PTP1B / TC-PTP dual inhibitor and protein degradation agent

Abstract

The present disclosure relates to compounds that are dual inhibitors and dual degradation agents of protein tyrosine phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TC-PTP); compositions comprising the compounds; and their use in the treatment of diseases or conditions mediated by PTP1B and TC-PTP.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 443,582, filed February 6, 2023, the entire contents of which are incorporated herein by reference.

[0003] Statement as to Government Support

[0004] This invention was developed with government funding under license number CA069202 from the National Institutes of Health (NIH). The government holds certain rights to this invention. Technical Field

[0005] This disclosure relates to inhibitors of dual protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TC-PTP), as well as PTP1B and TC-PTP protein degraders and their use in the treatment of cancer and other diseases. Background Technology

[0006] This section provides information to help in a better understanding of aspects of this disclosure. Therefore, these statements should be understood in this context and should not be construed as an admission of what is or is not prior art.

[0007] Protein tyrosine phosphorylation is a crucial post-translational modification controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), playing a vital role in regulating essential cellular functions. Given that many human diseases are associated with abnormal protein tyrosine phosphorylation, both PTKs and PTPs are highly favored targets in drug development. Among the PTP family members, protein tyrosine phosphatase 1B (PTP1B, also known as PTPN1) and T-cell protein tyrosine phosphatase (TC-PTP, also known as PTPN2) are two of the most closely related cytoplasmic PTPs, sharing over 72% amino acid sequence identity between their catalytic domains. Despite their structural similarities, PTP1B and TC-PTP play non-redundant and synergistic roles in coordinating multiple important signaling pathways.

[0008] PTP1B and TC-PTP have long been considered to play a synergistic role in regulating both insulin and leptin-mediated cellular processes. PTP1B negatively modulates the intensity of insulin action by dephosphorylating the insulin receptor and insulin receptor substrate 1, while TC-PTP catalyzes the dephosphorylation of the insulin receptor to limit the duration of insulin signaling. PTP1B and TC-PTP also attenuate leptin signaling by dephosphorylating JAK2 and STAT3, respectively.

[0009] PTP1B and TC-PTP play non-redundant roles in attenuating IFN-g signaling. Abrogation of PTP1B increases JAK2 phosphorylation and enhances IFN-g-mediated STAT1 activation, whereas removal of TC-PTP from tumor cells enhances IFN-g signaling and antigen presentation due to increased phosphorylation of JAK1 and its downstream effector STAT1. Notably, PTP1B and TC-PTP also function as negative regulators of T cell activation. To this end, deletion of PTP1B in T cells promotes antigen-induced CD8 + T cell expansion and its cytotoxicity against solid tumors. Genetic deletion of TC-PTP in T cells enhances CD8 + T cell expansion and survival and promotes CD8 + T cell activation.

[0010] Based on the roles of PTP1B and TC-PTP in cell signaling, simultaneous targeting of both enzymes can have synergistic effects on multiple therapeutic applications, including type II diabetes, obesity, and anti-cancer immunotherapy. However, combination therapy is prone to complex pharmacokinetic / pharmacodynamic, unexpected drug interactions, toxicity, and / or patient compliance issues. Polypharmacology, i.e., the design or use of multi-target compounds that act on two or more selected targets, has attracted wide attention in the field of drug development due to the increasing understanding of the complexity of multifactorial human diseases (Anighoro, A. et al., 2014, J. Med. Chem. 57, 7874-7887). Multi-target drugs or multi-target ligands offer a valuable alternative with multiple advantages, such as better therapeutic efficacy, lower risk of drug interactions, more predictable pharmacokinetic / pharmacodynamic profiles, and simplified treatment regimens, compared to single-target drugs or polypharmacy.

[0011] Therefore, there is an unmet need for PTP1B / TC-PTP dual inhibitors and PTP1B / TC-PTP dual degraders with physical and pharmacological properties that enable their use in therapeutic applications for treating diseases. It is an object of the present disclosure to provide such compounds. The objects, advantages and other objects, advantages, and features of the present application will be apparent from the detailed description provided herein. SUMMARY

[0012] Provided is a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof:

[0013]

[0014] wherein

[0015] R1and R2are each independently a carboxylic acid residue or a pharmaceutically acceptable salt thereof, wherein R1and R2may be the same or different;

[0016] R3, R4, R5, R6, R7, and R8are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene, 4-6 membered heterocyclyl, and -C1-C6alkylene-4-6 membered heterocyclyl, wherein C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene, 4-6 membered heterocyclyl, and -C1-C6alkylene-4-6 membered heterocyclyl are optionally substituted on one or more available carbons by one or more substituents each independently selected from deuterium, halogen, hydroxyl, C=O, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C6cycloalkyl, -C1-C6-alkylene-C3-C6cycloalkyl, C1-C6alkyl-S(O)2-, C3-C6cycloalkyl-S(O)2-, C1-C6alkyl-C(O)-, C1-C6alkoxy-C(O)-, -NH-C(O)-R a and -C(O)-NH-R a wherein R a is C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene, 4-6 membered heterocyclyl, and -C1-C6alkylene-4-6 membered heterocyclyl, which is optionally substituted on one or more available carbon atoms by one or more substituents each independently selected from deuterium, halogen, hydroxyl, C=O, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C6cycloalkyl, -C1-C6-alkylene-C3-C6cycloalkyl, C1-C6alkyl-S(O)2-, C1-C6cycloalkyl-S(O)2-, C1-C6alkyl-C(O)-, C1-C6alkoxy-C(O)-, -NH-C(O)-R b and -C(O)-NH-R b wherein R b is independently selected from deuterium, halogen, hydroxyl, C=O, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C6cycloalkyl, -C1-C6-alkylene-C3-C6cycloalkyl, C1-C6alkyl-S(O)2-, C3-C6cycloalkyl-S(O)2-, C1-C6alkyl-C(O)-, and C1-C6alkoxy-C(O)-;

[0017] t is 0 to 6;

[0018] R9is H or a group represented by the formula L-B, wherein L is a linker selected from the group consisting of:

[0019]

[0020]

[0021] Where w is 1-5, x is 1-15, and a and b are each independently 0-3; marked with " The "" bond is connected to B; the bond marked with "*" represents the attachment point of R9; and B is selected from groups B1, B2, and B3, where B1 is represented by the following structure:

[0022]

[0023] Where R 3a It can be fluorine, hydrogen, or deuterium;

[0024] B2 is represented by the following structure:

[0025]

[0026] Where R 3b It is fluorine, hydrogen, or deuterium; and

[0027] B3 is represented by the following structure:

[0028]

[0029] R4 is methyl, hydrogen, or deuterium.

[0030] Compounds of formula (II), or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof, are also provided:

[0031]

[0032] R1 and R2 are defined as in equation (I) above.

[0033] In some implementations, R1 or R2 is:

[0034]

[0035] In some implementations, R1 or R2 is:

[0036]

[0037] In some implementations, R1 or R2 is:

[0038]

[0039] In some embodiments, the compound of formula (II) is:

[0040]

[0041] or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof.

[0042] Also provided are compounds of Formula (III), or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof:

[0043]

[0044] wherein R1, R2, L, and B are as defined above for Formula (I). In some embodiments, B is B3:

[0045]

[0046] wherein R4 is methyl, hydrogen, or deuterium.

[0047] In some embodiments, R1or R2is selected from:

[0048] In some embodiments, linker L is selected from:

[0049]

[0050] In some embodiments, the carboxylic acid in the compounds of Formulae (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 wherein the aliphatic group or the aromatic group is substituted with C1-C 24 alkyl, C1-C 24 alkenyl, C1-C 24 alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroaralkyl, aralkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl, wherein the R groups are optionally substituted with at least one group selected from C1-C 24 alkyl, hydroxyl, alkoxy, cyano, halogen, nitro, aryl, amino, C1-C 24 alkenyl, C1-C 24 alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroaralkyl, aralkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl.

[0051] In some embodiments, the carboxylic acid is selected from the group consisting of 3-dimethylaminobenzoic acid, 2-(2-cyanophenylsulfanyl)benzoic acid, 2-(4- chlorobenzoyl)benzoic acid, (-)-2-oxo-4-thiazolidine-carboxylic acid, (-)-N-acetylneuraminic acid, (+)-6-methoxy-alpha-methyl-2-naphthoic acid, (+)-benzyloxycarbonyl-D-proline, (+)-menthoxyacetic acid, (±)-2-(2-chlorophenoxy)propionic acid, (±)-1- methyl-2-cyclohexen-1-carboxylic acid, (1-naphthyloxy)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)-(+)-camphoric acid, (1S,3R,4S,5R)-1,3,4,5- tetrahydroxycyclohexanecarboxylic acid, (2,4-di-tert-amylphenoxy)acetic acid, (2- naphthyloxy)acetic acid, (2-pyrimidinylsulfanyl)acetic acid, (4-carboxybutyl)triphenylphosphonium bromide, (4-chlorophenylsulfanyl)acetic acid, (4-methylphenoxy)acetic acid, (alpha,alpha,alpha-trifluoro-m-tolyl)acetic acid, (E)-2-[(4-hydroxyphenyl)azo]- 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-pyrrolidinone-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-phenylpropionic 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-tetrahydrofurylcarboxylic 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)propionic acid, (S)-2-(phenylcarbamoyloxy)propionic acid, (S)-3-2-benzene dioo diacetic acid, 1,4-dihydro-2-methylbenzoic acid, 1,4-dihydroxy-2-naphthoic acid, 10-hydroxydecanoic acid, 10-undecynoic acid, 1-adamantane carboxylic acid, 1-cyano-1-cyclopropane carboxylic acid, 1-hydroxy-2-naphthoic acid, 1- isoquinoline carboxylic acid, 1-methyl-(1S,2R)-(+)-cis-1,2,3,6-tetrahydrophthalic acid, 1- methyl-1-cyclohexane carboxylic acid, 1-methyl-1H-indole-2-carboxylic acid, 1-methyl-2- pyrrole carboxylic acid, 1-methylcyclopropane carboxylic acid, 1-naphthoic acid, 1-phenyl-1- cyclopentane carboxylic acid, 1-phenyl-1-cyclopropane carboxylic acid, 1-pyrene acetic acid, 1- pyrene butyric acid, 1-pyrene carboxylic acid, 2-((1R,2R,3R,4S)-3-hydroxy-4,7,7- trimethylbicyclo[2.2.1]heptan-2-yl)acetic acid, 2-[(benzyloxy carbonyl)(methyl)amino]-2- methylpropanoic acid, 2-(2-(trifluoromethyl)phenyl)acetic acid, 2-(2,4,5-trichlorophenoxy)propanoic acid, 2-(2,4-dichlorophenoxy)propanoic acid, 2-(3,5-dinitrobenzamido)-2- phenylacetic acid, 2-(3,5-dinitrobenzamido)-4-methylpentanoic acid, 2-(3-chlorophenoxy)propanoic acid, 2-(4-(trifluoromethyl)phenyl)acetic acid, 2-(4-chloro-3-nitrobenzoyl)benzoic acid, 2-(4-chlorophenoxy)-2-methylpropanoic acid, 2-(4-chlorophenoxy)propanoic acid, 2-(4-fluorobenzoyl)benzoic acid, 2-(4-hydroxy-3- methoxyphenyl)acetic acid, 2-(4-hydroxyphenoxy)propanoic acid, 2-(4-isobutylphenyl)propanoic acid, 2-(4-nitrophenyl)propanoic acid, 2-(benzyloxy carbonyl amino)-3-(1H-indol-3- yl)propanoic acid, 2-(trifluoromethyl)propenoic acid, 2-(trifluoromethyl)benzoic acid, 2- (trifluoromethyl)cinnamic acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid, 2,2-bis(hydroxymethyl)propanoic acid, 2,3,4,5,6-pentafluorocinnamic acid, 2,3,4,5,6- pentafluorophenoxyacetic acid, 2,3,4,5,6-pentafluorophenylacetic 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-hydroxybenzoic 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, 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, 2,4,6-4-dichloro-5-sulfamoylbenzoic 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-bromo-3-nitrobenzoic acid, 2-bromo-4,5-dimethoxybenzoic acid, 2-bromo-5-methoxybenzoic acid, 2-bromo-5-nitrobenzoic acid, 2-bromopropenoic 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-(trifluoromethyl)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-hydroxybutanoic acid, 2-ethylbutanoic acid, 2-ethylhexanoic acid, 2-ethylthio-2,2-diphenylacetic 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-methylbutanoic acid, 2-hydroxy-6-isopropyl-3-methylbenzoic acid, 2-hydroxyhexanoic acid, 2-hydroxymandelic 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-cyclohexanecarboxylic acid (cis and trans), 2-methyl-3-nitrobenzoic acid, 2-methyl-3- phenylpropionic acid, 2-methyl-4-oxo-4-phenylbutanoic acid, 2-methyl-6- nitrobenzoic acid, 2-methylbutanoic acid, 2-methylcinnamic acid, 2- methylcyclopropanecarboxylic acid (cis and trans), 2-methylhexanoic acid, 2- methylmandelic acid, 2-methylpentanoic 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-phenoxybutanoic acid, 2-phenoxypropanoic acid, 2- propylpentanoic acid, 2-quinoxalinecarboxylic acid, 2-thiopheneacetic acid, 2- thiopheneacetic acid, 2-thiopheneacetic acid, 3-(2-hydroxyphenyl)propionic acid, 3-(2-thienyl)propenoic 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)phenylacetic acid, 3,4- dichlorobenzoic acid, 3,4-dichlorophenoxyacetic acid, 3,4-diethoxybenzoic acid, 3,4-difluorobenzoic acid, 3,4-dihydroxybenzoic acid, 3,4-dihydroxyhydrocinnamic 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, 3,5-5-di-tert-butylbenzoic acid, 3,7-dihydroxy-2-naphthoic acid, 3-thiopheneacetic acid, 3-benzoyl-2-pyridinecarboxylic 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-proxazole, 3-chloro-2-nitrobenzoic acid, 3-chloro-4-fluorobenzoic acid, 3-chloro-4-hydroxyphenylacetic acid, 3-chlorosalicylic acid, 3-cyanobenzoic acid, 3-fluoro-2-methylbenzoic acid, 3-fluoro-4-hydroxyphenylacetic acid, 3-fluoro-4-methoxybenzoic acid, 3-fluorophenylacetic acid, 3-furan carboxylic acid, 3-hydroxy-2-naphthoic acid, 3-hydroxy-2-quinoxalinecarboxylic acid, 3-hydroxy-4-methoxybenzoic acid, 3-hydroxy-4-methoxycinnamic acid, 3-hydroxy-4-nitrobenzoic acid, 3-hydroxybenzoic acid, 3-hydroxybutyric acid, 3-hydroxyphenylacetic acid, 3-indolebutyric acid, 3-indoleglycolic acid, 3-indolepropionic acid, 3-iodo-4-methylbenzoic acid, 3-iodobenzoic acid, 3-isoquinolinecarboxylic acid hydrate, 3-methoxy-4-nitrobenzoic acid, 3-methoxycyclohexanecarboxylic 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-noradamantane carboxylic acid, 3-oxo-1-indene carboxylic acid, 3-phenoxybenzoic acid, 3-phenylbutyric acid, 3-p-tolylpropionic acid, 3-thiophenecarboxylic acid, 4-(1,3-dioxoisoindoline-2-yl)-2-hydroxybutyric acid, 4-(2,4,5-trichlorophenoxy)butyric acid, 4-(2,4-dichlorophenoxy)butyric acid, 4-(2,4-di-tert-amylphenoxy)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)phenylacetic 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-acetylb enzoic acid, 4-acetylphenoxyacetic acid, 4-benzyloxy-3-methoxyphenylacetic 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-ethylbenzoic acid, 4'-ethylbiphenyl-4-carboxylic acid, 4- fluorenecarboxylic acid, 4-fluoro-1-naphthoic acid, a-fluoro-2-(trifluoromethyl)benzoic acid, 4-fluoro-3-nitrobenzoic acid, 4-fluorobenzoic acid, 4-fluorobenzoic acid, 4-fluorocinnamic acid, 4-fluorophenoxyacetic acid, a-heptyloxybenzoic acid, 4-hexylbenzoic acid, 4-hexyloxybenzoic acid, 4-hydroxy-3-(morpholinomethyl)benzoic acid hydrate, 4-hydroxy-3,5-dinitrobenzoic acid, 4-hydroxy-3-methoxybenzoic acid, 4-hydroxy-3-methoxymandelic 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, a-hydroxyphenylpyruvic acid, 4-iodobenzoic acid, 4-isopropoxybenzoic acid, 4-methoxy-3-nitrobenzoic acid, 4-methoxycyclohexanecarboxylic acid, 4-methoxysalicylic acid, a-methyl-1-cyclohexanecarboxylic acid (cis and trans), 4-methyl-3-nitrobenzoic acid, a-methylhippuric acid, 4-methylsalicylic acid, 4-methylvaleric acid, 4-nitro-3-pyrazolecarboxylic acid, 4-nitrohippuric acid, 4-nonyloxybenzoic acid, 4-octylbenzoic acid, 4-oxo-4H-1-benzopyran-2-carboxylic acid, 4-oxo-6-phenyl-5-hexenoic acid, a-pentenoic acid, 4-pentylbenzoic acid, 4-pentyldicyclo[2.2.2]octane-1-carboxylic acid, a-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-furan carboxylic 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-hydantoinic acid, 5-hydroxy-2-indolecarboxylic 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-pyrazinecarboxylic acid, 5-nitro-2-furan carboxylic acid, 5-nitro-3-pyrazolecarboxylic acid, 5-phenylvaleric acid, 6-(benzyloxycarbonylamino)hexanoic 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-nitrohexanoic acid, 6-oxoheptanoic acid, 6-phenylhexanoic acid, 7-(carboxymethyloxy)-4-methylcoumarin, 7-hydroxycoumarin-4-acetic acid, 7-methoxy-2-benzofurancarboxylic acid, 7-methoxycoumarin-4-acetic acid, 7-oxooctanoic acid, 9-anthracene carboxylic acid, 9-fluoreneacetic acid, 9-fluoren-1-carboxylic acid, α,α,α-trifluorom-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-hydroxymandelic acid, anthranilic acid, trans-3-oxotricyclo[2.2.1.02'6]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, benzyloxycarbonyl-DL-alanine, benzyloxycarbonyl-L-alanine, benzyloxycarbonyl-L-glutamine, benzyloxycarbonyl-L-valine, cis-2-methoxycinnamic acid, crotonic acid, cyclohexanebutyric acid, cyclohexanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanepropionic acid, cyclopentylacetic acid, D,L-3,4-dihydroxymandelic acid, D-3-phenyllactic acid, decanoic acid, dicyclohexylacetic acid, diethylphosphonoacetic acid, dihydroxyfumaric acid hydrate, diphenylacetic acid, fumaric acid monoethyl ester, fusaric acid, gallic acid, geranic acid, glycolic acid, heptadecafluorononanoic acid, heptanoic acid, hexanoic acid, hippuric acid, hydrogenated cinnamic 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, mono-(1R)-(-)-menthyl phthalate, mono-(1S)-(+)-menthyl phthalate, cis-5-norbornene-inn-2,3-dicarboxylic acid monomethyl ester, phthalic acid monomethyl ester, terephthalic acid monomethyl ester, N-(2-furoyl)glycine, N-(3,5-dinitrobenzoyl)-DL-α-phenylglycine, N-(3-indoleacetyl)-L-alanine, N-(3-indoleacetyl)-L-isoleucine, N-(3-indoleacetyl)-L-leucine, N-(3-indoleacetyl)-L-phenylalanine, N-(3-indoleacetyl)-L-valine, N-(benzyloxycarbonyl)-L-phenylalanine, N,N-diethyl-3,6-difluorophthalamic acid, N-[(R)-1-(1-naphthyl)ethyl]phthalamic acid, N-[5-(trifluoromethyl)-2-pyridinyl]-L-valine, N-acetyl-4-fluoro-DL-phenylalanine, N-acetyl-DL-tryptophan, N-acetyl-L-leucine, N-acetyl-L-methionine, N-acetyl-L-phenylalanine, N-acetyl-L-tyrosine, N-benzoyl-(2R,3(S)-3-phenylisoserine, N-benzoyl-L-threonine, N-benzyloxycarbonyl-2- methylalanine, N-benzyloxycarbonyl-L-glutamic acid 1 -methyl ester, N- benzyloxycarbonyl-L-isoleucine, N-benzyloxycarbonyl-L-leucine, N- benzyloxycarbonyl-L-threonine, N-ethoxycarbonyl-L-phenylalanine, nonanoic acid, N-p-toluenesulfonylglycine, N-p-toluenesulfonyl-L-phenylalanine, o-anisic acid, p-anisic acid, pentafluorobenzoic acid, phenoxyacetic acid, phenylacetic acid, podocarpic acid, pyruvic acid, rhodanine-3-acetic acid, S-(thiobenzoyl)mercaptoacetic acid, S-benzyl-n-benzyloxycarbonyl-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-difluorocinnamic acid, trans-2,6-difluorocinnamic acid, trans-2-chloro-6-fluorocinnamic acid, trans-2-hexenoic acid, trans-3-(2,3,5,6-tetramethylbenzoyl)acrylic acid, trans-3-(2,5-dimethylbenzoyl)acrylic acid, trans-3-(4-ethoxybenzoyl)acrylic acid, trans-3-(4-methoxybenzoyl)acrylic acid, trans-3-(4-methylbenzoyl)acrylic acid, trans-3,4-difluorocinnamic acid, trans-3-fluorocinnamic acid, trans-3-furanylacrylic acid, trans-3-hexenoic acid, trans-4-chloro-3-nitrocinnamic acid, trans-4-hydroxy-3-methoxycinnamic 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.

