluoro-3-methyl-2-butenoic acid, 4,4-bis(4-hydroxyphenyl)-valeric acid, 4,5-dimethoxy-2-nitrobenzoic acid, 4,6-dioxoheptanoic acid, 4-[4-(2-carboxybenzoyl)-phenyl]butyric acid, 4-acetamidobenzoic acid, α-acetylbenzoic acid, 4-acetylphenoxyacetic acid, 4-benzyloxy-3-methoxyphenyl-acetic acid, 4-biphenylacetic acid, 4-bromo-3,5 -dihydroxy-benzoic acid, 4-bromobenzoic acid, 4-bromocinnamic acid, 4-bromophenylacetic acid, 4-butoxybenzoic acid, α-butoxyphenylacetic acid, 4-butylbenzoic acid, 4-chloro-2,5-difluorobenzoic acid, 4-chloro-3-sulfamoylbenzoic acid, 4-chlorobenzoic acid, 4-chloro-o-tolyloxyacetic acid, α-chlorophenylacetic acid, 4-chlorosalicylic acid, 4-ethoxycarbonyloxy-3,5-dimethoxybenzoic acid, 4-ethoxyphenylacetic acid, 4-ethylbenzo carboxylic acid, 4'-ethylbiphenyl-4-carboxylic acid, 4-fluorenecarboxylic acid, 4-fluoro-1-naphthoic acid, α-fluoro-2-(trifluoromethyl)-benzoic acid, 4-fluoro-3-nitrobenzoic acid, 4-fluorobenzoic acid, 4-fluorobenzoic acid, 4-fluorocinnamic acid, 4-fluorophenoxyacetic acid, α-heptyloxybenzoic acid, 4-hexylbenzoic acid, 4-hexyloxybenzoic acid, 4-hydroxy-3-(morpholino-methyl)benzoic acid hydrate, 4-hydroxy-3,5-Dinitrobenzoic acid, 4-hydroxy-3-methoxy-benzoic acid, 4-hydroxy-3-methoxy-mandelic acid, 4-hydroxy-3-nitrobenzoic acid, 4-hydroxy-3-nitrophenylacetic acid, 4-hydroxybenzoic acid, 4'-hydroxybiphenyl-4-carboxylic acid, 4-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid, α-hydroxyphenylpyruvic acid, 4-iodobenzoic acid, 4-isopropoxybenzoic acid, 4-methoxy-3-nitrobenzoic acid, 4-methoxycyclohexane-carboxylic acid, 4-methoxy Cisalicylic acid, 1-methyl-1-cyclohexane-carboxylic acid (cis and trans), 4-methyl-3-nitrobenzoic acid, α-methylhippuric acid, 4-methylsalicylic acid, 4-methylvaleric acid, 4-nitro-3-pyrazolecarboxylic acid, 4-nitrohippuric acid, 4-nonyloxybenzoic acid, 4-octylbenoic acid, 4-oxo-4H-1-benzopyran-2-carboxylic acid, 4-oxo-6-phenyl-5-hexenoic acid, α-pentenoic acid, 4-pentylbenzoic acid, 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid, α- Pentyloxybenzoic acid, 4-pentynoic acid, 4-phenylbutyric acid, 4-propoxybenzoic acid, 4-propylbenzoic acid, 4-pyrazolecarboxylic acid, 4-tert-butylbenzoic acid, 4-tert-butylcyclohexanecarboxylic acid, 4-vinylbenzoic acid, 5-(4-chlorophenyl)-2-furoic acid, 5,6-dichloronicotinic acid, 5-bromo-2,4-dihydroxybenzoic acid, 5-fluoro-2-methylbenzoic acid, 5-fluoroindole-2-carboxylic acid, 5-fluorosalicylic acid, 5-hydantoinacetic acid, 5-hydroxy- 2-Indole-carboxylic acid, 5-methoxy-1-indanone-3-acetic acid, 5-methoxy-2-methyl-3-indoleacetic acid, 5-methoxy-2-nitrobenzoic acid, 5-methoxysalicylic acid, 5-methyl-2-nitrobenzoic acid, 5-methyl-2-pyrazine-carboxylic acid, 5-nitro-2-furoic acid, 5-nitro-3-pyrazolecarboxylic acid, 5-phenylvaleric acid, 6-(carbobenzyloxyamino)-caproic acid, 6-acetamidohexanoic acid, 6-bromohexanoic acid, 6-chloronicotinic acid, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, 6-methylchromone-2-carboxylic acid, 6-methylnicotinic acid, 6-nitrocaproic acid, 6-oxoheptaoic acid, 6-phenylhexanoic acid, 7-(carboxymethyoxy)-4-methylcoumarin, 7-hydroxycoumarin-4-acetic acid, 7-methoxy-2-benzofuran-carboxylic acid, 7-methoxycoumarin-4-acetic acid, 7-oxooctanoic acid, 9-anthracenecarboxylic acid, 9-fluoreneacetic acid, 9-fluorenone-1-carboxylic acid, α,α,α-trifluoro-m-toluic acid, α-acetamidocinnamic acid, abietic acid, acetic acid, acetyl-L-asparagine, acetylsalicylic acid, α-cyano-4-hydroxycinnamic acid, adipic acid monoethyl ester, α-hydroxyhippuric