RU2782063C2 - Compounds and methods for improved cleavage of target proteins - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a bifunctional compound having the chemical structure ULM-L-PTM, where (a) PTM is a fragment directionally acting on protein, which is a small molecule, which binds to intracellular target protein; (b) L is a chemical linker group connecting ULM and the specified PTM, where the chemical linker group is represented by the chemical structure -A₁-...-A_q-, where q is an integer from 1 to 20; each A is independently selected from CR^L1R^L2, O, NR^L3, CO, C_3-11cycloalkyl optionally substituted with 1-6 R^L1 groups, C_3-11heterocyclyl optionally substituted with 1-6 R^L1 groups, 6-element aryl optionally substituted with 1-6 R^L1 and 5- or 6-element heteroaryl optionally substituted with 1-6 R^L1 groups; and R^L1, R^L2, R^L3, each independently, is H, halogen, C_1-8alkyl, OC_1-8alkyl, NHC_1-8alkyl, N(C_1-8alkyl)₂, OH, NH₂, CN, or CF₃; (c) ULM is a binding fragment of E3 ubiquitin ligase (hereinafter – ULM) of von Hippel-Lindau (VHL), having the chemical structure

, where E is C=O; G is C=O; M is

; each R₉ and R₁₀ is independently H, optionally substituted C_1-6 alkyl, optionally substituted C_1-6hydroxyalkyl, or C_1-6haloalkyl; R₁₁ is optionally substituted 5- or 6-element heteroaryl, optionally substituted 6-element aryl, or

,

, or

; each R₁₈ is independently halogen, C_1-6 alkoxy, cyano, or optionally substituted C_1-6 alkyl; and p from ULM is 0, 1, 2, 3, or 4; R₁₂ is H or optionally substituted C_1-6 alkyl; R₁₃ is H, optionally substituted C_1-6 alkyl, optionally substituted acetyl, or optionally substituted C_1-6 alkyl carbonyl, each R₁₄ is independently H, C_1-6 haloalkyl, or optionally substituted C_1-6 alkyl, where one R₁₄ is C_1-6 haloalkyl, or optionally substituted C_1-6 alkyl; R₁₅ is optionally substituted 5- or 6-element heteroaryl, optionally substituted 6-element aryl or

; each R₁₆ is independently halogen, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 haloalkyl, CN, or optionally substituted C_1-6haloalkoxy; o from ULM is equal to 0, 1, 2, 3, or 4; each heteroaryl and heterocyclyl has 1-3 heteroatoms independently selected from O, N, and S; and optionally substituted relates to optional substitutions by means of one or more elements independently selected from a group consisting of C_1-6 alkyl, C_1-6 alkoxy, =O, amino, amide, C_3-7 heterocycle, 6-element aryl, CN, halogen, COOH, hydroxyl, C_1-6 composite ester, C_1-6 acyl, and phenyl, or its pharmaceutically acceptable salt, where (i) target protein is selected from a group consisting of Ras, Raf, MEK, ERK path, estrogen receptor, and androgen receptor; or (ii) PTM is a compound, which targets human BET bromodomain-containing proteins, a compound, which targets RAF, a compound, which targets an estrogen receptor, a compound, which targets an androgen receptor, or a compound, which targets an epidermal growth factor receptor. The invention also relates to a pharmaceutical composition based on the above-mentioned bifunctional compound, a method for causing the cleavage of intracellular target protein in a cell, and a method for cleavage of intracellular target protein in a cell, based on the use of a compound of the above -mentioned structure or a composition based on it.

EFFECT: new heterocyclic compounds are obtained, which can be used as modulators of specific ubiquitination.

18 cl, 1 dwg, 4 tbl, 208 ex

Description

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority based on US Provisional Application No. 62/135,125, filed March 18, 2015; entitled: Compounds and methods for improved cleavage of target proteins and other E3 polypeptides by ubiquitin ligase, which is incorporated herein by reference in its entirety.

STATEMENT REGARDING PUBLIC RESEARCH

This invention was made with government support under grant No. AI084140 of the National Institutes of Health. The government has certain rights to this invention.

BACKGROUND OF THE INVENTION

1. Opening area.

This invention relates to a bifunctional compound that is used as modulators of specific ubiquitination. In particular, this invention relates to compounds which contain at one end a VHL ligand that binds to the VHL E3 ubiquitin ligase and at the other end a fragment that binds a target protein such that cleavage of the protein/polypeptide occurs. This invention demonstrates a wide range of pharmacological activity associated with the compounds in accordance with this invention, indicating the cleavage/inhibition of target polypeptides.