[0052] In some embodiments, the compound of Formula (III) is:

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070] or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof.

[0071] Also provided is a pharmaceutical composition comprising one or more compounds of Formula (I) or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof, and a pharmaceutically acceptable carrier or excipient. Also provided is a pharmaceutical composition comprising one or more compounds of Formula (II) or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof, and a pharmaceutically acceptable carrier or excipient. Also provided is a pharmaceutical composition comprising one or more compounds of Formula (III) or pharmaceutically acceptable salts, hydrates, tautomers, and stereoisomers thereof, and a pharmaceutically acceptable carrier or excipient.

[0072] Also provided is a method of treating or preventing cancer in a patient, wherein the method comprises inhibiting dual protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TC-PTP) inhibitors by administering to the patient in need 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 compounds, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing cancer in the patient.

[0073] Also provided are methods of treating or preventing cancer in a patient, wherein the method comprises degrading dual PTP1 B and TC-PTP proteins by 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 compounds, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing cancer in the patient.

[0074] In some embodiments, the cancer is colon cancer, lung adenocarcinoma, squamous cell carcinoma, and melanoma. The compound is administered orally.

[0075] Also provided are methods of treating or preventing type II diabetes in a patient, wherein the method comprises inhibiting dual PTP1 B and TC-PTP inhibitors 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 compounds, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing type II diabetes in the patient.

[0076] Also provided are methods of treating or preventing type II diabetes in a patient, wherein the method comprises degrading dual PTP1 B and TC-PTP proteins by 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 compounds, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing type II diabetes in the patient.

[0077] Also provided are methods of treating or preventing obesity in a patient, wherein the method comprises inhibiting dual PTP1 B and TC-PTP inhibitors 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 compounds, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing obesity in the patient.

[0078] Also provided are methods of treating or preventing obesity in a patient, wherein the method comprises degrading dual PTP1 B and TC-PTP proteins by 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 compounds, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing obesity in the patient.

[0079] Also provided are methods of inhibiting or degrading dual PTP1B and TC-PTP in a patient, wherein the method comprises 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 compound, thereby inhibiting or degrading dual PTP1B and TC-PTP 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.

[0080] Provided are uses of a compound of Formula (I) in the treatment of a disease or disorder that can be treated by inhibiting or degrading dual PTP1B or TC-PTP proteins. Also provided are uses of a compound of Formula (II) in the treatment of a disease or disorder that can be treated by inhibiting dual PTP1B or TC-PTP proteins. Also provided are uses of a compound of Formula (III) in the treatment of a disease or disorder that can be treated by degrading dual PTP1B or TC-PTP proteins. In some embodiments, the treatable disease or disorder is cancer, type II diabetes, or obesity. BRIEF DESCRIPTION OF DRAWINGS

[0081] The present disclosure can be more easily understood and further advantages and benefits can be obtained, when the following detailed description of embodiments is considered in conjunction with the accompanying drawings, in which:

[0082] Figure 1 The compound of Example 7 was shown to be a potent, selective dual competitive inhibitor of protein tyrosine phosphatase 1B (PTP1B) / T-cell protein tyrosine phosphatase (TC-PTP). (A) shows the effect of the compound of Example 7 on PTP1B-catalyzed pNPP hydrolysis. (B) shows the effect of the compound of Example 7 on TC-PTP-catalyzed pNPP hydrolysis. The Lineweaver-Burk plot shows a characteristic intersecting line pattern consistent with competitive inhibition. The concentrations of the compound of Example 7 were 0 (·), 5 (■), and 10 nM (A), respectively. The compound of Example 7 inhibited PTP1B and TC-PTP with K; values of 2.4 and 3.6 nM, respectively. (C) shows the selectivity of the compound of Example 7 for the 12 mammalian PTP groups.

[0083] Figure 2A Western blots of whole cell lysates of the indicated cell lines treated with compound 47 at the indicated concentrations for 16 hours (4 hours in the case of the particular cell line) and stimulated with 10 ng / ml of IFN-γ for 15 minutes are shown.

[0084] Figure 2BWestern blots of whole cell lysates of indicated cell lines treated with compound 47 at indicated concentrations for 16 hours (4 hours in specific cases) and stimulated with 10 ng / ml of IFN-gamma for 15 minutes are shown.

[0085] Figure 3A Quantitative results of PTP1B and TC-PTP levels after compound 47 induced degradation of PTP1B and TC-PTP are shown. GAPDH protein was used as a loading control. Compound 47 at low nanomolar DC 50s induced degradation of PTP1B and TC-PTP.

[0086] Figure 3B Quantitative results of pSTAT1 levels after compound 47 upregulated STAT1 phosphorylation in various cell lines are shown. GAPDH protein was used as a loading control. Compound 47 treatment increased pSTAT1 levels in all cell lines. Changes in pSTAT1 levels in all cell lines positively correlated with TC-PTP / PTP1B degradation.

[0087] Figure 4 MC38 cells were treated with DMSO or 500 nM of compound 47 for 16 hours for PTP1B and TC-PTP degradation, then stimulated with mouse IFN-gamma for 48 hours for MHC-I expression induction. Mouse MHC-I complex was stained with mouse H2K(b) / H2D(b) antibody and measured by flow cytometry. Compound 47 treated MC38 cells showed elevated MHC-I expression.

[0088] Figure 5Compound 47 effectively depletes PTP1B and TC-PTP proteins in mouse MC38 syngeneic tumors and inhibits the growth of xenograft tumors. (A) The concentration of compound 47 in mouse blood over time after a single intraperitoneal (i.p.) injection of 25 mg / kg (■) or 50 mg / kg (·) of compound 47 is shown. (B) The growth curve of MC38 tumors during ten days of treatment with 25 mg / kg (■) and 50 mg / kg (A) of compound 47 or saline (·) is shown, demonstrating that compound 47 significantly inhibits MC38 tumor growth. (C) The change in body weight of mice during the ten days of treatment is shown. (D) Immunoblots of MC38 tumor extracts from mice treated with 25 mg / kg of compound 47, 50 mg / kg of compound 47, or saline are shown, demonstrating that PTP1B and TC-PTP are degraded after in vivo treatment with compound 47. (E and F) CD8a immunohistochemistry (IHC) staining images and quantification results of MC38 tumor sections from mice treated with 25 mg / kg of compound 47 or saline are shown. Tumors from mice treated with compound 47 exhibit high levels of CD8 + T cell infiltration. Quantitative analysis was based on six representative images from six sections.

[0089] Figure 6A Compound 47 is a PTP1B / TC-PTP dual PROTAC. This figure shows the mechanistic study of compound 47-induced PTP1B / TC-PTP degradation in HEK293 cells. Cells were pretreated with the indicated concentrations of MLN4924 (blocks ubiquitination), MG132 (blocks proteasome activity), lenalidomide (blocks CR b N binding), or (S,R,S)-AHPC-Me (blocks VHL binding) and then treated with 100 nM of 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 after treating cells with 100 nM of cis-compound 47 (inactivating degrader) for 4 hours.

[0090] Figures 6B-6C Immunofluorescence results of PTP1B and TC-PTP in U2OS cells treated with DMSO and 1 mM of compound 47 for 3 hours and 24 hours are shown. Compound 47 degrades PTP1B located in the cytoplasm and TC-PTP located in both the nucleus and cytoplasm. MG132 (20 mM) was used in combination with compound 47 to block the degradation of PTP1B and TC-PTP.

[0091] Figure 7Proteomic analysis is shown demonstrating the specificity of compound 47 for PTP1B degradation when HEK293 cells were treated with DMSO or 100 nM compound 47 for 4 hours.

[0092] Figure 8 Immunoblotting results of whole cell lysates of wild-type, PTP1B-deleted, or TC-PTP-deleted MEF cells treated with 0.5 mM compound 47 for 16 hours and stimulated with 20 ng / ml mouse IFN-gamma for 15 minutes are shown. Deletion of TC-PTP or PTP1B abrogated compound 47-induced phosphorylation of TC-PTP substrate JAK1 or PTP1B substrate JAK2. Thus, compound 47 potently augmented cell IFN-gamma signaling by degrading PTP1B and TC-PTP. U2OS cells were treated with DMSO or 0.2 mM compound 47 for 16 hours and stimulated with 20 ng / ml of IFN-gamma for 30 minutes. Immunofluorescence analysis showed that compound 47 significantly enhanced IFN-gamma-mediated STAT1 phosphorylation and nuclear translocation. DAPI was used for nuclear staining.

[0093] Figure 9 Compound 47 induces CD8 + T cells) in mice. + T-cells) in mice. + T cell activation. (A) Purified CD8 fl / fl T cells from control (Ptpn2 fl / fl ) and Lck-Cre;Ptpn2 + mice (n=3 / genotype / condition) were incubated with IL-7 in the presence or absence of compound 47 for 48 hours and TC-PTP and PTP1B protein levels were monitored by flow cytometry. (B) Control, TCPTP-deficient Lck-Cre;Ptpn2 fl / fl and compound 47-treated control primary CD8 + T cells were stimulated with plate-bound a-CD3 / a-CD28 for 48 hours to promote T cell activation. Phosphorylation of basal STAT-1 (p(Y701)STAT-1) and STAT-5 (p(Y694)STAT-5) 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 Ptpn2 fl / fl + vehicle, and squares (■) represent Lck-Cre;Ptpn2 fl / fl+ solvent, triangle (▲) represents Ptpn2 fl / fl + compound 47).

[0094] Figure 10 Pharmacokinetic studies of compound 47 in mice are shown. Compound 47 plasma concentrations were determined by LCMS after intraperitoneal injection of different formulations at indicated times.

[0095] Figure 11 Compound 47 reduced blood glucose levels in high-fat diet fed (HFD) mice. (A) shows blood glucose level reduction in high-fat diet fed male mice (about 50 g) after injection of 0, 15 or 50 mg / kg of compound 47. Blood glucose levels were measured 24 or 48 hours after injection. No fasting treatment was performed. NFD = normal fat diet fed mice. (B) shows blood glucose levels in MC38 syngeneic tumor study. Mice were treated daily by intraperitoneal injection of 25 or 50 mg / kg of compound 47. Blood glucose levels were measured multiple times during the experiment before injection.

[0096] Figure 12A Western blotting technique is shown. Wild type HEK293 cells were treated with compound 47 or ABBV-CLS-484 for 16 hours and stimulated with 20 ng / ml of IFN-gamma to induce JAK-STAT signaling pathway activation. Western blot results show that compound 47 induced TC-PTP degradation and pSTAT1 elevation, while ABBV-CLS-484 also elevated pSTAT1 levels. Compound 47 activated pSTAT1 more efficiently than ABBV-CLS-484 in HEK293 cells.

[0097] Figure 12B Quantitative results of pSTAT1 levels based on western blot results are shown. DETAILED DESCRIPTION

[0098] To assist in understanding 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 same. It will, nevertheless, be understood that no limitation of the scope of the application is intended by this use of specific language.

[0099] The term "PTP1B / TC-PTP dual inhibitor" refers to a compound that inhibits both protein tyrosine phosphatase 1B (PTP1B, also known as non-receptor tyrosine-protein phosphatase 1; non-receptor protein-tyrosine phosphatase 1; placental protein-tyrosine phosphatase; PTPN1; EC 3.1.3.48; and PTP-1B) and T-cell protein tyrosine phosphatase (TC-PTP, also known as PTPN2; non-receptor tyrosine-protein phosphatase 2; TCELLPTP, T-cell protein-tyrosine phosphatase) proteins.

[0100] The term “PTP1B / TC-PTP dual degrader” refers to a compound that degrades both PTP1B and TC-PTP proteins.

[0101] The term “protein degrader” or “proteolysis targeting chimera (PROTAC)” refers to a heterobifunctional compound composed of three parts: a ligand that binds to a target protein to be degraded, a linker that can remove a particular unwanted protein, and a protein-binding moiety that binds to an E3 ubiquitin ligase ligand.

[0102] The term von Hippel–Lindau (VHL) E3 ligase ligand “(S,R,S)-AHPC” refers to the following compound:

[0103]

[0104] The term VHL E3 ligase ligand “(S,R,S)-AHPC-Me” refers to the following compound:

[0105]

[0106] 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 a variety of therapeutic applications. The compound-mediated degradation of PTP1B and TC-PTP is dependent on the target proteins and the VHL E3 ligase ligand, and also on ubiquitination and the proteasome. The ubiquitin-proteasome pathway (UPP) is used to induce selective protein degradation, including ubiquitination of artificial target proteins using fusion proteins, and proteasome-dependent degradation induced using synthetic small-molecule probes.

[0107] The present disclosure provides compounds that are dual inhibitors and dual degraders of PTP1B and TC-PTP.

[0108] Provided is a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof:

[0109]

[0110] wherein

[0111] R1and R2are each independently a carboxylic acid residue or a pharmaceutically acceptable salt thereof, wherein R1and R2may be the same or different;

[0112] R3, R4, R5, R6, R7, and R8are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene, 4-6 membered heterocyclyl, and -C1-C6alkylene-4-6 membered heterocyclyl, wherein C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene, 4-6 membered heterocyclyl, and -C1-C6alkylene-4-6 membered heterocyclyl are optionally substituted on one or more available carbons with one or more substituents each independently selected from deuterium, halogen, hydroxyl, C=0, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C6cycloalkyl, -C1-C6-alkylene-C3-C6cycloalkyl, C1-C6alkyl-S(O)2-, C3-C6cycloalkyl-S(O)2-, C1-C6alkyl-C(O)-, C1-C6alkoxy-C(O)-, -NH-C(O)-R a and -C(O)-NH-R a wherein R a is C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene, 4-6 membered heterocyclyl, and -C1-C6alkylene-4-6 membered heterocyclyl, which is optionally substituted on one or more available carbon atoms with one or more substituents each independently selected from deuterium, halogen, hydroxyl, C=0, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C6cycloalkyl, -C1-C6-alkylene-C3-C6cycloalkyl, C1-C6alkyl-S(O)2-, C1-C6cycloalkyl-S(O)2-, C1-C6alkyl-C(O)-, C1-C6alkoxy-C(O)-, -NH-C(O)-R b and -C(O)-NH-R b wherein R b is independently selected from deuterium, halogen, hydroxyl, C=0, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C6cycloalkyl, -C1-C6-alkylene-C3-C6cycloalkyl, C1-C6alkyl-S(O)2-, C3-C6cycloalkyl-S(O)2-, C1-C6alkyl-C(O)-, and C1-C6alkoxy-C(O)-;

[0113] t is 0 to 6;

[0114] R9is H or a group represented by the formula L-B, wherein L is a linker selected from the group consisting of:

[0115]

[0116] wherein w is 1-5, x is 1-15, and a and b are each independently 0-3;

[0117] marked with an the bond marked with “*” represents the point of attachment of R9; and

[0118] B is selected from groups B1, B2, and B3, wherein B1 is represented by the following structure:

[0119]

[0120] wherein R 3a is fluorine, hydrogen, or deuterium;

[0121] B2 is represented by the following structure:

[0122]

[0123] wherein R 3b is fluorine, hydrogen, or deuterium; and

[0124] B3 is represented by the following structure:

[0125]

[0126] wherein R4 is methyl, hydrogen, or deuterium.

[0127] In some embodiments, the compound of Formula (I) can comprise (i) a first ligand, represented by the following structure and bound to the PTP1B / TC-PTP protein:

[0128]

[0129] (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 binds to the first ligand and the second ligand, wherein L, R1, R2, R3, R4, R5, R6, R7, R8, and t are as defined above.

[0130] Provided is a compound of Formula (II), which is a dual inhibitor of PTP1B / TC-PTP, or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof:

[0131]

[0133] wherein R1 and R2 are as defined above in Formula (I).

[0134] In some embodiments, R1 or R2 is:

[0135]

[0136] In some embodiments, R1 or R2 is:

[0137]

[0138] In some embodiments, R1or R2is:

[0139]

[0140] In some embodiments, the compound of Formula (II) is:

[0141]

[0142] or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof.

[0143] In some embodiments, provided are PROTAC compounds comprising: (i) a first target protein binding ligand that binds PTP1B and TC-PTP target proteins; (ii) a linker connecting the first ligand and a second ligand; and (iii) a second ligand that binds an E3 ligase that utilizes the ubiquitin-proteasome system of a cell to effect selective target protein degradation. They induce the formation of a ternary complex by binding simultaneously to the E3 ligase, PTP1B, and TC-PTP, bringing PTP1B and TC-PTP in close proximity to the E3 ligase, thereby effecting efficient ubiquitination and subsequent proteasome-mediated degradation.

[0144] Also provided are compounds of Formula (III) that are PTP1B / TC-PTP dual degraders:

[0145]

[0146] or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein R1, R2, L, and B are as defined above for Formula (I).

[0147] In some embodiments, R1or R2is selected from:

[0148]

[0149] In some embodiments, the linker L is selected from:

[0150]

[0151] In some embodiments, the carboxylic acid in the compounds of Formula (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 wherein the aliphatic group or the aromatic group is substituted with C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6haloalkyl, C1-C6haloalkenyl, C1-C6haloalkynyl, C1-C6heteroalkyl, C1-C6heteroalkenyl, C1-C6heteroalkynyl, C3-C8cycloalkyl, C3-C8halocycloalkyl, C2-C8alkylcarbonyl, C2-C8alkoxycarbonyl, C2-C8haloalkylcarbonyl, C2-C8haloalkoxycarbonyl, C2-C8alkylaminocarbonyl, C2-C8haloalkylaminocarbonyl, C2-C8dialkylaminocarbonyl, C2-C8halodialkylaminocarbonyl, C1-C6alkylsulfonyl, C1-C6haloalkylsulfonyl, C1-C6alkylsulfinyl, C1-C6haloalkylsulfinyl, C1-C6alkylsulfanyl, C1-C6haloalkylsulfanyl, C6-C10aryl, C6-C10haloaryl, C2-C8heteroaryl, C2-C8halo heteroaryl, C3-C8heterocycloalkyl, C3-C8halo heterocycloalkyl, C1-C6alkylamino, C1-C6haloalkylamino, C1-C6dialkylamino, C1-C6halodialkylamino, halogen, cyano, oxo, hydroxyl, or combinations thereof. 24 alkyl, C1-C 24 alkenyl, C1-C 24alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroaralkyl, aralkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl. 24 alkyl, hydroxy, alkoxy, cyano, halogen, nitro, aryl, amino, C1-C 24 alkenyl, C1-C 24 alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroaralkyl, aralkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl.