acid, anthranilic acid, anti-3-oxotricyclo[2.2.1.0, ２，６ ]heptane-7-carboxylic acid, α-phenylcyclopentaneacetic acid, α-phenyl-o-toluic acid, atrolactic acid, benzilic acid, benzotriazole-5-carboxylic acid, benzoylformic acid, bis(4-chlorophenyl)acetic acid, carbobenzyloxy-DL-alanine, carbobenzyloxy-L-alanine, carbobenzyloxy-1-glutamine, carbobenzyloxy-L-valine, cis-2-methoxycinnamic acid, crotonic acid, cyclohexanebutyric acid, cyclohexanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanepropionic acid Acid, Cyclopentylacetic acid, D,L-3,4-dihydroxymandelic acid, D-3-phenyllactic acid, Decanoic acid, Dicyclohexylacetic acid, Diethylphosphonoacetic acid, Dikeglac hydrate, Diphenylacetic acid, Fumaric acid monoethyl ester, Fusaric acid, Gallic acid, Gelanic acid, Glycolic acid, Heptadecafluorononanoic acid, Heptanoic acid, Hexanoic acid, Hippuric acid, Hydrocinnamic acid, Indole-3-carboxylic acid, Indole-4-carboxylic acid, Isovaleric acid, L-3-phenyllactic acid, Lauric acid, L-Lactic acid (85%), Maleamic acid, Methoxyacetic acid, Phthalic acid mono- (1R)-(-)-Menthyl, mono-(1S)-(+)-menthyl phthalate, monomethyl cis-5-norbornene-endo-2,3-dicarboxylate, monomethyl phthalate, monomethyl terephthalate, N-(2-furoyl)glycine, N-(3,5-dinitrobenzoyl)-DL-α-phenylglycine, N-(3-indolylacetyl)-L-alanine, N-(3-indolylacetyl)-L-isoleucine, N-(3-indolylacetyl)-L-leucine, N-(3-indolylacetyl)-L-phenylalanine, N-(3-indolylacetyl)-L-phenylalanine, N-acetyl)-L-valine, N-(carbobenzyloxy)-1-phenyl-alanine, N,N-diethyl-3,6-difluoro-phthalamic acid, N-[(R)-1-(1-naphthyl)ethyl]-phthalamic acid, N-[5-(trifluoromethyl)-2-pyridyl]-L-valine, N-acetyl-4-fluoro-DL-phenylalanine, N-acetyl-DL-tryptophan, N-acetyl-1-leucine, N-acetyl-L-methionine, N-acetyl-L-phenylalanine, N-acetyl-1-tyrosine, N-benzoyl-(2R,3S)-3-Phenyl-isoserine, N-benzoyl-L-threonine, N-carbobenzyloxy-2-methyl-alanine, N-carbobenzyloxy-L-glutamic acid 1-methyl ester, N-carbobenzyloxy-L-isoleucine, N-carbobenzyloxy-L-leucine, N-carbobenzyloxy-1-threonine, N-ethoxycarbonyl-1-phenylalanine, nonanoic acid, N-p-tosylglycine, N-p-tosyl-L-phenylalanine, o-anisic acid, p-anisic acid, pentafluorobenzoic acid, phenoxyethanol Cinnamic acid, phenylacetic acid, podocarpic acid, pyruvic acid, rhodanine-3-acetic acid, S-(thiobenzoyl)thioglycolic acid, S-benzyl-N-carbobenzyloxy-1-cysteine, sebacic acid monomethyl ester, succinamic acid, succinic acid 2,2-dimethylhydrazide, tetrahydro-2-furoic acid, trans-1-acetyl-4-hydroxy-L-proline, trans-2,3-dimethoxycinnamic acid, trans-2,4-dichlorocinnamic acid, trans-2,4-difluorocinnamic acid, trans-2,5-difluorocinnamic acid Olocinnamic acid, trans-2,6-difluorocinnamic acid, trans-2-chloro-6-fluoro-cinnamic acid, trans-2-hexenoic acid, trans-3-(2,3,5,6-tetramethyl-benzoyl)acrylic acid, trans-3-(2,5-dimethylbenzo-yl)-acrylic acid, trans-3-(4-ethoxy-benzoyl)acrylic acid, trans-3-(4-methoxybenzoyl)-acrylic acid, trans-3-(4-methylbenzoyl)-acrylic acid, trans-3,4-difluorocinnamic acid, trans R, is selected from the group consisting of trans-3-fluorocinnamic acid, trans-3-furanacrylic acid, trans-3-hexenoic acid, trans-4-chloro-3-nitrocinnamic acid, trans-4-hydroxy-3-methoxy-cinnamic acid, trans-4-methyl-1-cyclohexanecarboxylic acid, trans-4-pentylcyclohexanecarboxylic acid, trans-5-bromo-2-methoxycinnamic acid, trans-styrylacetic acid, tridecafluoroheptanoic acid, trimethylacetic acid, triphenylacetic acid, valeric acid, and yohimbic acid monohydrate; １ and R ２ The compound of claim 1 , wherein