[0152] In some embodiments, the carboxylic acid is selected from the group consisting of 3-dimethylaminobenzoic acid, 2-(2-cyanophenylsulfanyl)benzoic acid, 2-(4- chlorobenzoyl)benzoic acid, (-)-2-oxo-4-thiazolidine-carboxylic acid, (-)-N-acetylneuraminic acid, (+)-6-methoxy-alpha-methyl-2-naphthoic acid, (+)-benzyloxycarbonyl-D-proline, (+)-menthoxyacetic acid, (±)-2-(2-chlorophenoxy)propionic acid, (±)-1- methyl-2-cyclohexen-1-carboxylic acid, (1-naphthyloxy)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)-(+)-camphoric acid, (1S,3R,4S,5R)-1,3,4,5- tetrahydroxycyclohexanecarboxylic acid, (2,4-di-tert-amylphenoxy)acetic acid, (2- naphthyloxy)acetic acid, (2-pyrimidinylsulfanyl)acetic acid, (4-carboxybutyl)triphenylphosphonium bromide, (4-chlorophenylsulfanyl)acetic acid, (4-methylphenoxy)acetic acid, (alpha,alpha,alpha-trifluoro-m-tolyl)acetic acid, (E)-2-[(4-hydroxyphenyl)azo]- 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-pyrrolidinone-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-phenylpropionic 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-tetrahydrofurylcarboxylic 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)propionic acid, (S)-2-(phenylcarbamoyloxy)propionic acid, (S)-3-2-benzene dioo diacetic acid, 1,4-dihydro-2-methylbenzoic acid, 1,4-dihydroxy-2-naphthoic acid, 10-hydroxydecanoic acid, 10-undecynoic acid, 1-adamantane carboxylic acid, 1-cyano-1-cyclopropane carboxylic acid, 1-hydroxy-2-naphthoic acid, 1- isoquinoline carboxylic acid, 1-methyl-(1S,2R)-(+)-cis-1,2,3,6-tetrahydrophthalic acid, 1- methyl-1-cyclohexane carboxylic acid, 1-methyl-1H-indole-2-carboxylic acid, 1-methyl-2- pyrrole carboxylic acid, 1-methylcyclopropane carboxylic acid, 1-naphthoic acid, 1-phenyl-1- cyclopentane carboxylic acid, 1-phenyl-1-cyclopropane carboxylic acid, 1-pyrene acetic acid, 1- pyrene butyric acid, 1-pyrene carboxylic acid, 2-((1R,2R,3R,4S)-3-hydroxy-4,7,7- trimethylbicyclo[2.2.1]heptan-2-yl)acetic acid, 2-[(benzyloxy carbonyl)(methyl)amino]-2- methylpropanoic acid, 2-(2-(trifluoromethyl)phenyl)acetic acid, 2-(2,4,5-trichlorophenoxy)propanoic acid, 2-(2,4-dichlorophenoxy)propanoic acid, 2-(3,5-dinitrobenzamido)-2- phenylacetic acid, 2-(3,5-dinitrobenzamido)-4-methylpentanoic acid, 2-(3-chlorophenoxy)propanoic acid, 2-(4-(trifluoromethyl)phenyl)acetic acid, 2-(4-chloro-3-nitrobenzoyl)benzoic acid, 2-(4-chlorophenoxy)-2-methylpropanoic acid, 2-(4-chlorophenoxy)propanoic acid, 2-(4-fluorobenzoyl)benzoic acid, 2-(4-hydroxy-3- methoxyphenyl)acetic acid, 2-(4-hydroxyphenoxy)propanoic acid, 2-(4-isobutylphenyl)propanoic acid, 2-(4-nitrophenyl)propanoic acid, 2-(benzyloxy carbonyl amino)-3-(1H-indol-3- yl)propanoic acid, 2-(trifluoromethyl)propenoic acid, 2-(trifluoromethyl)benzoic acid, 2- (trifluoromethyl)cinnamic acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid, 2,2-bis(hydroxymethyl)propanoic acid, 2,3,4,5,6-pentafluorocinnamic acid, 2,3,4,5,6- pentafluorophenoxyacetic acid, 2,3,4,5,6-pentafluorophenylacetic 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-hydroxybenzoic 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, 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, 2,4,6-4-dichloro-5-sulfamoylbenzoic 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-bromo-3-nitrobenzoic acid, 2-bromo-4,5-dimethoxybenzoic acid, 2-bromo-5-methoxybenzoic acid, 2-bromo-5-nitrobenzoic acid, 2-bromopropenoic 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-(trifluoromethyl)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-hydroxybutanoic acid, 2-ethylbutanoic acid, 2-ethylhexanoic acid, 2-ethylthio-2,2-diphenylacetic 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-methylbutanoic acid, 2-hydroxy-6-isopropyl-3-methylbenzoic acid, 2-hydroxyhexanoic acid, 2-hydroxymandelic 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-cyclohexanecarboxylic acid (cis and trans), 2-methyl-3-nitrobenzoic acid, 2-methyl-3- phenylpropionic acid, 2-methyl-4-oxo-4-phenylbutanoic acid, 2-methyl-6- nitrobenzoic acid, 2-methylbutanoic acid, 2-methylcinnamic acid, 2- methylcyclopropanecarboxylic acid (cis and trans), 2-methylhexanoic acid, 2- methylmandelic acid, 2-methylpentanoic 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-phenoxybutanoic acid, 2-phenoxypropanoic acid, 2- propylpentanoic acid, 2-quinoxalinecarboxylic acid, 2-thiopheneacetic acid, 2- thiopheneacetic acid, 2-thiopheneacetic acid, 3-(2-hydroxyphenyl)propionic acid, 3-(2-thienyl)propenoic 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)phenylacetic acid, 3,4- dichlorobenzoic acid, 3,4-dichlorophenoxyacetic acid, 3,4-diethoxybenzoic acid, 3,4-difluorobenzoic acid, 3,4-dihydroxybenzoic acid, 3,4-dihydroxyhydrocinnamic 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, 3,5-5-di-tert-butylbenzoic acid, 3,7-dihydroxy-2-naphthoic acid, 3-thiopheneacetic acid, 3-benzoyl-2-pyridinecarboxylic 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-proxazole, 3-chloro-2-nitrobenzoic acid, 3-chloro-4-fluorobenzoic acid, 3-chloro-4-hydroxyphenylacetic acid, 3-chlorosalicylic acid, 3-cyanobenzoic acid, 3-fluoro-2-methylbenzoic acid, 3-fluoro-4-hydroxyphenylacetic acid, 3-fluoro-4-methoxybenzoic acid, 3-fluorophenylacetic acid, 3-furan carboxylic acid, 3-hydroxy-2-naphthoic acid, 3-hydroxy-2-quinoxalinecarboxylic acid, 3-hydroxy-4-methoxybenzoic acid, 3-hydroxy-4-methoxycinnamic acid, 3-hydroxy-4-nitrobenzoic acid, 3-hydroxybenzoic acid, 3-hydroxybutyric acid, 3-hydroxyphenylacetic acid, 3-indolebutyric acid, 3-indoleglycolic acid, 3-indolepropionic acid, 3-iodo-4-methylbenzoic acid, 3-iodobenzoic acid, 3-isoquinolinecarboxylic acid hydrate, 3-methoxy-4-nitrobenzoic acid, 3-methoxycyclohexanecarboxylic 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-noradamantane carboxylic acid, 3-oxo-1-indene carboxylic acid, 3-phenoxybenzoic acid, 3-phenylbutyric acid, 3-p-tolylpropionic acid, 3-thiophenecarboxylic acid, 4-(1,3-dioxoisoindoline-2-yl)-2-hydroxybutyric acid, 4-(2,4,5-trichlorophenoxy)butyric acid, 4-(2,4-dichlorophenoxy)butyric acid, 4-(2,4-di-tert-amylphenoxy)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)phenylacetic 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)pentanoic acid, 4,5-dimethoxy-2-nitrobenzoic acid, 4,6-dioxoheptanoic acid, 4-[4-(2-carboxybenzoyl)phenyl]butyric acid, 4-acetamidobenzoic acid, α-acetylb enzoic acid, 4-acetylphenoxyacetic acid, 4-benzyloxy-3-methoxyphenylacetic 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-ethylbenzoic acid, 4'-ethylbiphenyl-4-carboxylic acid, 4- fluorenecarboxylic acid, 4-fluoro-1-naphthoic acid, a-fluoro-2-(trifluoromethyl)benzoic acid, 4-fluoro-3-nitrobenzoic acid, 4-fluorobenzoic acid, 4-fluorobenzoic acid, 4-fluorocinnamic acid, 4-fluorophenoxyacetic acid, a-heptyloxybenzoic acid, 4-hexylbenzoic acid, 4-hexyloxybenzoic acid, 4-hydroxy-3-(morpholinomethyl)benzoic acid hydrate, 4-hydroxy-3,5-dinitrobenzoic acid, 4-hydroxy-3-methoxybenzoic acid, 4-hydroxy-3-methoxymandelic 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, a-hydroxyphenylpyruvic acid, 4-iodobenzoic acid, 4-isopropoxybenzoic acid, 4-methoxy-3-nitrobenzoic acid, 4-methoxycyclohexanecarboxylic acid, 4-methoxysalicylic acid, a-methyl-1-cyclohexanecarboxylic acid (cis and trans), 4-methyl-3-nitrobenzoic acid, a-methylhippuric acid, 4-methylsalicylic acid, 4-methylvaleric acid, 4-nitro-3-pyrazolecarboxylic acid, 4-nitrohippuric acid, 4-nonyloxybenzoic acid, 4-octylbenzoic acid, 4-oxo-4H-1-benzopyran-2-carboxylic acid, 4-oxo-6-phenyl-5-hexenoic acid, a-pentenoic acid, 4-pentylbenzoic acid, 4-pentyldicyclo[2.2.2]octane-1-carboxylic acid, a-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-furancarboxylic 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-hydantoinic acid, 5-hydroxy-2-indolecarboxylic 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-pyrazinecarboxylic acid, 5-nitro-2-furancarboxylic acid, 5-nitro-3-pyrazolecarboxylic acid, 5-phenylvaleric acid, 6-(benzyloxycarbonylamino)hexanoic 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-nitrohexanoic acid, 6-oxoheptanoic acid, 6-phenylhexanoic acid, 7-(carboxymethyloxy)-4-methylcoumarin, 7-hydroxycoumarin-4-acetic acid, 7-methoxy-2-benzofurancarboxylic acid, 7-methoxycoumarin-4-acetic acid, 7-oxooctanoic acid, 9-anthracene carboxylic acid, 9-fluoreneacetic acid, 9-fluoren-1-carboxylic acid, α,α,α-trifluorom-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-hydroxymandelic acid, anthranilic acid, trans-3-oxotricyclo[2.2.1.02'6]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, benzyloxycarbonyl-DL-alanine, benzyloxycarbonyl-L-alanine, benzyloxycarbonyl-L-glutamine, benzyloxycarbonyl-L-valine, cis-2-methoxycinnamic acid, crotonic acid, cyclohexanebutyric acid, cyclohexanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanepropionic acid, cyclopentylacetic acid, D,L-3,4-dihydroxymandelic acid, D-3-phenyllactic acid, decanoic acid, dicyclohexylacetic acid, diethylphosphonoacetic acid, dihydroxyfumaric acid hydrate, diphenylacetic acid, fumaric acid monoethyl ester, fusaric acid, gallic acid, geranic acid, glycolic acid, heptadecafluorononanoic acid, heptanoic acid, hexanoic acid, hippuric acid, hydrogenated cinnamic 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, mono-(1R)-(-)-menthyl phthalate, mono-(1S)-(+)-menthyl phthalate, cis-5-norbornene-inn-2,3-dicarboxylic acid monomethyl ester, phthalic acid monomethyl ester, terephthalic acid monomethyl ester, N-(2-furoyl)glycine, N-(3,5-dinitrobenzoyl)-DL-α-phenylglycine, N-(3-indoleacetyl)-L-alanine, N-(3-indoleacetyl)-L-isoleucine, N-(3-indoleacetyl)-L-leucine, N-(3-indoleacetyl)-L-phenylalanine, N-(3-indoleacetyl)-L-valine, N-(benzyloxycarbonyl)-L-phenylalanine, N,N-diethyl-3,6-difluorophthalamic acid, N-[(R)-1-(1-naphthyl)ethyl]phthalamic acid, N-[5-(trifluoromethyl)-2-pyridinyl]-L-valine, n-acetyl-4-fluoro-DL-phenylalanine, N-acetyl-DL-tryptophan, n-acetyl-L-leucine, N-acetyl-L-methionine, N-acetyl-L-phenylalanine, N-acetyl-L-tyrosine, N-benzoyl-(2R,3(S)-3-phenylisoserine, N-benzoyl-L-threonine, N-benzyloxycarbonyl-2- methylalanine, N-benzyloxycarbonyl-L-glutamic acid 1 -methyl ester, N- benzyloxycarbonyl-L-isoleucine, N-benzyloxycarbonyl-L-leucine, N- benzyloxycarbonyl-L-threonine, N-ethoxycarbonyl-L-phenylalanine, nonanoic acid, N-p-toluenesulfonylglycine, N-p-toluenesulfonyl-L-phenylalanine, o-anisic acid, p-anisic acid, pentafluorobenzoic acid, phenoxyacetic acid, phenylacetic acid, podocarpic acid, pyruvic acid, rhodanine-3-acetic acid, S-(thiobenzoyl)mercaptoacetic acid, S-benzyl-n-benzyloxycarbonyl-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-difluorocinnamic acid, trans-2,6-difluorocinnamic acid, trans-2-chloro-6-fluorocinnamic acid, trans-2-hexenoic acid, trans-3-(2,3,5,6-tetramethylbenzoyl)acrylic acid, trans-3-(2,5-dimethylbenzoyl)acrylic acid, trans-3-(4-ethoxybenzoyl)acrylic acid, trans-3-(4-methoxybenzoyl)acrylic acid, trans-3-(4-methylbenzoyl)acrylic acid, trans-3,4-difluorocinnamic acid, trans-3-fluorocinnamic acid, trans-3-furanylacrylic acid, trans-3-hexenoic acid, trans-4-chloro-3-nitrocinnamic acid, trans-4-hydroxy-3-methoxycinnamic 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.

[0153] In some embodiments, the compound of Formula (III) is,

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171] or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof.

[0172] The compounds of Formula (I), (II), and (III), and intermediates used to make them, are enantiomerically enriched, e.g., having an enantiomeric excess value or "ee" of about 5% or more, as measured by chiral HPLC.

[0173] 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%.

[0174] In some embodiments, B is an E3 ligase binding moiety in the molecule that can be enantiomerically enriched. In exemplary embodiments, the E3 ligase binding moiety of the molecule is racemic. The present disclosure encompasses all possible stereoisomers, e.g., diastereomeric forms, of the compounds of Formula (I), (II), and (III).

[0175] Pharmaceutically acceptable salts of the above compounds, and their preparation and use are provided. The salts can be prepared during the final isolation and purification of the compounds, or separately, by reacting the compound with the appropriate acid.

[0176] In some embodiments, the salt can 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, phosphoric acid. Examples of organic acids include, but are not limited to, oxalic acid, maleic acid, succinic acid, citric acid.

[0177] Examples of salts of the compounds described herein include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, mesylate, trisylate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartarate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate, p-toluenesulfonate.

[0178] Amino groups in the compounds can be quaternized with the following: 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, dipentyl sulfate; decyl chloride, lauryl chloride, myristyl chloride, stearyl chloride; decyl bromide, lauryl bromide, myristyl bromide, stearyl bromide; decyl iodide, lauryl iodide, myristyl iodide, stearyl iodide; and benzyl bromide or phenethyl bromide.

[0179] Solvates of the above compounds, and their preparation and use are provided. Solvates are typically not significantly more active or toxic than the base compounds and are considered pharmacologically equivalent thereto.

[0180] The term "solvate" refers to a combination or physical association of a compound described herein with a solvent molecule, for example, a disolvate, monosolvate, or hemisolvate, wherein the solvent molecule is about 2: 1, about 1: 1, or about 1:2, respectively, to the compound. Such physical associations involve varying degrees of ionic and covalent character, 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.

[0181] Solvated forms of the compounds can be prepared using pharmaceutically acceptable solvents. Examples of solvents include, but are not limited to, water, methanol, and ethanol, and the present disclosure is intended to cover both solvated and unsolvated forms of the compounds described above. One type of solvate is a hydrate. "Hydrate" refers to one particular subclass of solvates wherein the solvent molecule is water. Solvates typically can be formed as pharmacologically equivalent alternatives. 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 solvates of fluconazole with ethyl acetate and with water. E. C. van Tonder et al., AAPS Pharm. Sci. Tech., 2004, 5(1): Article 12, and A. L. Bingham et al, 200, Chem. Commun., 603-604 describe the preparation of similar solvates, hemisolvate, hydrates, and the like. A typical, non-limiting process for preparing a solvate can include dissolving the compound in a desired solvent (organic solvent, water, 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 (e.g., filtration). Analytical techniques such as infrared spectroscopy can be used to confirm the presence of a solvate in the solvate crystals.

[0182] The term "pharmaceutically acceptable salt" refers to a salt or zwitterionic form of a compound described herein.

[0183] Any reference to a compound of the present disclosure appearing herein is intended to include a compound of the present disclosure and a pharmaceutically acceptable salt or hydrate thereof.

[0184] The term "alkyl" refers to a straight or branched carbon atom chain (C1-C 20 ), 1 to 12 carbon atoms (C1-C 12substituted or unsubstituted straight and branched chain alkyl and cycloalkyl groups having 1 to 8 carbon atoms (Ci-C8), or in certain embodiments, 1 to 6 carbon atoms (Ci-C6). Examples of straight chain alkyl groups include, but are not limited to, alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, iso-pentyl, and 2,2-dimethylpropyl. The term "alkyl" encompasses normal alkyl, isoalkyl, anti-isoalkyl, and other branched forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, such as amino, hydroxyl, cyano, carboxyl, nitro, thio, alkoxy, and halogen groups.

[0185] The term "alkylene," used alone or as part of another substituent, unless otherwise indicated, refers to a divalent radical derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Generally, an alkyl group (or alkylene) contains from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in various embodiments.

[0186] The term "cycloalkyl" refers to substituted or unsubstituted cyclic alkyl groups, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, cycloalkyl groups can have from 3 to about 8-12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. In some embodiments, cycloalkyl groups can have from 3 to 6 carbon atoms (C3-C6). Cycloalkyl groups also include polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, borneolyl, campherenyl, isocamphenyl, and carenyl, as well as fused rings, such as, but not limited to, decahydronaphthyl, and the like.

[0187] The term "alkenyl" refers to substituted or unsubstituted straight and branched chain divalent alkenyl and cycloalkenyl groups having 2 to 20 carbon atoms (C2-C 20 ), 2 to 12 carbon atoms (C2-C 12 ), 2 to 8 carbon atoms (C2-C8), or in certain embodiments, 2 to 4 carbon atoms (C2-C4) and at least one carbon-carbon double bond. Examples of straight chain alkenyl groups include straight chain alkenyl groups having 2 to 8 carbon atoms, such as -CH=CH-, -CH=CHCH2-, and the like. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH3)-, and the like.

[0188] The term "alkenylene," used alone or as part of another substituent, unless otherwise indicated, refers to a divalent radical derived from an alkene. Alkenylene groups can be described, for example, as 1-6 membered alkenylene groups, where "membered" refers to the non-hydrogen atoms in the moiety.

[0189] The term "alkynyl" refers to an unsaturated monovalent carbon atom chain containing at least one triple bond, which can be optionally branched. In embodiments containing alkynyl groups, exemplary examples include lower alkynyl groups, such as C2-C6 alkynyl, C2-C4 alkynyl, and the like.

[0190] The term "alkoxy" refers to an oxygen atom linked to an alkyl group (including cycloalkyl groups) as defined herein. Examples of straight-chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, t-butoxy, isopentoxy, isohexyloxy, and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like. Alkoxy groups can also contain double or triple bonds, and can contain heteroatoms. For example, allyloxy is an alkoxy group as defined herein. Methoxyethoxy is also an alkoxy group as defined herein, as is methylene dioxy when two adjacent atoms in the structure are substituted thereby.

[0191] The term "halogen" is used to describe compounds containing one or more halogen atoms such as fluorine, chlorine, bromine, and iodine.

[0192] It is to be understood that alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkylidene, and heterocyclyl groups can each be optionally substituted with independently selected groups such as alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxylic acid and its derivatives including esters, amides, and nitriles, hydroxyl, alkoxy, acyloxy, amino, alkyl and dialkylamino, acylamino, thio, and the like, and combinations thereof.

[0193] 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 are heteroatoms such as, but not limited to, B, N, O, and S. Thus, a heterocyclyl group can be a cycloheteroalkyl or heteroaryl group, and if polycyclic, any combination thereof. In some embodiments, a heterocyclyl group contains 3 to about 20 ring members, while other such groups contain 3 to about 15 ring members. In some embodiments, a heterocyclyl group can contain 3 to 8 carbon atoms (C3-C8), 3 to 6 carbon atoms (C3-C6), or 6 to 8 carbon atoms (C6-C8).

[0194] The term "substituted" refers to a functional group in which one or more hydrogen atoms contained in the functional group are replaced by one or more non-hydrogen atoms. The term "functional group" or "substituent" refers to a group that can be or has been substituted onto a molecule. Examples of substituents or functional groups include, but are not limited to: halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl, alkoxy, aryloxy, aralkyloxy, oxo (carbonyl), carboxyl (including carboxylic acids, carboxylate salts, and carboxyl esters); sulfur atoms in groups such as thiol, alkyl sulfide, and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in groups such as amines, azides, hydroxylamines, cyano groups, nitro groups, N-oxides, hydrazides, and enamines; and other heteroatoms in other various groups.

[0195] 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)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thioxo), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, (CH2) 0-2 P(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)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, where R can be hydrogen or a carbon-based moiety, and where the carbon-based moiety can itself be further substituted; e.g., when R can be hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl, any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl or R can be independently mono- or poly-substituted; or when two R groups attached to a nitrogen atom or to adjacent nitrogen atoms can form, together with the nitrogen atom or nitrogen atoms to which they are attached, a heterocyclyl group, the heterocycle can be mono- or independently poly-substituted.

[0196] The terms“optionally substituted” and“optionally substituted group” mean 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 can be the same or different. When used with the terms“independently,”“independently is,” and“independently selected from,” the groups in question can be the same or different. Certain terms defined herein can appear multiple times in the specification, and when so appearing, each term is defined independently of the other.

[0197] The term“amine” refers to primary, secondary, and tertiary amines, for example, an amine having the formula N(group)3, where each group can independently be hydrogen or non-hydrogen, for example, alkyl, aryl, and the like. Amines include, but are not limited to, R-NH2, for example, alkylamines, arylamines, alkylaryl amines; R2NH, where each R is independently selected, for example, dialkylamines, diaryl amines, aralkylamines, heterocyclic amines, and the like; and R3N, where each R is independently selected, for example, trialkylamines, dialkylaryl amines, alkyl diaryl amines, triaryl amines, and the like. The term“amine” also includes ammonium ions.

[0198] The term“amino” refers to -NH2, -NHR, -NR2, -NR3 + substituents, where each R is independently selected, and the protonated form of each R other than -NR3 + which cannot be protonated. Thus, any compound substituted with an amino group can be considered an amine. An“amino” can be a primary amino, secondary amino, tertiary amino, or quaternary amino. An“alkylamino” includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0199] Compounds can contain one or more chiral centers, or can exist in the form of multiple stereoisomers. In various embodiments, compounds are not limited by any particular stereochemistry, and compounds, as well as compositions, methods, uses, and medicaments comprising them, can be optically pure, or mixtures of various stereoisomers, including racemates and other enantiomeric mixtures, other diastereomeric mixtures, and the like. Such stereoisomeric mixtures can contain a single stereochemical configuration at one or more chiral centers, while containing a mixture of stereochemical configurations at one or more other chiral centers.

[0200] Similarly, the compounds described herein can 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 requirement, and the compounds, as well as compositions, methods, uses, and medicaments comprising them, can be pure or any of a mixture of geometric isomers. Such mixtures of geometric isomers can contain a single configuration at one or more double bonds, while containing a mixture of geometric configurations at one or more other double bonds.

[0201] The term "compound" as used herein is intended to include all stereoisomers, geometric isomers, and tautomers of the illustrated structures.

[0202] In some embodiments, the degree to which the compound inhibits PTP1B and TC-PTP can be the same. In other embodiments, the degree to which the compound inhibits PTP1B is greater than the degree to which it inhibits TC-PTP. In still other embodiments, the degree to which the compound inhibits TC-PTP is greater than the degree to which it inhibits PTP1B. When there is differential inhibition between PTP1B and TC-PTP, the range of differential inhibition can be from as little as about 1% (e.g., 1%) to as much as about 80% (e.g., 80%). In various embodiments, it can be preferable, if not ideal, for the degree of inhibition of PTP1B and TC-PTP by the compound to be at least approximately the same.

[0203] In some embodiments, a pharmaceutical composition is provided comprising one or more compounds of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer of any of the foregoing compounds, and a pharmaceutically acceptable carrier or excipient. The carrier or excipient can vary depending on the particular route of administration (see, e.g., Remington’s The Science and Practice of Pharmacy, 23rd ed. (2020)).

[0204] 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 compounds, with a pharmaceutically acceptable carrier or excipient, and optionally one or more additional pharmaceutically active agents.

[0205] A pharmaceutical composition is provided 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 compounds, and (ii) one or more other prophylactic or therapeutic agents, and a pharmaceutically acceptable carrier or excipient.

[0206] The compound and one or more other prophylactic or therapeutic agents can be administered simultaneously or sequentially, in any order, by the same or different routes of administration, either in two separate compositions or in a single composition.

[0207] The compounds of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer of any of the foregoing, are capable of inhibiting or degrading both PTP1B and TC-PTP. Thus, they can treat or prevent various diseases and conditions associated with PTP1B and TC-PTP. In particular, these compounds are useful in treating or preventing diseases or conditions in which the simultaneous inhibition or degradation of PTP1B and TC-PTP confers a benefit.

[0208] Methods of treating or preventing cancer in a patient are provided. The methods include 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 in the form of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, thereby treating or preventing cancer in the patient.

[0209] Methods of treating or preventing cancer in a patient are also provided. The methods include 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 in the form of a pharmaceutical composition comprising (i) and (ii) and a pharmaceutically acceptable carrier or excipient. The other prophylactic or therapeutic agent can be selected from drugs known to be useful in the prevention or treatment of cancer, for example, monoclonal antibodies useful in the treatment of a particular cancer.

[0210] Examples of cancer include, but are not limited to, colon cancer, lung adenocarcinoma, squamous cell carcinoma, and melanoma.

[0211] In some embodiments, the compounds of the present disclosure can facilitate weight loss and improve glucose metabolism.

[0212] Also provided are methods of treating or preventing type II diabetes. The methods include 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 compounds, optionally in the form of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, to thereby treat or prevent type II diabetes in the patient. The effective amount of the compound can optionally be administered with one or more other prophylactic or therapeutic agents. The other prophylactic or therapeutic agents can be selected from drugs known to prevent or treat type II diabetes.

[0213] Also provided are methods of treating or preventing obesity. The methods include 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 compounds, optionally in the form of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, to thereby treat or prevent obesity in the patient. The effective amount of the compound can optionally be administered with one or more other prophylactic or therapeutic agents. The other prophylactic or therapeutic agents can be selected from drugs known to prevent or treat obesity.

[0214] Because the compounds described herein are inhibitors or degraders of PTP1B and TC-PTP proteins, a variety of diseases and conditions mediated by PTP1B and / or TC-PTP can be treated (e.g., prophylactically or therapeutically) by using these compounds.

[0215] Also provided are methods of treating or preventing a disease or condition responsive to PTP1B / TC-PTP inhibition or degradation. The methods include administering to a patient in need thereof an effective amount of a compound described above, or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, optionally in the form of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient. The effective amount of the compound can optionally be administered with one or more other prophylactic or therapeutic agents. The other prophylactic or therapeutic agents can be selected from drugs known to prevent or treat the disease or condition.

[0216] Also provided are methods of inhibiting or degrading dual PTP1B and TC-PTP in a patient, wherein the methods include administering to a patient in need thereof an effective amount of a compound described above, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient, to thereby inhibit or degrade dual PTP1B and TC-PTP 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.

[0217] The method includes administering an effective amount of the compound described above in a purified form or in a pharmaceutical composition. The compound or pharmaceutical composition can be administered during or after the onset of the disease or disorder. Typically, the pharmaceutical composition is sterile, free of toxic, carcinogenic, or mutagenic compounds that cause adverse reactions upon administration.

[0218] Also provided is the use of the compound described above in the treatment of a disease or disorder that can be treated by inhibiting or degrading the dual PTP1B or TC-PTP protein. In some embodiments, the disease or disorder is cancer, type II diabetes, or obesity.

[0219] Also provided is a kit comprising the compound described above, and optionally one or more other prophylactic or therapeutic agents, packaged alone or together, and an insert with instructions for using these active agents.

[0220] The other therapeutic agents can be administered simultaneously or sequentially, by the same or different routes, to achieve the intended effect. The compound described herein and one or more other prophylactic or therapeutic agents can be administered by a single composition or two separate compositions, for example, by the same or different routes. The prophylactic or therapeutic agents can be administered in amounts that provide their intended prophylactic or therapeutic effects. The effective dosage range for each prophylactic or therapeutic agent is well known in the art or can be determined according to methods known to those of ordinary skill in the art for determining dosage ranges, and the therapeutic agents can be administered to a patient in need thereof within the established range. The compound described herein and one or more other prophylactic or therapeutic agents can be administered together as a single unit dose, or separately as multiple unit doses, wherein the compound can be administered prior to the other prophylactic or therapeutic agents, or vice versa. One or more doses of the compound and / or one or more doses of the second prophylactic or therapeutic agent can be administered.

[0221] The term "effective amount" or "effective dose" refers to the amount of active ingredient which is sufficient to effectively deliver the active ingredient to a subject in need thereof to treat the disease or condition of interest when administered. The prophylactically or therapeutically effective amount of the compound will vary depending on the patient and the disease or condition being treated, the patient's body weight and age, the severity of the disease or condition, the mode of administration and the like, which can readily be determined by one of ordinary skill in the art. In the case of cancer or other proliferative disorders, a prophylactically or therapeutically effective amount of the agent can reduce (i.e., inhibit to some extent or prevent) unwanted cellular proliferation; reduce the number of cancer cells; reduce tumor size; inhibit (or prevent) cancer cell infiltration into peripheral organs including the central nervous system; inhibit (or prevent) tumor metastasis; inhibit or prevent tumor growth, e.g., to some extent; and / or relieve to some extent one or more signs or symptoms associated with the cancer. It can have cytostatic and / or cytotoxic effects, with respect to existing cancer cells, by arresting or preventing their growth and / or killing them.

[0222] The compounds can generally be administered in admixture with a pharmaceutical carrier, excipient, or vehicle and in a form to be used in a manner consistent with the treatment regimen. The pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and / or auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. When treating a therapeutically effective amount of a compound described herein is administered orally, the composition is typically in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition can also include a solid carrier such as gelatin or an adjuvant. Tablets, capsules, and powders can 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 an oil of either vegetable or animal origin can be added. The liquid form of the composition can also contain physiological saline, glucose or other sugar solution, or glycol. When administered in liquid form, the composition contains from about 0.1% to about 90%, preferably from about 1% to about 50% of the compound by weight.

[0223] The compounds can be administered by any appropriate route, for example, orally, buccal, inhalationally, sublingually, rectally, vaginally, intracisternally, intrathecally via lumbar puncture, transurethrally, nasally, transdermally (i.e., transdermally), or parenterally, including intravenously, intramuscularly, subcutaneously, intracoronary, intradermally, intramammarily, intraperitoneally, intraarticularly, intrathecally, retrobulbarly, intrapulmonarily, and / or surgical implantation at a specific site. Parenteral administration can be by use of needles and syringes or high pressure techniques.

[0224] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art. These carriers, excipients or diluents enable the compounds to be formulated as tablets, pills, powders, dragees, capsules, liquids, gels, syrups, pastes, suspensions, solutions, and the like, for oral ingestion by a patient to be treated.

[0225] The specific formulation of the pharmaceutical compositions containing the effective amount of the compounds, the route of administration, and the dosage, are determined by each physician, in the light of the specific disease or condition being treated, the age, weight, and response of the patient, and the severity of the patient's symptoms. The dosage and interval between doses can be adjusted according to individual patient requirements and in accordance with recognized principles.

[0226] Toxicity and therapeutic efficacy of the compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., determining the maximum tolerated dose (MTD) of the compounds, which is defined as the highest dose that does not cause toxicity in animals. The therapeutic index is the dose ratio between the maximum tolerated dose and the therapeutic effect (e.g., inhibition of tumor growth). The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. Determining the therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0227] The effective amount of the compounds required to treat a particular disorder will depend on the nature of the disorder, the desired activity duration, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician. The dosage and interval between doses can be adjusted according to individual patient requirements and in accordance with recognized principles. The desired dose can be administered in a single dose, or in multiple doses, at appropriate intervals, for example, one, two, three, four or more divided doses per day. Multiple dosing is often desirable or required. For example, the compounds can be administered at a frequency of 1 dose per day, 4 doses given at 4-day intervals (q4d x 4); 4 doses given at 3-day intervals (q3d x 4); 1 dose per day for 5 days (qd x 5); 1 dose per week for 3 weeks (qwk3); 1 dose per day for 5 consecutive days, 2 days off, and 1 dose per day for 5 consecutive days (5 / 2 / 5); or any other regimen determined to be appropriate under the circumstances.

[0228] The amount of compound administered can be from about 0.005 mg to about 500 mg per dose, from about 0.05 mg to about 250 mg per dose, or from about 0.5 mg to about 100 mg per dose. For example, the amount of compound administered can be about 0.005 mg, about 0.05 mg, about 0.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg per dose, including all dosages in between 0.005 mg and 500 mg.

[0229] Compositions comprising the compounds can be formulated in unit dosage form, each dosage containing from about 5 mg to about 1000 mg (1 g), more usually from about 100 mg to about 500 mg, of the active ingredient.

[0230] The dosage range of compositions comprising the compounds described herein can be from about 1 mg / kg to about 200 mg / kg, from about 1 mg / kg to about 100 mg / kg, or from about 1 mg / kg to about 50 mg / kg. The above dosages are exemplary of the average case; more or less can be administered in

[0231] As described above, the compounds described herein can 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. An immune checkpoint inhibitor is a drug that blocks proteins known as checkpoints produced by certain types of immune system cells (e.g., T cells) and certain cancer cells. These checkpoints help to suppress immune responses that are too strong and sometimes can prevent T cells from killing cancer cells. When these checkpoints are blocked, T cells can better 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.

[0232] 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 key role in the ability of tumor cells to evade the host immune system. Blocking the interaction between PD-1 and PD-L1, a ligand for PD-1, enhances immune function and mediates anti-tumor activity. Specific examples of PD-1 inhibitors include, but are not limited to, antibodies that specifically bind to PD-1. Anti-PD-1 antibodies are selected from the group consisting of nivolumab, pembrolizumab, STI-A1014, and pidilizumab. The availability, methods of production, mechanism of action, and clinical studies 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, the teachings of all of which regarding the foregoing are hereby expressly incorporated by reference herein.

[0233] 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, mechanism of action, and clinical studies 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. WO2015036499, and Naido et al., British Journal of Cancer 2014, 111 2214-19, the teachings of all of which regarding the foregoing are hereby expressly incorporated by reference herein.

[0234] 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 thought to be a “brake” that binds to a costimulatory molecule on antigen-presenting cells, preventing it from interacting with CD28 on T cells, and also produces a dominant inhibitory signal to suppress T cell activation. Examples of CTLA-4 inhibitors include antibodies that specifically bind CTLA-4. Particular anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. The availability, methods of production, mechanism of action, and clinical studies 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, 111 2214-19, the teachings of all of which regarding the foregoing are hereby expressly incorporated by reference herein.

[0235] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor. LAG-3, lymphocyte-activation gene 3, is a negative costimulatory receptor that modulates T cell homeostasis, proliferation, and activation. In addition, LAG-3 has been reported to be involved in the suppressive function of regulatory T cells (Tregs). The majority of LAG-3 molecules remain intracellular, near the microtubule organizing center, and are only induced upon antigen-specific T cell activation. (See U.S. Patent Application Publication No. 2014 / 0286935). LAG-3 inhibitors include antibodies that specifically bind 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 related studies, 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, the teachings of all of which regarding the foregoing are hereby expressly incorporated by reference herein.

[0236] 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 intensity of TH1 and TC1 T cell responses. The TIM-3 pathway has been implicated in the dysfunction of CD8 T cells in chronic viral infections and cancer. +expression on T cells and Tregs, both of which immune cell populations have been reported to contribute to immune suppression in tumor tissue and are considered targets 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, methods of production, mechanism of action, and studies of TIM-3 inhibitors, see U.S. Patent Application Publication No. 2015 / 0225457, U.S. Patent Application Publication No. 2013 / 0022623, U.S. 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, the teachings of all of which regarding the foregoing are hereby incorporated by reference herein.

[0237] In some embodiments, the immune checkpoint inhibitor is a CD47 inhibitor (see Unanue, E.R., PNAS 2013, 110: 10886-87, the teachings of which regarding the foregoing are hereby incorporated by reference herein).

[0238] The term "antibody" refers to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity. In some embodiments, "antibody" refers to soluble receptors that do not have the Fc portion of an antibody. In some embodiments, these antibodies are humanized monoclonal antibodies and fragments thereof prepared by recombinant genetic engineering.

[0239] Another class of immune checkpoint inhibitors includes polypeptides that bind to and block the PD-1 receptor on T cells without triggering inhibitory signal transduction. U.S. Patent No. 8,114,845 (the teachings of which regarding the foregoing are hereby incorporated by reference herein) describes such peptides, including B7-DC polypeptides, B7-H1 polypeptides, B7-1 polypeptides, and B7-2 polypeptides, and soluble fragments thereof.

[0240] Another class of immune checkpoint inhibitors includes compounds having a peptide moiety that inhibits PD-1 signaling, as disclosed in U.S. Patent No. 8,907,053, the teachings of which regarding the foregoing are hereby incorporated by reference herein.

[0241] Another class of immune checkpoint inhibitors includes inhibitors of certain metabolic enzymes, such as indoleamine 2,3 dioxygenase (IDO), which is expressed by infiltrating myeloid cells and tumor cells. The IDO enzyme suppresses the immune response by depleting amino acids necessary for T cell anabolic function, or by synthesizing natural ligands for specific cytosolic receptors that alter lymphocyte function (Lob, Cancer Immunol Immunother, 2009, 58. T53-57). Particular IDO blockers include, but are not limited to, L-levo-l-methyl-tryptophan (L-lMT) and l-methyl-tryptophan (1MT) (Lob et al., Cancer Immunol Immunother 2009, 58. T53-7; the teachings of which regarding the foregoing are hereby incorporated by reference herein).

[0242] 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.

[0243] The other prophylactically or therapeutically active agents described above, one or more of which can be used in conjunction with the compounds of Formula (I), (II), or (III), are prepared and administered according to methods described in the art.

[0244] The terms "disease or disorder in which inhibition or degradation of PTP1B / TC-PTP confers a benefit" and the like refer to a disease or disorder in which PTP1B / TC-PTP is important or necessary for, e.g., the occurrence, development, manifestation of the disease or disorder, or a disease or disorder that is known to be treatable by a PTP1B / TC-PTP inhibitor or degrader.

[0245] The term "additional prophylactic or therapeutic agent" refers to a prophylactic or therapeutic agent other than the compound of the present disclosure and known to treat the disease or disorder of interest.

[0246] The terms "disease" or "disorder" mean a condition that is generally regarded as a pathological state or a functional disorder and / or abnormality, and can manifest in the form of specific signs, symptoms, and / or dysfunction.

[0247] The terms "treat," "treating," "treatment," and the like, as used herein, refer to eliminating, reducing, or ameliorating a disease or condition and / or symptoms associated therewith. While not excluding, treatment of a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. The term "treatment" and synonyms thereof encompass administration of a prophylactically or therapeutically effective amount of a compound described herein to a subject in need of such treatment. Treatment can be directed to symptoms, e.g., inhibiting symptoms. It can be short term treatment, intermediate term treatment, or can be long term treatment, e.g., in the context of maintenance therapy.

[0248] The terms "prevent," "preventing," and "prevention" refer to a method of preventing the onset and / or symptoms associated with a disease or condition, or preventing a subject from acquiring a disease. As used herein, "prevention" also includes delaying the onset of a disease and / or symptoms associated therewith, and reducing the risk of a subject acquiring a disease. The term "prevention" can include "prophylactic treatment," which refers to reducing the likelihood of a disease or condition recurring, or reducing the likelihood of a previously controlled disease or condition relapsing, in a subject who is not currently afflicted with the disease or condition, but who is at risk of, or susceptible to, the disease or condition recurring or relapsing.

[0249] Those skilled in the art will appreciate that the disclosure is not limited to the specific details and embodiments described above. Rather, the scope of the disclosure includes combinations and sub-combinations of various features described above, as well as variations and modifications that can be apparent to those skilled in the art upon reading this description, and which are not outside the scope of the disclosure.

[0250] Examples

[0251] Unless otherwise indicated, all reagents were purchased from commercial suppliers and used without further purification. The protected non-hydrolysable phosphotyrosine mimic 4-(difluorophosphonomethyl)-N-(9-fluorenylmethyloxycarbonyl)-L-phenylalanine) (Fmoc F2Pmp-OH) used as a starting point for inhibitor development was prepared using methods known in the art (M. F. Gordeev et al., Tetrahedron Letters, 1994, 35, 7585-7588), the teachings of which with respect to the foregoing are hereby incorporated by reference herein.

[0252] Thin layer chromatography was performed on glass pre-coated Merck silica gel 60 F254 plates and column chromatography was performed on KP-SIL silica gel (Biotage, USA). Flash column chromatography was performed on Biotage pre-packed columns using the automated flash chromatography system Biotage Isolera One.