4. A compound of formula (II) or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer thereof: 【Transformation 6】 (In the formula, R １ and R ２ are each independently a residue of a carboxylic acid or a pharmaceutically acceptable salt thereof; R １ and R ２ may be the same or different).

5. The carboxylic acid is represented by the formula RCOOH, wherein R is selected from the group consisting of hydrogen, an aliphatic group, or an aromatic group, the aliphatic group being saturated or unsaturated, and the aliphatic group or the aromatic group being selected from the group consisting of C １ ~C ２４ Alkyl, C １ ~C ２４ Alkenyl, C １ ~C ２４ alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl, wherein the R group is １ ~C ２４ Alkyl, hydroxy, alkoxy, cyano, halo, nitro, aryl, amino, C １ ~C ２４ Alkenyl, C １ ~C ２４ 5. The compound of claim 4, optionally substituted with at least one of the group selected from alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl.

6. R １ or R ２ but, 【Transformation 7】 5. The compound of claim 4, wherein:

7. R １ or R ２ but, 【Transformation 8】 5. The compound of claim 4, wherein:

8. R １ or R ２ but, 【Chemistry 9】 5. The compound of claim 4, wherein: [Request Item 9] [Chemistry 10] 6. The compound of claim 4 or 5, which is: or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof.

10. A compound of formula (III) or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof: 【Chemistry 11】 (In the formula, R １ and R ２ are each independently a residue of a carboxylic acid or a pharmaceutically acceptable salt thereof; R １ and R ２ may be the same or different, L is, Table 2 is a linker selected from the group consisting of w is 1 to 5, x is 1 to 15, a and b are each independently 0 to 3, 【Chemistry 12】 The bond indicated by is attached to B and ＊ The bond indicated by " is R ９ represents the point of attachment of B is B １ , B ２ , and B ３ represented by a structure selected from B １ is the structure: 【Chemistry 13】 is represented by R ３ａ is fluoro, hydrogen, or deuterium, B ２ is the structure: 【Chemistry 14】 is represented by R ３ｂ is fluoro, hydrogen, or deuterium, B ３ is the structure: 【Chemistry 15】 is represented by R ４ is methyl, hydrogen, or deuterium).

11. The carboxylic acid is represented by the formula RCOOH, wherein R is selected from the group consisting of hydrogen, an aliphatic group, or an aromatic group, the aliphatic group being saturated or unsaturated, and the aliphatic group or the aromatic group being selected from the group consisting of C １ ~C ２４ Alkyl, C １ ~C ２４ Alkenyl, C １ ~C ２４ alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl, wherein the R group is １ ~C ２４ Alkyl, hydroxy, alkoxy, cyano, halo, nitro, aryl, amino, C １ ~C ２４ Alkenyl, C １ ~C ２４ 11. The compound of claim 10, optionally substituted with at least one of the group selected from alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl.

12. B is B ３ 【Chemistry 16】 and R ４ The compound of claim 10 , wherein is methyl, hydrogen, or deuterium.

13. R １ or R ２ but, 【Chemistry 17】 11. The compound of claim 10, selected from:

14. The linker L is [Chemistry 18] 11. The compound of claim 10, selected from: 【Request Item 15】 【Table 3-1】 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21 or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof 15. The compound of any one of claims 10 to 14, wherein

16. 4. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 3, or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof, and a pharmaceutically acceptable carrier or excipient.

17. 10. A pharmaceutical composition comprising one or more compounds according to any one of claims 4 to 9, or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof, and a pharmaceutically acceptable carrier or excipient.

18. 15. A pharmaceutical composition comprising one or more compounds according to any one of claims 10 to 14, or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof, and a pharmaceutically acceptable carrier or excipient.