[0253] 1 H and 13 C10 NMR spectra were recorded on a Bruker AVANCE 500 MHz spectrometer using dimethyl sulfoxide (DMSO-d6) as the solvent. Chemical shifts are expressed in ppm (δ-scale) with reference to the residual protonated solvent. Peak multiplicity is indicated by the following abbreviations: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplex), or br (broad singlet).

[0254] Mass spectrometry and purity data were acquired using an Agilent Technologies 6470 series triple quadrupole LC-MS. The purity of all final tested compounds was determined to be >95% (UV, λ = 254 nm). High-resolution mass spectrometry analysis was performed on an Agilent 6550iFunnel Q-TOF mass LC–MS.

[0255] Recombinant mouse IFN-γ was purchased from PeproTech Inc. Anti-ERK1 / 2 (product number: 4696), anti-phosphorylated ERK1 / 2 (product number: 9101), anti-p38 (product number: 9212), anti-phosphorylated p38 (product number: 9211s), anti-AKT (product number: 2920s), and anti-phosphorylated Akt473 (product number: 9271s) antibodies were purchased from Cell Signaling. Anti-HA (product number: SC-7392) and anti-GAPDH (product number: SC-59541) antibodies were purchased from Santa Cruz. pNPP was purchased from Thermo Scientific (product number: PI34045).

[0256] Abbreviations Used

[0257] rt - room temperature; HPLC - high performance liquid chromatography; LC / MS - liquid chromatography-mass spectrometry;

[0258] 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-tetramethylurea hexafluorophosphate; HOBt - hydroxybenzotriazole; TFA - trifluoroacetic acid; TIS - triisopropylsilane; DMSO - dimethyl sulfoxide; AcOH - acetic acid; 5(6)-FAM SE - 5-(and-6)-carboxyfluorescein, succinimide ester mixed isomer; JAK - Janus kinase; STAT - signal transduction and transcription activator.

[0259] Example 1

[0260] General procedure for solid phase peptide synthesis

[0261] General procedure A: Activation of Rink amide resin.

[0262] The Rink amide resin was mixed with DCM (1 mL / 100 mg resin) and shaken for 30 min. After activation, the resin was washed with DMF (1 mL / 100 mg resin) three times.

[0263] General procedure B: Removal of Fmoc group from Rink amide resin

[0264] The Rink amide resin was mixed with 30% piperidine in DMF and shaken for 30 min, then washed with DMF (1 mL / 100 mg resin, 3 times), isopropanol (1 mL / 100 mg resin, 3 times) and DCM (1 mL / 100 mg resin, 3 times) in that order. Removal of the Fmoc group was confirmed by the ninhydrin test.

[0265] General procedure C: Removal of Alloc group from Rink amide resin.

[0266] The resin was washed with DCM (1 mL / 100 mg resin, 5 times) and shaken with a solution of tetrakis(triphenylphosphine)-palladium(0) (10 mg), AcOH (0.5 mL) and NMM (0.2 mL) in DCM (10 mL) under N2overnight. The resin was then washed with DMF (1 mL / 100 mg resin, 3 times), isopropanol (1 mL / 100 mg resin, 3 times) and DCM (1 mL / 100 mg resin, 3 times). Removal of the Alloc group was confirmed by the ninhydrin test.

[0267] General procedure D: Coupling of carboxylic acid to Rink amide resin.

[0268] The carboxylic acid (5 equivalents, 0.5 M in DMF) was first mixed with HBTU (5 equivalents, 0.5 M in DMF), HOBt (5 equivalents, 0.5 M in DMF) and NMM (15 equivalents, 1.5 M in DMF). The mixture was then added to the resin and shaken for 2 h. The resin was then washed with DMF (1 mL / 100 mg resin, 3 times), isopropanol (1 mL / 100 mg resin, 3 times) and DCM (1 mL / 100 mg resin, 3 times). Completion of the coupling reaction was confirmed by the ninhydrin test.

[0269] General procedure E: Cleavage of peptide from Rink amide resin.

[0270] The resin was washed with DCM (1 mL / 100 mg resin, 5 times) and then shaken with 95% TFA, 2.5% TIS and 2.5% H2O (1 mL / 100 mg resin). The resin was removed by filtration and the TFA was evaporated in vacuo. The crude peptide was obtained after trituration with diethyl ether (5 mL / 100 mg resin, 2 times).

[0271] Example 2

[0272] Library Assembly

[0273] Libraries were prepared on a FreedomEVO workstation (Tecan) using a 96 channel MCA tip module, using disposable tips. The procedure was as follows:

[0274] DMF solutions of 576 different carboxylic acids (40 mM, 10 μL) were placed in six 96-well microplates. HBTU (35 mM, 10 μL), HOBt (50 mM, 10 μL) and NMM (200 mM, 10 μL) were added sequentially to each well of the microplates. Library precursor 1, 2 or 3 (2 mM in DMF, 10 μL) was then added to each well. After 1 hour, the reaction was quenched with cyclohexylamine (87 mM in DMF, 10 μL). Finally, 190 μL of DMSO was added to each well to make a format ready for screening. The libraries were stored at -20°C.

[0275] As shown, the fluorescein-labelled precursors for each generation of library were synthesised by solid phase peptide synthesis.

[0276] Synthesis of first generation library intermediate 1

[0277]

[0278]

[0279] 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-F2Pmp-OH / HBTU / HOBt / NMM; (f) AcOH / HBTU / HOBt / NMM; (g) tetrakis(triphenylphosphine)- palladium(0), AcOH / NMM / CH2Cl2; (h) Fmoc-Cl / NMM; (i) TFA / H2O / TIS (95:2.5:2.5); (j) 5-(and-6) carboxyfluorescein succinimidyl ester / NMM.

[0280] Synthesis of compound 1a

[0281] Compound 1a was synthesized on Rink amide resin using standard Fmoc chemistry. The resin was first activated using General Procedure A (200 mg, loading 0.5 mmol / g). Fmoc group was removed using General Procedure B with 30% piperidine in DMF. The resin was then coupled with Fmoc-Lys(Boc)-OH using General Procedure D and the Fmoc group was removed using General Procedure B. Then the resin was sequentially coupled with Fmoc-Ala-OH, Fmoc-Lys(Alloc)-OH, Fmoc-F2Pmp-OH and AcOH. The Alloc group was 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, yield 35%). Mass calculated [M] 884.36, found [M+H] 885.41. + 885.41.

[0282] Synthesis of compound 1b

[0283] Compound 1a (31.5 mg) was treated with 5(6)-FAMSE (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, yield 37%). Mass calculated [M] 1243.41, found [M+H] 1244.39. + 1244.39.

[0284] Synthesis of intermediate 1

[0285] Compound 1b (16.39 mg) was treated with 30% piperidine in DMF (10 mL) for 30 min. After evaporation of the solvent, the crude product was purified by reverse phase HPLC to give intermediate 1 (6.9 mg, yield 51%). Mass calculated [M] 1021.34, found [M+H] 1022.37. + 1022.37.

[0286] Example 3

[0287] Synthesis of second generation library intermediate 2

[0288]

[0289] 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 / CH2Cl2; (f) 3-bromo-4-methylbenzoic acid / HBTU / HOBt / NMM; (g) Fmoc-F2Pmp-OH / HBTU / HOBt / NMM; (h) TFA / H2O / TIS (95:2.5:2.5); (i) 5-(and-6)-carboxyfluorescein succinimidyl ester / NMM.

[0290] Synthesis of compound 2a

[0291] Compound 2a was synthesised on Rink amide resin using standard Fmoc chemistry. The resin was first activated (200 mg, loading 0.5 mmol / g) (General procedure A) and then the Fmoc group was removed (General procedure B). The resin was then coupled with Fmoc-Lys(Boc)-OH, Fmoc-Ala-OH and Fmoc-Lys(Alloc)-OH in turn (General procedure D). The Alloc group was then removed (General procedure C) and the exposed amine coupled with 3-bromo-4-methylbenzoic acid. The Fmoc group was removed and the exposed amine coupled with Fmoc-F2Pmp-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). Mass calculated [M] 1039.31, found [M+H] 1040.32. +

[0292] Synthesis of compound 2a

[0293] Compound 2a (33.3 mg) was treated with a solution of 5(6)-FAMSE (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). Mass calculated [M] 1397.35, found [M+H] 1398.31. +

[0294] Synthesis of intermediate 2

[0295] ​​Compound 2b (13.9 mg) was treated with 30% piperidine in DMF (10 mL) for 30 min. After evaporation of the solvent, the crude product was purified by reverse phase HPLC to give intermediate 2 (6.4 mg, 55% yield). Mass calculated [M] 1175.29, found [M+H] 1176.33. + 1176.33.

[0296] Example 4

[0297] Synthesis of third generation library intermediate 3

[0298]

[0299] 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 / CH2Cl2; (f) 3-bromo-4-methylbenzoic acid / HBTU / HOBt / NMM; (g) Fmoc-F2Pmp-OH / HBTU / HOBt / NMM; (h) Fmoc-Phe-OH / HBTU / HOBt / NMM; (i) TFA / H2O / TIS (95:2.5:2.5); (j) 5-(and-6)-carboxyfluorescein succinimidyl ester / NMM.

[0300] Synthesis of compound 3a

[0301] Compound 3a was synthesized on Rink amide resin using standard Fmoc chemistry. The resin (200 mg, loading 0.5 mmol / g) was first activated (General procedure A) and then the Fmoc group was removed (General procedure B). The exposed amine group was coupled sequentially 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 group was coupled with 3-bromo-4-methylbenzoic acid. After that, the Fmoc group was removed and coupled sequentially with Fmoc-F2Pmp-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). Mass calculated [M] 1186.37, found [M+H] 1187.34. + 1187.34.

[0302] Synthesis of compound 3b

[0303] Compound 3a (43.6 mg) was treated with a solution of 5(6)-FAMSE (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, yield 31 %). Mass calculated [M] 1544.42, found [M+H] 1545.40. + 1545.40.

[0304] Synthesis of intermediate 3.

[0305] Compound 3b (17.6 mg) was treated with a solution of 30% piperidine in DMF (10 mL) for 30 min. After evaporation of the solvent, the crude product was purified by reverse phase HPLC to give intermediate 3 (9.5 mg, yield 63 %). Mass calculated [M] 1322.35, found [M+H] 1323.39. + 1323.39.

[0306] Example 5

[0307] 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

[0308] ((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, loading 0.5 mmol / g) was first activated (General procedure A) and then 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. After removal of the Fmoc group, the resin was sequentially coupled with Fmoc-F2Pmp-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, yield 35 %). Mass calculated [M] 660.12, found [M+H] 661.40. +661.17. 1 H 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).

[0309]

[0310] 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 / CH2Cl2; (d) 3-bromo-4-methylbenzoic acid / HBTU / HOBt / NMM; (e) Fmoc-F2Pmp-OH / HBTU / HOBt / NMM; (f) AcOH / HBTU / HOBt / NMM; (g) TFA / H2O / TIS (95:2.5:2.5).

[0311] Example 6

[0312] 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

[0313] ((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, loading 0.5 mmol / g) 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 then coupled sequentially with Fmoc-F2Pmp-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). Mass calcd [M] 807.18, found [M+H] + 808.17. 1H 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).

[0314]

[0315] 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. (a) 30% piperidine / DMF; (b) Fmoc-Lys(Alloc)-OH / HBTU / HOBt / NMM; (c) tetrakis(triphenylphosphine)-palladium(0), AcOH / NMM / DCM; (d) 3-bromo-4-methylbenzoic acid / HBTU / HOBt / NMM; (e) Fmoc-F2Pmp-OH / HBTU / HOBt / NMM; (f) Fmoc-Phe-OH / HBTU / HOBt / NMM; (g) AcOH / HBTU / HOBt / NMM; (h) TFA / H2O / TIS (95:2.5:2.5).

[0316] Example 7

[0317] 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

[0318] ((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 was activated (200 mg, loading 0.5 mmol / g) (General Procedure A) and then 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-F2Pmp-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 calcd [M] 929.22, found [M+H] 930.24. + 930.24. 1H 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).

[0319]

[0320] 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 / CH2Cl2; (d) 3-bromo-4- ethylbenzoic acid / HBTU / HOBt / NMM; (e) Fmoc-F2Pmp-OH / HBTU / HOBt / NMM; (f) Fmoc-Phe-OH / HBTU / HOBt / NMM; (g) homovanillic acid / HBTU / HOBt / NMM; (h) TFA / H2O / TIS (95:2.5:2.5).

[0321] Example 8

[0322] Synthesis of Intermediate 6

[0323] (S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl)propionic acid benzyl ester (Intermediate 4)

[0324] To a stirred mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-(4- iodophenyl)propionic 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 (r.t.) for 4 h. Upon 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 Na2SO4and evaporated in vacuo. The product was then purified by flash chromatography (EtOAc / n-hexane, 0%→10%). Yield: 8.80 g (72%). 1 H 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 (ddd, J = 9.8, 8.0, 5.6 Hz, 1H), 2.94 (dd, J = 13.7, 5.6 Hz, 1H), 2.83 (dd, J = 13.7, 9.8 Hz, 1H), 1.30 (s, 9H). LC / MS m / z calcd [M+H] + 482.08, found 482.18.

[0325] (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((diethoxyphosphoryl)difluoromethyl)phenyl)propionic acid benzyl ester (Intermediate 5)

[0326] Intermediate 4 (10.00 g, 20.8 mmol, 1.0 eq) was dissolved in anhydrous DMF (100 mL) and then CuBr (5.97 g, 41.6 mmol, 2 eq) and half of the supernatant of Cd reagent 7 (about 1.7 eq, according to C. Meyer, M. Prepared according to the procedure described in WO 2011 / 006, 6). After 3 h, CuBr (2.98 g, 20.8 mmol, 1 equiv.) and the other half of the Cd reagent solution were added. The reaction was stirred at room temperature for a total of 19 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with EtOAc (500 mL), filtered over Celite, extracted with aqueous NH4CI (2 x 500 mL) and brine (500 mL). The organic layer was dried over anhydrous Na2S04and evaporated in vacuo. The product was purified by flash chromatography (EtOAc / n-hexane, 0% 10%). Yield 11.86 g (57%). 1 H 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, 4H), 3.09 (dd, J = 13.8, 5.4 Hz, 1H), 2.95 (dd, J = 13.8, 10.0 Hz, 1H), 1.29 (s, 9H), 1.19 (td, J = 7.1, 1.5 Hz, 6H). LC / MS m / z calcd for [M+H] + 542.21, found 542.28.

[0327] (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((diethoxyphosphoryl)difluoromethyl)phenyl)propanoic acid (Intermediate 6)

[0328] To a solution of Intermediate 5 (8.98 g, 16.6 mmol, 1.0 equiv.) in EtOAc (50 mL) was added Pd / C (10 wt% loading, 750.0 mg). The reaction mixture was evacuated and charged with H2three 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% 5%). Yield 6.66 g (89%). 1 H 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, 4H), 3.09 (dd, J = 13.8, 5.4 Hz, 1H), 2.95 (dd, J = 13.8, 10.0 Hz, 1H), 1.29 (s, 9H), 1.19 (td, J = 7.1, 1.5 Hz, 6H). LC / MS m / z calcd for [M+H] + 452.16, found 452.23.

[0329]

[0330] Synthesis of Intermediate 6

[0331] Example 9

[0332] Synthesis of Intermediate 10

[0333] N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysine benzyl ester (Intermediate 8)

[0334] To a mixture of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert- butoxycarbonyl)-L-lysine (10.00 g, 21.34 mmol, 1.0 equiv) and K2CO3(4.42 g, 32.01 mmol, 1.5 equiv) in DMF (100 mL) was added benzyl bromide (5.47 g, 32.01 mmol, 1.5 equiv). The mixture was then stirred at room temperature for 4 hours. Upon 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 Na2SO4and evaporated in vacuo. The product was then purified by flash chromatography (EtOAc / n-hexane, 0%→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 calcd [M+H] + 559.28, found 559.39.

[0335] N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(3-bromo-4-methylbenzoyl)-L-lysine benzyl ester (Intermediate 9)

[0336] To a solution of Intermediate 8 (7.50 g, 13.42 mmol, 1.0 equiv) in DCM (80 mL) was added trifluoroacetic acid (20 mL) and stirred at room temperature for 4 hours. The excess reagent and solvent were then evaporated under reduced pressure to give the deprotected amine which was used in the next step without further purification.

[0337] The deprotected amine, 3-bromo-4-methylbenzoic acid (3.17 g, 14.76 mmol, 1.1 equiv), HOAt (2.19 g, 16.10 mmol, 1.2 equiv) and DIPEA (12.14 g, 93.94 mmol, 7.0 equiv) were then dissolved in DMF (100 mL) and stirred at 0 °C. To the stirring solution, HATU (7.65 g, 20.13 mmol, 1.5 equiv) was slowly added. After 15 min, the reaction mixture was diluted with EtOAc (800 mL) and washed with brine (3 x 500 mL). The organic layer was dried over anhydrous Na2S04and evaporated in vacuo. The product was then purified by flash chromatography (EtOAc / n-hexane, 0%→ 40%). Two-step yield 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 calcd [M+H] + 655.18, found 655.22.

[0338] N6-(3-bromo-4-methylbenzoyl)-N2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4- ((diethoxyphosphoryl)difluoromethyl)phenyl)propanoyl)-L-lysine benzyl ester (Intermediate 10)

[0339] To a solution of Intermediate 9 (7.10 g, 10.82 mmol, 1.0 equiv) in DCM (80 mL) was added diethylamine (20 mL) and stirred at room temperature for 4 h. Then, the excess reagent and solvent were evaporated under reduced pressure to give the crude deprotected amine, which was then purified by flash chromatography (MeOH / DCM, 0%→ 10%).

[0340] The deprotected amine, intermediate 6 (5.37 g, 11.90 mmol, 1.1 equiv), HOAt (1.77 g, 12.98 mmol, 1.2 equiv) and DIPEA (5.59, 43.28 mmol, 4.0 equiv) were then dissolved in DMF (100 mL) and stirred at 0 °C. To the stirring solution was slowly added HATU (6.17 g, 16.23 mmol, 1.5 equiv). After 15 min, the reaction mixture was diluted with EtOAc (800 mL) and washed with brine (3 x 500 mL). The organic layer was dried over anhydrous Na2S04and evaporated in vacuo. The product was then purified by flash chromatography (cyclohexane-EtOAc, 6:1→ 2:1). Two-step yield 7.22 g (77%). 1 H 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 calcd [M+H] + 866.26, found 866.28.

[0341]

[0342] Synthesis of intermediate 10

[0343] Example 10

[0344] Synthesis of intermediate 12

[0345] Methyl (2-(4-hydroxy-3-methoxyphenyl)acetyl)-L-phenylalaninate (intermediate 11)

[0346] L-phenylalanine methyl ester (5.00 g, 27.90 mmol, 1.0 equiv), 2-(4-hydroxy-3- methoxyphenyl)acetic acid (5.59 g, 30.69 mmol, 1.1 equiv), HOAt (4.56 g, 33.48 mmol, 1.2 equiv) and DIPEA (14.42 g, 111.60 mmol, 4.0 equiv) were dissolved in DMF (100 mL) and stirred at 0 °C. To the stirring solution was added HATU (15.91 g, 41.85 mmol, 1.5 equiv) slowly. After 15 min, the reaction mixture was diluted with EtOAc (600 mL) and washed with brine (3 x 500 mL). The organic layer was dried over anhydrous Na2SO4and evaporated in vacuo. The product was then purified by flash chromatography (cyclohexane-ethyl acetate, 6:1→ 2:1) to 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 calcd for [M+H] + 344.15, found 344.24.

[0347] (2-(4-hydroxy-3-methoxyphenyl)acetyl)-L-phenylalanine (Intermediate 12)

[0348] To a solution of Intermediate 11 (5.22 g, 15.20 mmol) in THF (50 mL) was added 0.5 M aqueous LiOH. The mixture was stirred at room temperature for 4 h. To the reaction mixture was then added 50 mL of 1.0 M aqueous HC1. 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 Na2SO4, and evaporated in vacuo to give crude Intermediate 8. This crude product was used in the subsequent synthesis without further purification.

[0349]

[0350] Synthesis of Intermediate 12

[0351] Example 11

[0352] Synthesis of intermediate 14 (PTP1B / TC-PTP dual ligand)

[0353] N6-(3-bromo-4-methylbenzoyl)-N2-((S)-3-(4-((diethoxyphosphoryl)difluoromethyl)phenyl)-2- ((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)propionyl)-L- lysine benzyl ester (intermediate 13)

[0354] 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 room temperature for 6 h. Then, excess reagent and solvent were evaporated under reduced pressure to give the crude deprotected amine, which was used in the next step without further purification.