19. 19. A method of treating or preventing cancer in a patient, said method comprising the step of administering to said patient in need thereof an effective amount of a compound of any one of claims 1 to 3 or a pharmaceutical composition of claim 16, thereby inhibiting or degrading dual protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TC-PTP), thereby treating or preventing said cancer in said patient.

20. 20. The method of claim 19, wherein the cancer is colon cancer, lung adenocarcinoma, squamous cell carcinoma, or melanoma.

21. 20. The method of claim 19, wherein the compound is administered orally.

22. 19. A method of treating or preventing cancer in a patient, said method comprising the step of inhibiting a dual PTP1B and TC-PTP inhibitor by administering to said patient in need thereof an effective amount of a compound of any one of claims 4 to 9 or a pharmaceutical composition of claim 17, thereby treating or preventing said cancer in said patient.

23. 23. The method of claim 22, wherein the cancer is colon cancer, lung adenocarcinoma, squamous cell carcinoma, or melanoma.

24. 23. The method of claim 22, wherein the compound is administered orally.

25. 19. A method of treating or preventing cancer in a patient, said method comprising the step of administering to said patient in need thereof an effective amount of a compound of any one of claims 10 to 14 or a pharmaceutical composition of claim 18, thereby degrading dual PTP1B and TC-PTP proteins, thereby treating or preventing said cancer in said patient.

26. 26. The method of claim 25, wherein the cancer is colon cancer, lung adenocarcinoma, squamous cell carcinoma, or melanoma.

27. 26. The method of claim 25, wherein the compound is administered orally.

28. 19. A method for treating or preventing type II diabetes in a patient, said method comprising the step of administering to said patient in need thereof an effective amount of a compound of any one of claims 1 to 3 or a pharmaceutical composition of claim 16, thereby inhibiting or degrading dual PTP1B and TC-PTP, thereby treating or preventing said type II diabetes in said patient.

29. 19. A method of treating or preventing type II diabetes in a patient, said method comprising the step of inhibiting a dual PTP1B and TC-PTP inhibitor by administering to said patient in need thereof an effective amount of a compound of any one of claims 4 to 9 or a pharmaceutical composition of claim 17, thereby treating or preventing said type II diabetes in said patient.

30. 19. A method of treating or preventing type II diabetes in a patient, said method comprising the step of administering to said patient in need thereof an effective amount of a compound of any one of claims 10 to 14 or a pharmaceutical composition of claim 18, thereby degrading dual PTP1B and TC-PTP proteins, thereby treating or preventing said type II diabetes in said patient.

31. 19. A method for treating or preventing obesity in a patient, said method comprising the step of administering to said patient in need thereof an effective amount of a compound of any one of claims 1 to 3 or a pharmaceutical composition of claim 16, thereby inhibiting or degrading dual PTP1B and TC-PTP, thereby treating or preventing said obesity in said patient.

32. 19. A method of treating or preventing obesity in a patient, said method comprising the step of inhibiting a dual PTP1B and TC-PTP inhibitor by administering to said patient in need thereof an effective amount of a compound of any one of claims 4 to 9 or a pharmaceutical composition of claim 17, thereby treating or preventing said obesity in said patient.

33. 19. A method for treating or preventing obesity in a patient, said method comprising the step of administering to said patient in need thereof an effective amount of a compound of any one of claims 10 to 14 or a pharmaceutical composition of claim 18, thereby degrading dual PTP1B and TC-PTP proteins, thereby treating or preventing said obesity in said patient.

34. 19. A method of inhibiting or degrading dual PTP1B and TC-PTP in a patient, said method comprising administering to said patient in need thereof an effective amount of a compound of any one of claims 1 to 14 or a pharmaceutical composition of any one of claims 16 to 18, such that dual PTP1B and TC-PTP are inhibited or degraded in said patient.

35. 35. The method of claim 34, wherein the patient has colon cancer, lung adenocarcinoma, squamous cell carcinoma, or melanoma.

36. 35. The method of claim 34, wherein the patient has type II diabetes.

37. 35. The method of claim 34, wherein the patient is obese.

38. 10. Use of a compound according to any one of claims 1 to 9 in the treatment of a disease or condition treatable by inhibiting a dual PTP1B or TC-PTP protein.

39. 39. The use of claim 38, wherein the disease or condition is cancer, type II diabetes, or obesity.

40. 16. Use of a compound according to any one of claims 1 to 3 or 10 to 14 in the treatment of a disease or condition treatable by degrading a dual PTP1B or TC-PTP protein.

41. 41. The use of claim 40, wherein the disease or condition is cancer, type II diabetes, or obesity.

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