[0355] 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. To the stirred solution was added HATU (3.81 g, 10.02 mmol, 1.5 eq) slowly. After 15 min, the reaction mixture was diluted with EtOAc (300 mL) and washed with brine (3 x 300 mL). The organic layer was dried over anhydrous Na2S04and evaporated in vacuo. The product was then purified by flash chromatography (EtOAc / n-hexane, 50%→100%). Two-step yield 4.89 g (69%). 1HNMR (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 calcd [M+H] + 1077.32, found 1077.38.

[0356] N6-(3-bromo-4-methylbenzoyl)-N2-((S)-3-(4-(difluoro(phosphoryl)methyl)phenyl)-2- ((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)propanoyl)-L- lysine (Intermediate 14)

[0357] 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 purged with hydrogen gas three times. The mixture was then stirred at room temperature for 12 hours. After the reaction was complete, 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.

[0358] A solution of the deprotected carboxylic acid in anhydrous DCM (25 mL) was cooled to 0 °C and stirred vigorously. Trimethylsilyl iodide (3.25 g, 16.24 mmol, 7.0 equiv) was then added dropwise to the solution. The reaction was maintained at 0 °C and monitored by LC-MS. Upon completion of the reaction, the reaction mixture was added dropwise to a 50% MeCN / H2O mixture and stirred at room temperature for 30 min. The water and organic solvents were then evaporated in vacuo to give crude intermediate 10, which was further purified by preparative HPLC (MeOH / H2O, 50%→90%). Two-step yield 1.09 g (47%). 1 H 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 calcd [M-H] - 931.20, found 931.35.

[0359]

[0360] Synthesis of intermediate 14 (PTP1B / TC-PTP dual ligand)

[0361] Example 12

[0362] General synthetic method for the tethering of the linker-VHL ligand connection

[0363] The linker-VHL ligand attachment structure was based on 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 solution of the Boc-protected linker (0.50 mmol, 1.0 equiv, commercial), (S,R,S)-APLC / (S,R,S)-AHPC-Me (0.55 mmol, 1.1 equiv, synthesized using 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 equiv), and DIPEA (2.00 mmol, 4.0 equiv) in DMF was added HATU (0.75 mmol, 1.5 equiv). After 15 min, the reaction was quenched with deionized (D.I.) water and the mixture was purified by reverse-phase flash column to yield the indicated product (MeOH / H2O, 40%→100%). The yield was between 75% and 90%.

[0364]

[0365] General synthetic method for the synthesis of the linker-VHL ligand attachment structure of intermediates 15-22

[0366] Synthesis of intermediate 15

[0367]

[0368] 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). 1 HNMR (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

[0369] -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

[0370] - 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 calcd for [M+H] + 646.31, found 646.47.

[0371] Synthesis of Intermediate 16

[0372]

[0373] (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)carbamic acid tert-butyl ester (Intermediate 16). 1 H 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 calcd for [M+H] + 660.31, found 660.44.

[0374] Synthesis of Intermediate 17

[0375]

[0376] 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). 1 H 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 calcd [M+H] + 646.33, found 646.39.

[0377] Synthesis of Intermediate 18

[0378]

[0379] 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 8.97 (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 calcd [M+H] + 678.33, found 678.42.

[0380] Synthesis of Intermediate 19

[0381]

[0382] (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)carbamic acid tert-butyl ester (Intermediate 19). 1 H 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, J = 3.1 Hz, 2H), 2.43 (s, 3H), 2.06 - 2.01 (m, 1H), 1.93 - 1.88 (m, 1H), 1.37 (s, 9H), 1.01 (s, 9H). LC / MS m / z calcd [M+H] + 664.32, found 664.48.

[0383] Synthesis of Intermediate 20

[0384]

[0385] 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 tert-butyl carbonate (Intermediate 20). 1 H 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 calcd [M+H] + 670.36, found 670.43.

[0386] Synthesis of Intermediate 21

[0387]

[0388] 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 tert-butyl carbonate (Intermediate 20). 1H NMR (500 MHz, DMSO) 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 calcd [M+H] + 671.36, found 671.45.

[0389] Synthesis of Intermediate 22

[0390]

[0391] (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)carbamic acid tert-butyl ester (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 calcd [M+H] + 692.35, found 692.46.

[0392] Example 13

[0393] General synthetic method for PROTAC molecules

[0394]

[0395] To a solution of the Boc-protected linker-E3 ligand complex (1.0 equiv) in DCM (4 mL) was added trifluoroacetic acid (1 mL) and stirred at room temperature for 4 h. The excess reagent and solvent were then removed by evaporation under reduced pressure to give the crude deprotected amine, which was used in the next step without further purification.

[0396] The deprotected amine, intermediate 10 (1 equiv), HOAt (1.2 equiv), and DIPEA (7.0 equiv) were then dissolved in DMF (50 mL) and stirred at 0 °C. To the stirring solution was slowly added HATU (1.5 equiv). After 15 min, the reaction mixture was quenched with deionized water. The mixture was then purified by preparative HPLC (MeOH / H2O, 50%→90%) to give the indicated product. The yield was between 55% and 70%.

[0397] The linker-E3 ligand complexes of Examples 14-27 were synthesized using known methods (see, e.g., X. Han, et al., J. Med. Chem. 2019, 62, 941-964, the teachings of which with respect to the foregoing are hereby incorporated by reference herein).

[0398] Synthesis of PROTAC compound 6

[0399]

[0400] ((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)

[0401] The linker-E3 ligand complex was synthesized using known methods (X. Han, et al., J. Med. Chem. 2019, 62, 941-964). The NMR characterization results were consistent with the reported results. 1 H 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 calcd [M-H] - 1442.46, found 1442.58.

[0402] Example 14

[0403] Synthesis of PROTAC compound 8

[0404]

[0405] ((4-((S)-3-(((S)-6-(3-bromo-4-methylbenzamido)-1-((6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazo-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobut-2-yl)amino)-6-oxohexyl)amino)-1-oxohex-2-yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamityl)-3-phenylpropionamido)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid (compound 8)

[0406] The linker-E3 ligand complex was synthesized using a known method (X. Han, et al., J. Med. Chem. 2019, 62, 941–964). The NMR characterization results were consistent with the reported results. 1 H NMR(500MHz,DMSO)δ8.97(s,1H),8.57–8.45(m,2H),8.19(d,J=8.1Hz,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=2.0Hz,1H),6.56(d,J=8.1Hz,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). Calculated LC / MS m / z values ​​[MH] - 1456.47, the actual measured value is 1456.60.

[0407] Example 15

[0408] Synthesis of PROTAC compound 10

[0409]

[0410] ((4-((S)-3-(((S)-6-(3-bromo-4-methylbenzamido)-1-((7-(((R)-1-((2R,4S)-4-hydroxy-2-((4-(4-methylthiazo-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobut-2-yl)amino)-7-oxoheptyl)amino)-1-oxohex-2-yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamyl)-3-phenylpropionamido)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid (compound 10)

[0411] The linker-E3 ligand complex was synthesized using a known method (X. Han, et al., J. Med. Chem. 2019, 62, 941–964). The NMR characterization results were consistent with the reported results. 1 H NMR(500MHz,DMSO)δ8.96(d,J=3.7Hz,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=2.0Hz,1H),6.58(d,J=8.1Hz,1H),6.41(dd,J=8.2,2.1Hz,1H),4.55–4.48(m,2H),4.47–4.35(m,3H),4.35–4.2 8 (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). Calculated LC / MS m / z values ​​[MH] - 1470.49, measured value 1470.61.

[0412] Example 16

[0413] Synthesis of PROTAC compound 83

[0414]

[0415] ((4-((S)-3-(((S)-6-(3-bromo-4-methylbenzamido)-1-((8-(((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)-8-oxooctyl)amino)-1-oxohexan-2-yl)amino)-2-((S)-2-(2-(4- hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-3-oxopropyl)phenyl) difluoromethyl)phosphonic acid (Compound 83)

[0416] The linker-E3 ligand complex was synthesized using known methods (X. Han, et al., J. Med. Chem. 2019, 62, 941-964). The NMR characterization results were consistent with the reported results. 1 H 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 calcd [M-H] - 1484.50, found 1485.60.

[0417] Example 17

[0418] Synthesis of PROTAC Compound 14

[0419]

[0420] ((4-((S)-3-(((S)-6-(3-bromo-4-methylbenzamido)-1-((10-(((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)-10-oxodecyl)amino)-1-oxohexan-2-yl)amino)-2-((S)-2-(2-(4- hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-3-oxopropyl)phenyl) difluoromethyl)phosphonic acid (Compound 14)

[0421] The linker-E3 ligand complex was synthesized using known methods (X. Han, et al., J. Med. Chem. 2019, 62, 941-964). The NMR characterization results were consistent with the reported results. 1 H 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 calcd [M-H] - 1512.54, found 1512.61.

[0422] Example 18

[0423] Synthesis of PROTAC Compound 18

[0424]

[0425] ((4-((S)-3-(((S)-6-(3-bromo-4-methylbenzamido)-1-((12-(((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)-12-oxododecyl)amino)-1-oxohexan-2-yl)amino)-2-((S)-2-(2-(4- hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-3-oxopropyl)phenyl) difluoromethyl)phosphonic acid (Compound 18).

[0426] The linker-E3 ligand complex was synthesized using known methods (X. Han, et al., J. Med. Chem. 2019, 62, 941-964). The NMR characterization results were consistent with the 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 calcd [M-H] - 1540.57, found 1540.70.

[0427] Example 19

[0428] Synthesis of PROTAC Compound 28

[0429]

[0430] ((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-triazahexadecan-1-yl)phenyl) difluoromethyl)phosphonic acid (Compound 28)

[0431] 1 H 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 calcd [M-H] - 1458.45, found 1458.54.

[0432] Example 20

[0433] Synthesis of PROTAC Compound 27

[0434]

[0435] ((4-((2S,5S,15S)-5-(4-(3-bromo-4-methylbenzamido)butyl)-15-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)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-triazahexadecan-1-yl)phenyl) difluoromethyl)phosphonic acid (Compound 27)

[0436] 1 H NMR (500 MHz, DMSO) δ 9.01 (s, 1H), 8.53 - 8.47 (m, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.12 - 8.04 (m, 2H), 8.03 (d, J = 1.8 Hz, 1H), 8.00 - 7.84 (m, 1H), 7.87 (d, J = 9.3 Hz, 1H), 7.73 (dd, J = 7.9, 1.9 Hz, 1H), 7.44 - 7.29 (m, 9H), 7.17 - 7.08 (m, 5H), 6.65 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 7.9 Hz, 1H), 6.39 (dd, J = 8.1, 2.0 Hz, 1H), 4.93 - 4.84 (m, 1H), 4.61 - 4.49 (m, 2H), 4.49 - 4.38 (m, 2H), 4.29 - 4.20 (m, 2H), 3.66 - 3.52 (m, 7H), 3.41 - 3.30 (m, 2H), 3.29 - 3.10 (m, 6H), 3.07 (dd, J = 14.1, 4.2 Hz, 1H), 2.96 (dd, J = 14.0, 3.9 Hz, 1H), 2.89 - 2.79 (m, 1H), 2.73 - 2.65 (m, 1H), 2.52 (dd, J = 14.4, 6.9 Hz, 1H), 2.43 (s, 3H), 2.38 - 2.28 (m, 4H), 2.04 - 1.96 (m, 1H), 1.77 (ddd, J = 12.9, 8.5, 4.6 Hz, 1H), 1.69 - 1.41 (m, 4H), 1.37 - 1.19 (m, 5H), 0.91 (s, 9H). LC / MS m / z calcd [M-H] - 1472.47, found 1472.57.

[0437] Example 21

[0438] Synthesis of PROTAC Compound 40

[0439]

[0440] ((4-((S)-3-(((S)-6-(3-bromo-4-methylbenzamido)-1-((2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazo-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobut-2-yl)amino)-3-oxopropyl)benzyl)amino)-1-oxohex-2-yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamyl)-3-phenylpropionamido)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid (compound 40)

[0441] 1 H NMR(500MHz,DMSO)δ9.00(s,1H),8.52(dt,J=21.6,5.8Hz,2H),8.37(t,J=5.8Hz,1H ),8.17(dd,J=14.4,7.9Hz,1H),8.09–8.00(m,2H),7.96(d,J=9.3Hz,1H),7.76–7.69 (m,1H),7.42–7.26(m,9H),7.18–7.04(m,10H),6.65(d,J=1.9Hz,1H),6.56(d,J=8.0 Hz,1H),6.39(dd,J=8.1,2.0Hz,1H),4.62–4.50(m,2H),4.47–4.36(m,3H),4.35–4.2 8(m,4H),4.19(dd,J=15.9,5.4Hz,1H),3.69–3.53(m,6H),3.28–3.13(m,4H),3.06(d ,J=13.3Hz,1H),2.94(dd,J=13.8,3.7Hz,1H),2.88–2.73(m,3H),2.62–2.49(m,2H), 2.43–2.35 (m, 4H), 2.34 (d, J = 5.3 Hz, 3H), 2.01–1.95 (m, 1H), 1.93–1.83 (m, 1H), 1.75–1.65 (m, 1H), 1.64–1.55 (m, 1H), 1.54–1.44 (m, 2H), 1.37–1.18 (m, 2H), 0.87 (s, 9H). Calculated LC / MS m / z values ​​[MH] - 1504.47, measured value 1504.55.

[0442] Example 22

[0443] Synthesis of PROTAC compound 48

[0444]

[0445] ((4-((S)-3-(((S)-6-(3-bromo-4-methylbenzamido)-1-((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)amino)-1-oxohexan-2-yl)amino)-2-((S)-2-(2-(4- hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)-3-oxopropyl)phenyl) difluoromethyl)phosphonic acid (Compound 48)

[0446] 1 H NMR (500 MHz, DMSO) δ 8.99 (s, 1H), 8.56 (t, J = 6.1 Hz, 1H), 8.50 (t, J = 5.5 Hz, 1H), 8.42 (t, J = 6.1 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.16 - 8.00 (m, 4H), 7.73 (dd, J = 7.8, 1.8 Hz, 1H), 7.38 (dd, J = 10.5, 7.6 Hz, 6H), 7.31 (d, J = 8.0 Hz, 2H), 7.23 - 7.00 (m, 10H), 6.65 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.39 (dd, J = 8.1, 1.9 Hz, 1H), 4.60 - 4.54 (m, 1H), 4.51 - 4.37 (m, 4H), 4.33 - 4.14 (m, 5H), 3.66 - 3.55 (m, 6H), 3.42 (d, J = 13.9 Hz, 1H), 3.29 - 3.12 (m, 4H), 3.11 - 3.05 (m, 1H), 2.99 - 2.91 (m, 1H), 2.89 - 2.79 (m, 1H), 2.73 - 2.65 (m, 1H), 2.42 (s, 3H), 2.35 (s, 3H), 2.04 - 1.97 (m, 1H), 1.87 (ddd, J = 12.9, 8.6, 4.6 Hz, 1H), 1.75 - 1.65 (m, 1H), 1.64 - 1.44 (m, 3H), 1.38 - 1.25 (m, 2H), 0.90 (s, 9H). LC / MS m / z calcd [M-H] - 1490.46, found 1490.54.

[0447] Example 23

[0448] Synthesis of PROTAC Compound 54

[0449]

[0450] ((4-((S)-3-(((S)-6-(3-bromo-4-methylbenzamido)-1-((4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazo-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobut-2-yl)carbamoyl)benzyl)amino)-1-oxohex-2-yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamitrile)-3-phenylpropionamido)-3-oxopropyl)phenyl)difluoromethyl)phosphonic acid (compound 54)

[0451] 1 H NMR(500MHz,DMSO)δ8.98(s,1H),8.59–8.53(m,1H),8.53–8.44(m,2H),8.19(dd,J=24.3,7.9H z,2H),8.09–8.01(m,2H),7.91(d,J=9.0Hz,1H),7.81(d,J=7.9Hz,2H),7.75–7.68(m,1H),7.42 –7.35(m,7H),7.35–7.27(m,4H),7.17–7.08(m,5H),6.65(d,J=2.0Hz,1H),6.56(d,J=8.0Hz,1H ),6.39(dd,J=8.1,2.0Hz,1H),4.75(d,J=9.0Hz,1H),4.58(td,J=8.6,4.3Hz,1H),4.48–4.24(m ,7H),4.24–4.19(m,1H),3.73–3.67(m,2H),3.64(s,3H),3.62–3.57(m,1H),3.28–3.18(m,3H) ,3.16(d,J=13.6Hz,1H),3.12–3.04(m,1H),2.95(dd,J=13.8,4.1Hz,1H),2.84(dt,J=14.0,6.8 Hz, 1H), 2.69 (dd, J = 14.1, 10.2 Hz, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 2.05–1.98 (m, 1H), 1.90 (ddd, J = 12.9, 8.6, 4.6 Hz, 1H), 1.76–1.66 (m, 1H), 1.64–1.45 (m, 3H), 1.28–1.19 (m, 2H), 1.00 (s, 9H). Calculated LC / MS m / z values ​​[MH] - 1476.44, measured value 1476.59.

[0452] Example 24

[0453] Synthesis of PROTAC Compound 58

[0454]

[0455] ((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)

[0456] 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 calcd [M-H] - 1482.49, found 1482.61.

[0457] Example 25

[0458] Synthesis of PROTAC Compound 56

[0459]

[0460] ((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)

[0461] 1 H 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 calcd [M-H] - 1483.48, found 1483.62.

[0462] Example 26

[0463] Synthesis of PROTAC cis Compound 47

[0464]

[0465] 1H NMR (500 MHz, DMSO) δ 8.97 (d, J = 3.2 Hz, 1H), 8.70 (br s, 1H), 8.53 - 8.47 (m, 1H), 8.35 - 8.28 (m, 1H), 8.16 (dd, J = 23.7, 7.9 Hz, 1H), 8.09 - 8.00 (m, 2H), 7.73 (dd, J = 7.9, 1.9 Hz, 1H), 7.43 - 7.33 (m, 8H), 7.31 (d, J = 7.9 Hz, 2H), 7.22 - 7.07 (m, 9H), 7.07 (d, J = 7.6 Hz, 2H), 6.65 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.39 (dd, J = 8.2, 1.9 Hz, 1H), 5.30 (s, 1H), 4.95 - 4.87 (m, 1H), 4.61 - 4.54 (m, 1H), 4.48 - 4.37 (m, 2H), 4.34 - 4.21 (m, 5H), 4.15 (q, J = 5.7 Hz, 1H), 3.86 - 3.79 (m, 1H), 3.65 - 3.54 (m, 5H), 3.41 (d, J = 13.9 Hz, 1H), 3.34 (dd, J = 10.1, 5.3 Hz, 1H), 3.28 - 3.13 (m, 3H), 3.07 (d, J = 12.5 Hz, 1H), 2.95 (dd, J = 13.9, 4.0 Hz, 1H), 2.89 - 2.79 (m, 1H), 2.73 - 2.65 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H), 2.31 - 2.23 (m, 1H), 1.75 - 1.41 (m, 5H), 1.55 - 1.47 (m, 2H), 1.39 - 1.20 (m, 5H), 0.92 (s, 9H).

[0466] Example 27

[0467] Synthesis of PROTAC Compound 47

[0468]

[0469] ((4-((S)-3-(((S)-6-(3-bromo-4-methylbenzamido)-1-((3-(2-(((S)-1-((2S,4R)-4- hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)aminocarbonyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)benzyl)amino)-1-oxohexan-2- yl)amino)-2-((S)-2-(2-(4-hydroxy-3-methoxyphenyl)acetamido)-3-phenylpropanamido)- 3-oxopropyl)phenyl) difluoromethyl)phosphonic acid (Compound 47)

[0470] 1 H NMR (500 MHz, DMSO) δ 8.99 (s, 1H), 8.51 (t, J = 5.2 Hz, 1H), 8.41 (dd, J = 26.6, 6.9 Hz, 2H), 8.23 - 7.96 (m, 5H), 7.74 (d, J = 8.0 Hz, 1H), 7.44 - 7.35 (m, 6H), 7.32 (d, J = 8.1 Hz, 2H), 7.23 - 7.15 (m, 2H), 7.15 - 7.10 (m, 6H), 7.07 (d, J = 7.9 Hz, 2H), 6.65 (s, 1H), 6.57 (d, J = 7.9 Hz, 1H), 6.39 (d, J = 7.9 Hz, 1H), 4.90 (p, J = 7.2 Hz, 1H), 4.62 - 4.53 (m, 1H), 4.50 - 4.38 (m, 3H), 4.32 - 4.17 (m, 4H), 3.65 - 3.54 (m, 6H), 3.45 - 3.39 (m, 1H), 3.29 - 3.12 (m, 5H), 3.08 (d, J = 12.3 Hz, 1H), 2.95 (dd, J = 14.0, 4.0 Hz, 1H), 2.89 - 2.80 (m, 1H), 2.70 (dt, J = 13.9, 6.3 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 3H), 2.03 - 1.95 (m, 1H), 1.80 - 1.68 (m, 2H), 1.60 (d, J = 9.8 Hz, 1H), 1.52 - 1.44 (m, 2H), 1.39 - 1.18 (m, 5H), 0.89 (s, 9H). 13C NMR (126 MHz, DMSO) δ 171.91 (2C), 171.77, 171.07 (2C), 170.30, 169.88, 164.92, 158.36, 152.05, 147.62, 145.43, 145.14, 140.89, 140.43, 139.56, 138.22, 136.99, 134.60, 131.38, 131.13, 130.16, 129.64 (2C), 129.53, 129.30 (3C), 128.66, 128.57, 128.33 (2C), 127.98, 127.63, 127.16, 126.96, 126.69, 126.84 (3C), 126.57, 126.28, 125.40, 124.47, 121.68, 115.57, 113.61, 69.23, 59.04, 57.04, 56.76, 55.90, 54.10, 54.08, 53.20, 49.06, 48.17, 42.49, 42.17, 42.04, 38.19, 37.74, 37.52, 35.87, 32.48, 29.24, 26.86 (3C), 23.36, 22.90, 22.81, 16.44. LC / MS m / z calcd [M-H] - 1504.47, found 1504.55.

[0471] Example 28

[0472] Library screening based on FP

[0473] Screening of library 1

[0474] Library screening experiments were performed on a Tecan Genesis workstation equipped with a 96-channel pin module (with fixed pins). 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, adjusted to an ionic strength of 0.15 M by addition of NaCl) to give a set of six daughter plates, each at a concentration of approximately 75 nM per compound per well. In the first round of screening, PTP1B or TCPTP (2 μM in 50 mM 3,3-dimethylglutaric acid buffer, pH 7.0, containing 1 mM EDTA, adjusted to an ionic strength of 0.15 M by addition of NaCl, 50 μL) was dispensed into each well of a 384-well plate, and 2 μL of fluorescein-labeled library compound was then transferred from four 96-well intermediate plates into the 384-well plate (final concentration of compound approximately 3 nM). Fluorescence polarization values (A1) were recorded on an Envision 2021 multi-label microplate reader (Perkin-Elmer). In the second round of screening, a mixture of 50 μL 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, adjusted to an ionic strength of 0.15 M by addition of NaCl) was dispensed into each well of another 384-well plate, and 2 μL of fluorescein-labeled library compound (75 nM in 3,3-dimethylglutaric acid buffer, pH 7.0, containing 1 mM EDTA, adjusted to an ionic strength of 0.15 M by addition of NaCl) was then added. Fluorescence polarization values were again measured (A2). The percentage of displacement was calculated for each library compound as (A1-A2) / (A1-A0) x 100%, where A1 and A2 are the fluorescence anisotropy values for the respective samples, and A0 is the fluorescence anisotropy of the free library compound in 3,3-dimethylglutaric acid buffer. For simplicity, A0 was set to 30. The binding affinities of each compound were ranked according to the percentage of displacement: the smaller the percentage of displacement, the higher the binding affinity. The best candidate compounds (hits) were selected on the basis of affinity and are listed in Table 1.

[0475] Table 1 shows the top 5 candidate compounds from Library 1 (compounds with high and comparable binding affinities for PTP1B and TC-PTP were selected).

[0476]

[0477]

[0478] aThe percentage of displacement is 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 the binding of the library compound to the target enzyme in the absence and presence of the competing ligand (Fmoc-F2Pmp-OH), respectively. A0 is the fluorescence anisotropy of the free library compound. The ranking of the binding affinity of each compound is determined according to the percentage of displacement: the smaller the percentage of displacement, the higher the binding affinity.

[0479] Screening of library 2.

[0480] This library was screened using the same protocol as library 1, with the difference that 0.5 μΜ of PTP1B / TC-PTP and 1.5 mM of the competing ligand Fmoc-F2Pmp-OH were used. The best candidate compounds were selected according to the affinity and are listed in Table 2.

[0481] Table 2 shows the top 5 candidate compounds in library 2 (compounds with high and comparable binding affinity for PTP1B and TC-PTP were selected).a

[0482]

[0483]

[0484] aThe percentage of displacement is 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 the binding of the library compound to the target enzyme in the absence and presence of the competing ligand (Fmoc-F2Pmp-OH), respectively. A0 is the fluorescence anisotropy of the free library compound. The ranking of the binding affinity of each compound is determined according to the percentage of displacement: the smaller the percentage of displacement, the higher the binding affinity.

[0485] Screening of library 3

[0486] This library was screened using the same protocol as library 1, with the difference that 0.5 μΜ of PTP1B / TC-PTP and 5 μΜ 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 (as a competing agent) were used. The best candidate compounds were selected according to the affinity and are listed in Table 3.

[0487] Table 3 shows the top 5 candidate compounds in library 3 (compounds with high and comparable binding affinity for PTP1B and TC-PTP were selected).a

[0488]

[0489]

[0490] aThe percent displacement is calculated as (A1-A2) / (A1-A0) x 100% for each library compound. In this equation, A1and A2are the fluorescence polarization values generated by the binding of the library compound to the target enzyme in the absence and presence of the competing ligand (Fmoc-F2Pmp-OH), respectively. A0is the fluorescence anisotropy of the free library compound. The binding affinity ranking of each compound is determined according to the percent displacement: the smaller the percent displacement, the higher the binding affinity.

[0491] Example 29

[0492] Determination of inhibition constants (K i ) and IC 50 values

[0493] PTP activity was determined using p-nitrophenyl phosphate (pNPP) as substrate in DMG buffer (50 mM DMG, pH 7.0, 1 mM EDTA, 150 mM NaCl, 2 mM DTT, 0.1 mg / mL BSA) at 25 °C. Assays were performed in 96-well plates. Typically, to determine IC 50 values, reactions were initiated by adding enzyme (0.4 nM final concentration for PTP1B and TCPTP, 10 nM final concentration for other PTPs) to reaction mixtures (0.2 mL) containing 2 mM (Kmfor substrate) pNPP and varying concentrations of inhibitor (see Figure 1 ). Reaction rates were measured using a SpectraMax Plus 384 microplate spectrophotometer (Molecular Devices). Data were fitted using the SigmaPlot enzyme kinetics module (Systat Software, Inc.). To determine the mode of inhibition, reactions were initiated by adding enzyme (0.4 nM final concentration for TC-PTP and PTP1B) to reaction mixtures (0.2 mL) containing varying concentrations of pNPP and varying concentrations of inhibitor. Data fitting was performed using the SigmaPlot enzyme kinetics module (Systat Software, Inc.).

[0494] Example 30

[0495] Cell Culture

[0496] HEK293, MIAPaCa-2, HepG2, U2OS, H116, MEF, B16F10 and MC38 cells were grown in DMEM, while Jurkat and H358 cells were grown in RPMI1640 supplemented with 10% fetal bovine serum, penicillin (50 units / mL) and streptomycin (50 pg / mL) in a 37 °C incubator with 5% CO2. JAK / STAT pathway stimulation was performed using 20 ng / mL human (Biolegend #713906) or mouse (Biolegend #714006) interferon-gamma.

[0497] Immunoblotting

[0498] Tissues or cultured cells were lysed with ice-cold lysis buffer (50 mM Tris (pH 8.0, 150 mM NaCl, 10% glycerol, 1% Triton-X-100) containing phosphatase inhibitors (Bimake) and protease inhibitor cocktail (Roche Applied Science). Equal amounts of proteins were separated by SDS-PAGE, transferred to nitrocellulose membranes, and immunoblotted. Antibodies used in this study include 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 (Abeam #ab180764, 1 :3000), PTP1B (Abeam #ab244207, 1 :1500).

[0499] Degradation efficiency evaluation

[0500]

[0501] Table 4 shows the structure and degradation results of a set of initial degraders. Degradation experiments were performed in HEK293 cells with 1 mM degraders, incubated for 24 hours.

[0502]

[0503] Table 5 shows the structure and degradation results of a second set of degraders. Degradation experiments were performed in HEK293 cells with 0.2 mM degraders, incubated for 16 hours.

[0504]

[0505]

[0506]

[0507] Degradation mechanism validation

[0508] PROTAC-mediated protein degradation requires the formation of a target protein-PROTAC-E3 ligase functional ternary complex, enabling the ubiquitination of the target protein by the E3 ligase, and thus proteasome degradation. The dependency of the PTP1B and TC-PTP degradation induced by compound 47 on the VHL E3 ligase was confirmed by preparing the cis-isomer of compound 47 (cis-47), in which the VHL E3 ligand is replaced by (S,S,S)-AHPC-Me, which is an epimer of (S,R,S)-AHPC-Me, with lower affinity for VHL. The IC50 values of cis-47 for PTP1B and TC-PTP (25.1 ± 1.6 and 29.7 ± 2.1 nM) were similar to those of compound 47. 50 In agreement with the impaired binding of (S,S,S)-AHPC-Me to VHL, cis-47 was unable to degrade PTP1B or TC-PTP in HEK293 cells ( Figure 6A ). Moreover, the addition of the VHL ligand (S,R,S)-AHPC-Me reduced the degradation of both proteins mediated by compound 47 ( Figure 6A ). In contrast, the pre-treatment of cells with lenalidomide, a ligand for cereblon, another E3 ligase commonly used in PROTAC development, had no effect on the PTP1B and TC-PTP degradation mediated by compound 47 ( Figure 6A ). These observations indicate that the PTP1B and TC-PTP degradation induced by compound 47 is VHL-dependent. The ubiquitination and proteasome-dependence of the PTP1B and TC-PTP degradation induced by compound 47 was demonstrated by determining the effect of the E1 ubiquitin-activating enzyme inhibitor MLN-4924 and the proteasome inhibitor MG-132. The pre-treatment of cells with these inhibitors for 30 min significantly reduced the extent of the PTP1B and TC-PTP degradation by compound 47, indicating that indeed the E1 ubiquitin-activating enzyme and the 26S proteasome are required for the PTP1B and TC-PTP degradation induced by compound 47 ( Figure 6A ). The PTP1B and TC-PTP degradation mediated by compound 47 and the proteasome-dependence were also verified by immunofluorescence imaging ( Figure 6B and6C ). Taken together, the data indicate that compound 47 is a highly potent and selective dual PTP1B and TC-PTP degrader.

[0509] Selective proteomic analysis

[0510] The target scope of compound 47 degradation in HEK293 cells was determined by performing quantitative mass spectrometry-based proteomic experiments to assess the proteomic degradation selectivity of compound 47. As shown in FIG. 6, PTP1B was the only protein whose level was significantly reduced by 100 nM of compound 47. Mass spectrometry measurements under the given conditions did not detect TC-PTP. Taken together, the above results indicate that compound 47 is a highly potent dual PTP1B and TC-PTP degrader with extremely high selectivity. Figure 7

[0511] Flow cytometry

[0512] After incubation, MC38 cells were trypsinized and washed with PBS + 2% FBS, stained with Alexa Fluorescently labeled anti-mouse H-2Kb / H-2Db antibody against mouse MHC-I complex, and then analyzed on a BD Fortessa LSR flow cytometer. MC38 cells treated with compound 47 exhibited elevated MHC-I expression. Figure 4

[0513] In vivo anti-tumor studies

[0514] All in vivo studies were performed in accordance with the approved animal protocol (1511001324) by the Institutional Animal Care and Use Committee of the Purdue University, in compliance with the recommendations in the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

[0515] Pharmacokinetic studies

[0516] ​​Regarding pharmacokinetic (PK) studies: C57BL6 female mice (weighing 25–30 g) were intraperitoneally injected with 25 mg / kg or 50 mg / kg of compound 47 dissolved in 0.4 mL of saline. Blood samples were collected via tail vein at designated time points post-injection. Isoflurane was used as the anesthetic. All blood samples were centrifuged at 1500 g for 5 minutes, plasma was separated and stored at -80°C until analysis using a validated method based on reversed-phase liquid chromatography-mass spectrometry (LC / MS) using a reported procedure (Journal of Clinical Investigation, 2018, 128, 816–825), the teachings of which are hereby incorporated herein by reference. Figure 5 A).

[0517] Regarding the study of MC38 syngeneic tumors: 10 mg of MC38 was subcutaneously injected into 12-week-old female C57BL6 mice. 6 MC38 cells were used for tumor growth. When the average tumor volume reached 200 mm², [the cells were used]. 3 Mice were matched according to tumor size and randomly assigned to different experimental groups. Mice were injected intraperitoneally daily with physiological saline or 25 mg / kg or 50 mg / kg of compound 47. Tumor size and animal weight were measured twice weekly. Figure 5 B-5C). Tumor volume (mm) 3 = (length × width) 2 ) / 2. At the end of the experiment, the mice were euthanized, and the tumors were collected for analysis.

[0518] In mice, compound 47 was treated with PBS buffer instead of saline to improve PK characteristics. Figure 10 Compared to the above method of treatment with physiological saline, C max Both the area under the curve (AUC) and the area under the curve increased. No significant improvement was observed after adding the solubilizer Kolliphor.

[0519] Compound 47 enhances IFN-γ-induced activation of the JAK1 / 2-STAT1 pathway and promotes MHC-I expression in tumor cells. Compound 47 also activates CD8+ by enhancing phosphorylation of STAT1 and STAT5. + T cells. Importantly, compound 47 induces the degradation of PTP1B and TC-PTP in vivo and enhances CD8+. + T cell-mediated immune responses inhibit the growth of MC38 homologous tumors. Figure 5 D-5F).

[0520] Biochemical ICs with dual PROTAC 50The compounds of Example 7 were included as control compounds.

[0521] Table 6

[0522]

[0523] pJAK1 / 2 elevation and 1B / TC degradation in TC-PTP / PTP1B KO MEF cells.

[0524] Targeted binding of compound 47 in cells was determined. As negative regulators of IFN-γ signaling, PTP1B and TC-PTP dephosphorylate JAK2 at Y1007 / Y1008 and JAK1 at Y1034 / Y1035, respectively. In addition, TC-PTP can also directly dephosphorylate STAT family members, including STAT1 and STAT3, within the nucleus, thereby globally attenuating IFN signaling. Treatment of MEF cells with 500 nM of compound 47 for 16 hours resulted in complete depletion of PTP1B and TC-PTP and enhanced IFN-γ stimulated JAK2 Y1007 / Y1008 and JAK1 Y1034 / Y1035 phosphorylation Figure 8 ) by 2.5-fold. By using PTP1B or TC-PTP deficient MEF cells as negative controls, the increase in pJAK1 / Y1034 / Y1035 and pJAK2 / Y1007 / Y1008 due to PTP1B / TC-PTP degradation was confirmed. As shown in Figure 8 Compound 47 treatment of TC-PTP - / - MEF cells further elevated IFN-γ mediated PTP1B substrate JAK2 / Y1007 / Y1008 phosphorylation levels, while having no effect on the levels of TC-PTP substrate pJAK1 / Y1034 / Y1035. In contrast, addition of compound 47 to PTP1B - / - MEF cells further elevated IFN-γ mediated TC-PTP substrate pJAK1 / Y1034 / Y1035 levels, while having no change in PTP1B substrate JAK2 / Y1007 / Y1008 phosphorylation levels. These results indicate that compound 47 can block substrate dephosphorylation catalyzed by both PTP1B and TC-PTP.

[0525] Compound 47 induced CD8 + depletion of PTP1B and TC-PTP in naive T cells, enhanced STAT1 and STAT5 phosphorylation, and promoted CD8 + T cell activation.

[0526] In addition to attenuating JAK / STAT signaling in tumor cells, PTP1B and TC-PTP also play important roles in T cells, and deletion of either TC-PTP or PTP1B in T cells can significantly enhance anti-tumor immunity. TC-PTP attenuates T cell receptor (TCR) signaling by dephosphorylating and inactivating the Src family kinase LCK. TC-PTP attenuates JAK / STAT1 / 5 signaling upon the action of cytokines such as IFN and IL-2, which are required for T cell activation, clonal expansion, and differentiation. Deletion of TC-PTP in T cells enhances immune surveillance and suppresses the growth of syngeneic tumors and the anti-tumor efficacy of adoptively transferred T cells in mice. PTP1B also negatively regulates IL-2-induced JAK / STAT5 signaling in T cells, and its deletion or inhibition in vivo can enhance the anti-tumor activity of T cells. Therefore, the effect of compound 47 targeting PTP1B and TC-PTP on JAK / STAT signaling and T cell activation upon TCR crosslinking was evaluated. The effect of compound 47 was compared with the genetic deletion of TC-PTP (encoded by Ptpn2) in T cells (Lck-Cre; Ptpn2 fl / fl ). First, the effect of compound 47 on TC-PTP and PTP1B protein levels was evaluated by flow cytometry using validated antibodies. Upon 48 h of treatment, TC-PTP and PTP1B were efficiently degraded in T cells ( Figure 9 A). Upon TCR activation of T cells with a-CD3 / a-CD28 crosslinking, the degradation of TC-PTP and PTP1B was accompanied by a more than 3-fold increase in STAT1 Y701 phosphorylation and a 2-fold increase in STAT5 Y694 phosphorylation ( Figure 9 B). Importantly, the promoting effect of compound 47 on pSTAT1 / Y701 and pSTAT5 / Y694 exceeded that achieved by the genetic deletion of TC-PTP, which is consistent with compound 47 simultaneously targeting TC-PTP and PTP1B to enhance signaling. In addition, compound 47 treatment also enhanced TCR-induced T cell activation, as assessed by monitoring cell size and the expression of cell surface activation markers, including CD44, CD25 (IL-2 receptor a), and CD69 ( Figure 9 C). In this case, compound 47 only modestly, but not significantly, increased T cell activation compared with the effect achieved by TC-PTP deletion. This is not necessarily surprising because TC-PTP, but not PTP1B, attenuates TCR signaling in naive CD8 + T cells. Nonetheless, these results indicate that the combined targeting of PTP1B and TC-PTP by compound 47 acts to enhance JAK / STAT signaling and CD8 +Activation of T cells, which contributes to antiviral and antitumor immunity.

[0527] Blood glucose level studies - impact on diabetes and obesity

[0528] PTP1B and TC-PTP are known to act synergistically in co-regulating 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 impact of Compound 47 on blood glucose levels in mice was evaluated. The results showed that 15 mg / kg Compound 47 was sufficient to reduce blood glucose levels in high-fat diet (HFD)-fed mice to the level of normal-fat diet (NFD)-fed mice, and treatment with 50 mg / kg Compound 47 resulted in further reduction of blood glucose levels ( Figure 11 ). In the MC38 syngeneic tumor mouse model, 25 mg / kg Compound 47 did not result in a significant reduction of blood glucose levels, while 50 mg / kg slightly reduced blood glucose levels ( Figure 11 ), indicating that Compound 47 has little effect on blood glucose levels in mice with normal blood glucose levels.

[0529] Comparison of Compound 47 and TC-PTP inhibitor ABBV-CLS-484 on STAT1 phosphorylation

[0530] AbbVie and Calico developed a potent PTP1B / TC-PTP inhibitor, ABBV-CLS-484 (disclosed in international PCT application WO2019246513), which is currently being evaluated as a treatment regimen for locally advanced or metastatic tumors (NCT04777994). The effectiveness of Compound 47 was demonstrated by comparing its efficiency on STAT1 phosphorylation activation with ABBV-CLS-484 ( Figure 12A ). In HEK293 cells, Compound 47 dose-dependently induced TC-PTP degradation and activated pSTAT1 with an EC 50 of 9.1 nM, outperforming ABBV-CLS-484 (79.7 nM).

[0531] The following terms and expressions used herein shall have the following meanings. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art.

[0532] The term“about” can allow a value or a range to vary to some degree, for example, within 10%, within 5%, or within 1% of a stated value or of an indicated limit of a range.

[0533] The term“substantially” can permit a degree of variation, e.g., within 90%, within 95%, or within 99% of a specified value or of a specified range limit.

[0534] Unless the context clearly dictates otherwise, singular terms (“a,”“an,” or“the”) are to be construed to cover one or more. The term“or” is used to refer to a nonexclusive“or” unless otherwise indicated. Furthermore, the use of the term“including” as well as other forms such as“include,”“includes,”“comprise,”“comprises,”“comprising,” or variations of these terms, is intended to be broad and encompass the terms“consisting of” and / or“consisting essentially of,” unless otherwise indicated. The use of the terms“including,”“comprising,” or“having” are not limiting.

[0535] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in this specification are indicative of the level of skill of those 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 were 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: wherein R1and R2are each independently a carboxylic acid residue or a pharmaceutically acceptable salt thereof, wherein R1and R2may be the same or different; t is 0 to 6; R3, R4, R5, R6, R7, and R8are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-C6alkyl, C3-C6cycloalkyl, -C1-C6alkylene, 4-6 membered heterocyclyl, and -C1-C6alkylene-4-6 membered heterocyclyl, wherein C1-C6alkyl, C3-C6cycloalkyl, and C1-C6alkylene-4-6 membered heterocyclyl are optionally substituted on one or more available carbons with one or more substituents each independently selected from deuterium, halogen, hydroxyl, C=O, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C6cycloalkyl, -C1-C6-alkylene-C3-C6cycloalkyl, C1-C6alkyl-S(O)2-, C3-C6cycloalkyl-S(O)2-, C1-C6alkyl-C(O)-, C1-C6alkoxy-C(O)-, -NH-C(O)-R a and -C(O)-NH-R a wherein R a is C1-C6alkyl, C3-C6cycloalkyl, and -C1-C6alkylene-4-6 membered heterocyclyl, which is optionally substituted on one or more available carbon atoms with one or more substituents each independently selected from deuterium, halogen, hydroxyl, C=O, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C6cycloalkyl, -C1-C6-alkylene-C3-C6cycloalkyl, C1-C6alkyl-S(O)2-, C3-C6cycloalkyl-S(O)2-, C1-C6alkyl-C(O)-, C1-C6alkoxy-C(O)-, -NH-C(O)-R b and -C(O)-NH-R b wherein R b is independently selected from deuterium, halogen, hydroxyl, C=O, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C6cycloalkyl, -C1-C6-alkylene-C3-C6cycloalkyl, C1-C6alkyl-S(O)2-, C3-C6cycloalkyl-S(O)2-, C1-C6alkyl-C(O)-, and C1-C6alkoxy-C(O)-; R9is H or a group represented by the formula L-B, wherein L is a linker selected from the group consisting of: B is selected from groups B1, B2, and B3, wherein B1is represented by the following structure: wherein w is 1-5, x is 1-15, and each of a and b is independently 0-3; the bond marked with an asterisk is attached to B; the bond marked with a double asterisk represents the point of attachment of R9; and B2is represented by the following structure: wherein R 3a is fluorine, hydrogen or deuterium; B3is represented by the following structure: wherein R 3b is fluorine, hydrogen or deuterium; and wherein R4is methyl, hydrogen, or deuterium.

4. A compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer thereof:

2. The compound of claim 1, wherein 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, wherein the aliphatic group is saturated or unsaturated, and wherein the aliphatic group or the aromatic group is substituted with C1-C 24 alkyl, C1-C 24 alkenyl, C1-C 24 alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroaralkyl, aralkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl, wherein the R groups are optionally substituted with at least one group selected from C1-C 24 alkyl, hydroxyl, alkoxy, cyano, halogen, nitro, aryl, amino, C1-C 24 alkenyl, C1-C 24 alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroaralkyl, aralkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl.

3. The compound according to claim 1, wherein the carboxylic acid is selected from the group consisting of: 3-dimethylaminobenzoic acid, 2-(2-cyanophenylthio)benzoic acid, 2-(4-chlorobenzoyl)benzoic acid, (-)-2-oxo-4-thiazolidinyl-carboxylic acid, (-)-N-acetylneuraminic acid, (+)-6-methoxy-α-methyl-2-naphthylacetic acid, (+)-benzyloxycarbonyl-D-proline, (+)-mentholoxyacetic 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)-(+)-camphoric acid, (1S,3R,4S,5R)-1,3,4,5- tetrahydroxycyclohexanecarboxylic acid, (2,4-di-tert-amylphenoxy)acetic acid, (2- naphthyloxy)acetic acid, (2-pyrimidinylthio)acetic acid, (4-carboxybutyl)triphenylphosphonium bromide, (4-chlorophenylthio)acetic acid, (4-methylphenoxy)acetic acid, (a,a,a-trifluoro-m-tolyl)acetic acid, (E)-2-[(4-hydroxyphenyl)azo]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)-(-)-hexahydro-mandelic acid, (R)-(+)-2-pyrrolidine-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-phenylpropionic 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-tetrahydrofurylcarboxylic acid, (S)-(+)-hexahydro-mandelic acid, (S)-(+)-N-[1-(1-naphthyl)ethyl]phthalamidic acid, (S)-(+)-O-acetylmandelic acid, (S)-2-(1-phenylethylcarbamoyl)benzoic acid, (S)-2-(4-isobutylphenyl)propionic acid, (S)-2-(phenylcarbamoyloxy)propionic acid, (S)-3-(benzyloxycarbonyl)-2-oxoimidazolidine-4-carboxylic acid, (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid, (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropionic 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-(tert-butyl)hydrocinnamic acid, 1,2-benzenedioic acid, 1,4-dihydro-2-methylbenzoic acid, 1,4-dihydroxy-2-naphthoic acid, 10-hydroxydecanoic acid, 10-undecynoic acid, 1-adamantane carboxylic acid, 1-cyano-1-cyclopropanecarboxylic acid, 1-hydroxy-2-naphthoic acid, 1-isoquinolinecarboxylic acid, 1-methyl-(1S,2R)-(+)-cis-1,2,3,6-tetrahydrophthalic acid, 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-[(benzyloxy carbonyl)(methyl)amino]-2-methylpropanoic acid, 2-(2-(trifluoromethyl)phenyl)acetic acid, 2-(2,4,5-trichlorophenoxy)propanoic acid, 2-(2,4-dichlorophenoxy)propanoic acid, 2-(3,5-dinitrobenzamido)-2-phenylacetic acid, 2-(3,5-dinitrobenzamido)-4-methylpentanoic acid, 2-(3-chlorophenoxy)propanoic acid, 2-(4-(trifluoromethyl)phenyl)acetic acid, 2-(4-chloro-3-nitrobenzoyl)benzoic acid, 2-(4-chlorophenoxy)-2-methylpropanoic acid, 2-(4-chlorophenoxy)propanoic acid, 2-(4-fluorobenzoyl)benzoic acid, 2-(4-hydroxy-3-methoxyphenyl)acetic acid, 2-(4-hydroxyphenoxy)propanoic acid, 2-(4-isobutylphenyl)propanoic acid, 2-(4-nitrophenyl)propanoic acid, 2-(benzyloxy carbonyl amino)-3-(1H-indol-3-yl)propanoic acid, 2-(trifluoromethyl)propenoic acid, 2-(trifluoromethyl)benzoic acid, 2-(trifluoromethyl)cinnamic acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid, 2,2-bis(hydroxymethyl)propanoic acid, 2,3,4,5,6-pentafluorocinnamic acid, 2,3,4,5,6-pentafluorophenoxyacetic acid, 2,3,4,5,6-pentafluorophenylacetic 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-hydroxybenzoic 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, 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-sulfamoylbenzoic 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-bromo-3-nitrobenzoic acid, 2-bromo-4,5-dimethoxybenzoic acid, 2-bromo-5- methoxybenzoic acid, 2-bromo-5-nitrobenzoic acid, 2-bromopropenoic 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- (trifluoromethyl)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-hydroxybutanoic acid, 2-ethylbutanoic acid, 2-ethylhexanoic acid, 2-ethylthio-2,2- diphenylacetic acid, 2-fluoro-3-(trifluoromethyl)benzoic acid, 2-fluoro-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)phenylacetic acid, 3,4-dichlorobenzoic acid, 3,4-dichlorophenoxyacetic acid, 3,4-diethoxybenzoic acid, 3,4-difluorobenzoic acid, 3,4-dihydroxybenzoic acid, 3,4-dihydrocinnamic 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-hydroxybenzoic acid, 3,5-di-tert-butylbenzoic acid, 3,7-dihydroxy-2-naphthoic acid, 3-thiopheneacetic acid, 3-benzoyl-2-pyridinecarboxylic 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-proxazole, 3-chloro-2-nitrobenzoic acid, 3-chloro-4-fluorobenzoic acid, 3-chloro-4-hydroxyphenylacetic acid, 3-chlorosalicylic acid, 3-cyanobenzoic acid, 3-fluoro-2-methylbenzoic acid, 3-fluoro-4-hydroxyphenylacetic acid, 3-fluoro-4-methoxybenzoic acid, 3-fluorophenylacetic acid, 3-furanic acid, 3-hydroxy-2-naphthoic acid, 3-hydroxy-2-quinoxalinecarboxylic acid, 3-hydroxy-4-methoxybenzoic acid, 3-hydroxy-4-methoxycinnamic acid, 3-hydroxy-4-nitrobenzoic acid, 3-hydroxybenzoic acid, 3-hydroxybutyric acid, 3-hydroxyphenylacetic acid, 3-indolebutyric acid, 3-indoleglycolic acid, 3-indolepropionic acid, 3-iodo-4-methylbenzoic acid, 3-iodobenzoic acid, 3-isoquinolinecarboxylic acid hydrate, 3-methoxy-4-nitrobenzoic acid, 3-methoxycyclohexanecarboxylic 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-noradamantane carboxylic acid, 3-oxo-1-indene carboxylic acid, 3-phenoxybenzoic acid, 3-phenylbutyric acid, 3-p-tolylpropionic acid, 3-thiophenecarboxylic acid, 4-(1,3-dioxoisoindoline-2-yl)-2-hydroxybutyric acid, 4-(2,4,5-trichlorophenoxy)butyric acid, 4-(2,4-dichlorophenoxy)butyric acid, 4-(2,4-di-tert-amylphenoxy)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)phenylacetic 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-butenic acid, 4,4-bis(4-hydroxyphenyl)pentanoic acid, 4,5-dimethoxy-2-nitrobenzoic acid, 4,6-dioxoheptanoic acid, 4-[4-(2-carboxybenzoyl)phenyl]butyric acid, 4-acetamidobenzoic acid, α-acetyibenzoic acid, 4-acetylphenoxyacetic acid, 4-benzyloxy-3-methoxyphenylacetic acid, 4-biphenylacetic acid, 4-bromo-3,5-dihydroxybenzoic acid, 4-bromobenzoic acid, 4-bromocinnamic acid, 4-bromophenylacetic acid, 4-butyloxybenzoic acid, α-butyloxyphenylacetic 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, 4'-ethylbiphenyl-4-carboxylic acid, 4-5-dinitrobenzoic acid, 4-hydroxy-3-methoxybenzoic acid, 4-hydroxy-3-methoxymandelic 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, a-hydroxyphenylpyruvic acid, 4-iodobenzoic acid, 4-isopropoxybenzoic acid, 4-methoxy-3-nitrobenzoic acid, 4-methoxycyclohexanecarboxylic acid, 4-methoxysalicylic acid, 1-methyl-1-cyclohexanecarboxylic acid (cis and trans), 4-methyl-3-nitrobenzoic acid, a-methylhippuric acid, 4-methylsalicylic acid, 4-methylvaleric acid, 4-nitro-3-pyrazolecarboxylic acid, 4-nitrohippuric acid, 4-nonyloxybenzoic acid, 4-octylbenzoic acid, 4-oxo-4H-1-benzopyran-2-carboxylic acid, 4-oxo-6-phenyl-5-hexenoic acid, a-pentenoic acid, 4-pentylbenzoic acid, 4-pentyldicyclo[2.2.2]octane-1-carboxylic acid, a-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-furan carboxylic 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-hydantoinic acid, 5-hydroxy-2-indolecarboxylic 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-pyrazinecarboxylic acid, 5-nitro-2-furan carboxylic acid, 5-nitro-3-pyrazolecarboxylic acid, 5-phenylvaleric acid, 6-(benzyloxycarbonylamino)hexanoic 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-nitrohexanoic acid, 6-oxoheptanoic acid, 6-phenylhexanoic acid, 7-(carboxymethyloxy)-4-methylcoumarin, 7-hydroxycoumarin-4-acetic acid, 7-methoxy-2-benzofuran carboxylic acid, 7-methoxycoumarin-4-acetic acid, 7-oxooctanoic acid, 9-anthracene carboxylic acid, 9-fluoreneacetic acid, 9-fluoren-1-carboxylic acid, a,a,a-trifluorom-m-toluic acid, a-acetamidocinnamic acid, abietic acid, acetic acid, acetyl-L-asparagine, acetylsalicylic acid, a-cyano-4-hydroxycinnamic acid, adipic acid monoethyl ester, a-hydroxyhippuric acid, anthranilic acid, trans-3-oxotricyclo[3.3.1.0]nonane-1-carboxylic acid, 2.2.1.02,6]heptane-7-carboxylic acid, a-phenylcyclopentaneacetic acid, a-phenyl-o-toluic acid, aldotricarboxylic acid, benzhydrolactic acid, benzotriazole-5-carboxylic acid, benzoylformic acid, bis(4-chlorophenyl)acetic acid, benzyloxycarbonyl-DL-alanine, benzyloxycarbonyl-L-alanine, benzyloxycarbonyl-L-glutamine, benzyloxycarbonyl-L-valine, cis-2-methoxycinnamic acid, crotonic acid, cyclohexanebutyric acid, cyclohexanecarboxylic acid, cyclohexanepentanoic acid, cyclohexanepropionic acid, cyclopentylacetic acid, D,L-3,4-dihydroxymandelic acid, D-3-phenyllactic acid, decanoic acid, dicyclohexylacetic acid, diethylphosphonoacetic acid, diformic acid hydrate, diphenylacetic acid, fumaric acid monoethyl ester, fusaric acid, gallic acid, geranic 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, mono-(1R)-(-)-menthyl phthalate, mono-(1S)-(+)-menthyl phthalate, cis-5-norbornene-inn-2,3-dicarboxylic acid monomethyl ester, o-phthalic acid monomethyl ester, p-phthalic acid monomethyl ester, N-(2-furoyl)glycine, N-(3,5-dinitrobenzoyl)-DL-a-phenylglycine, N-(3-indoleacetyl)-L-alanine, N-(3-indoleacetyl)-L-isoleucine, N-(3-indoleacetyl)-L-leucine, N-(3-indoleacetyl)-L-phenylalanine, N-(3-indoleacetyl)-L-valine, N-(benzyloxycarbonyl)-L-phenylalanine, N,N-diethyl-3,6-difluorophthalamic acid, N-[(R)-1-(1-naphthyl)ethyl]phthalamic acid, N-[5-(trifluoromethyl)-2-pyridinyl]-L-valine, N-acetyl-4-fluoro-DL-phenylalanine, N-acetyl-DL-tryptophan, N-acetyl-L-leucine, N-acetyl-L-methionine, N-acetyl-L-phenylalanine, N-acetyl-L-tyrosine, N-benzoyl-(2R,3S)-3-phenylisoserine, N-benzoyl-L-threonine, N-benzyloxycarbonyl-2-methylalanine, N-benzyloxycarbonyl-L-glutamic acid 1-methyl ester, N-benzyloxycarbonyl-L-isoleucine, N-benzyloxycarbonyl-L-leucine, N-benzyloxycarbonyl-L-threonine, N-ethoxycarbonyl-L-phenylalanine, nonanoic acid, N-p-toluenesulfonylglycine, N-p-toluenesulfonyl-L-phenylalanine, o-anisic acid, p-anisic acid, pentafluorobenzoic acid, phenoxyacetic acid, phenylacetic acid, podocarpic acid, pyruvic acid, rhodanine-3-acetic acid, S-(thiobenzoyl)mercaptoacetic acid, S-benzyl-N-benzyloxycarbonyl-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-difluorocinnamic acid, trans-2,6-difluorocinnamic acid, trans-2-chloro-6-fluorocinnamic acid, trans-2-hexenoic acid, trans-3-(2,3,5,6-tetramethylbenzoyl)acrylic acid, trans-3-(2,5-dimethylbenzoyl)acrylic acid, trans-3-(4-ethoxybenzoyl)acrylic acid, trans-3-(4-methoxybenzoyl)acrylic acid, trans-3-(4-methylbenzoyl)acrylic acid, trans-3,4-difluorocinnamic acid, trans-3-fluorocinnamic acid, trans-3-furanacrylic acid, trans-3-hexenoic acid, trans-4-chloro-3-nitrocinnamic acid, trans-4-hydroxy-3-methoxycinnamic 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; wherein R1and R2may be the same or different. wherein R1and R2are each independently a carboxylic acid residue or a pharmaceutically acceptable salt thereof, wherein R1and R2may be the same or different.

6. The compound of claim 4, wherein R1or R2is:

5. The compound of claim 4, wherein 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, wherein the aliphatic group is saturated or unsaturated, and wherein the aliphatic group or the aromatic group is substituted with C1-C 24 alkyl, C1-C 24 alkenyl, C1-C 24 alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroaralkyl, aralkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl, wherein the R groups are optionally substituted with at least one group selected from C1-C 24 alkyl, hydroxyl, alkoxy, cyano, halogen, nitro, aryl, amino, C1-C 24 alkenyl, C1-C 24 alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroaralkyl, aralkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl.

7. The compound of claim 4, wherein R1or R2is:

8. The compound of claim 4, wherein R1or R2is:

9. The compound of claim 4 or 5, wherein the compound 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: wherein R1and R2are each independently a carboxylic acid residue or a pharmaceutically acceptable salt thereof, wherein R1and R2may be the same or different; L is a linker selected from the group consisting of: and wherein w is 1-5; x is 1-15; a and b are each independently 0-3; the bond marked with B; the bond marked with an "*" represents the point of attachment of R9; B is represented by a structure selected from B1, B2, and B3, wherein B1is represented by the following structure: B2is represented by the following structure: wherein R 3a is fluorine, hydrogen or deuterium; B3is represented by the following structure: wherein R 3b is fluorine, hydrogen or deuterium; and wherein R4is methyl, hydrogen, or deuterium.

12. The compound of claim 10, wherein B is B3 11. The compound of claim 10, wherein 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, wherein the aliphatic group is saturated or unsaturated, and wherein the aliphatic group or the aromatic group is substituted with C1-C 24 alkyl, C1-C 24 alkenyl, C1-C 24 alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroaralkyl, aralkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl, wherein the R groups are optionally substituted with at least one group selected from C1-C 24 alkyl, hydroxyl, alkoxy, cyano, halogen, nitro, aryl, amino, C1-C 24 alkenyl, C1-C 24 alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroaralkyl, aralkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, and acyl. wherein R4is methyl, hydrogen, or deuterium.

13. The compound of claim 10, wherein R1or R2is selected from:

14. The compound of claim 10, wherein linker L is selected from:

15. The compound of any one of claims 10-14, wherein the compound is: or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer thereof.

16. A pharmaceutical composition comprising one or more compounds according to any one of claims 1-3, or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

17. A pharmaceutical composition comprising one or more compounds according to any one of claims 4-9, or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

18. A pharmaceutical composition comprising one or more compounds according to any one of claims 10-14, or a pharmaceutically acceptable salt, hydrate, tautomer, and stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient. ​ 19. A method of treating or preventing cancer in a patient, wherein the method comprises inhibiting or degrading dual protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TC-PTP) by administering to a patient in need thereof an effective amount of a compound according to any one of claims 1-3 or a pharmaceutical composition according to claim 16, thereby treating or preventing cancer in the patient.

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

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

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

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

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

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

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

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

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

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

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

31. A method of treating or preventing obesity in a patient, wherein the method comprises inhibiting or degrading dual PTP1 B and TC-PTP by administering to a patient in need thereof an effective amount of a compound according to any one of claims 1-3 or a pharmaceutical composition according to claim 16, thereby treating or preventing obesity in the patient.

32. A method of treating or preventing obesity in a patient, wherein the method comprises inhibiting dual PTP1 B and TC-PTP inhibitor by administering to a patient in need thereof an effective amount of a compound according to any one of claims 4-9 or a pharmaceutical composition according to claim 17, thereby treating or preventing obesity in the patient.

33. A method of treating or preventing obesity in a patient, wherein the method comprises degrading dual PTP1 B and TC-PTP protein by administering to a patient in need thereof an effective amount of a compound according to any one of claims 10-14 or a pharmaceutical composition according to claim 18, thereby treating or preventing obesity in the patient.

34. A method of inhibiting or degrading dual PTP1 B and TC-PTP in a patient, wherein the method comprises administering to a patient in need thereof an effective amount of a compound according to any one of claims 1-14 or a pharmaceutical composition according to any one of claims 16-18, thereby inhibiting or degrading dual PTP1 B and TC-PTP in the patient.

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

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

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

38. Use of a compound according to any one of claims 1-9 in the treatment of a disease or disorder treatable by inhibiting dual PTP1 B or TC-PTP protein.

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

40. Use of a compound according to any one of claims 1-3 or 10-14 in the treatment of a disease or disorder treatable by degrading dual PTP1 B or TC-PTP protein.

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

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