2. Information of the prior art.

E3 ubiquitin ligases (of which over 600 are found in humans) provide substrate specificity for ubiquitination and are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. Although the development of E3 ligand ligands has proven difficult, due in part to the fact that they must break protein-protein interactions, recent studies have provided specific ligands that bind to these ligases. Protein-protein interactions are known to be difficult to attack by small molecules due to large contact surfaces and the presence of shallow grooves or flat boundaries. Conversely, most small molecule drugs bind enzymes or receptors into dense and well-defined pockets. Since the discovery of nutlins, the first small molecule inhibitors of E3 ligase, additional compounds have been described that target the apoptosis protein (APA) inhibitors SCFMet30 and SCFCdc4, however, the field remains underdeveloped.

One E3 ligase with excellent therapeutic potential is the Hippel-Lindau (VHL) anti-oncogene, a substrate recognition subunit of the E3 ligase complex of VCB, which also includes elongins B and C, Cul2 and Rbx1. The primary substrate for VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that activates genes such as the pro-angiogenic growth factor VEGF and the erythrocyte-stimulating cytokine erythropoietin in response to low oxygen levels. Although GIF-1α is constitutively expressed, intercellular levels remain very low under normal oxygen conditions through protein hydroxylation of the prolyl-3-hydroxylase-1 (DPH) domain and subsequent VHL-mediated ubiquitination (Figure 1).

A crystal structure of VHL with ligands was obtained, confirming that the small molecule compound can mimic the way the transcription factor HIF-1α, the main substrate of VHL, binds. Using rational design, the first small molecule Hippel-Lindau (VHL) ligands were created that recognize the substrate of the E3 subunit of VCB ligase, an important target in cancer, chronic anemia and ischemia.

However, there is a continuing need in the art for effective small molecular weight therapeutics for disease indications. This description provides a means to attract proteins to E3 ligases for ubiquitination and cleavage, prior to the completion of ongoing therapies based on the cleavage of target proteins.

SUMMARY OF THE INVENTION

This description relates to the discovery that a ubiquitin pathway protein ubiquitinates any target protein as soon as the ubiquitin pathway protein and the target protein are placed adjacent to a chimeric construct that binds the ubiquitin pathway protein and the target protein. Therefore, this invention relates to compositions and corresponding methods of application, which give ubiquitination and subsequent cleavage of the selected target protein. The present invention also provides a library of compositions and their use.

In one aspect, the disclosure provides small molecules (ie, non-peptide-based compounds) that recruit endogenous proteins to E3 ubiquitin ligase for cleavage.

In another aspect, the specification provides proteolysis-targeted chimeric compounds, or PROTACs, that modulate protein cleavage in a patient or subject and may be used to treat diseases or conditions that are modulated through the cleaved protein.

In another aspect, the description provides pharmaceutical compositions containing effective amounts of the compounds described herein, especially including inhibitors for therapeutic treatment of a patient or subject, preferably including a human or subject.

In another aspect, the disclosure provides methods for identifying endogenous proteins in a biological system, especially including a human system, that bind to protein-binding moieties in the compounds of this invention.

In another aspect, the specification provides methods for identifying cleavage of target proteins in a biological system using compounds of the invention.

In another aspect, the disclosure provides methods for treating a disease or disorder in a subject, eg, a patient such as a human, wherein cleavage of the target protein produces the desired therapeutic effect.

In another aspect, the description provides compounds and compositions that can be used as a first medical application.

If applicable or not specifically denied, it is contemplated that any of the aspects or options described herein may be combined with any other one or more options, even if the options are described for other aspects of the invention.

The above general applications are given by way of example only and do not limit the scope of the invention and the claims. Additional objects and advantages associated with the compositions, methods and processes of the present invention will be clear to a person skilled in the art from the presented formula, description and examples. For example, various aspects and variations of the invention may be used in a variety of combinations, all of which are covered by this description. These additional advantages and variations are included within the scope of this invention. Publications and other materials used here to highlight the prior art of the invention, and in specific cases, to obtain additional details regarding the practice, are included by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The present drawings, which are included and form part of the description, illustrate certain embodiments of the invention and, together with the description, serve to explain the principles of the invention. The drawings are given only to illustrate a variant of the invention and do not limit the invention. Other objects, characteristics and advantages will become apparent from the present detailed description in conjunction with the accompanying drawings showing illustrative embodiments of the invention in which:

The figure 1 shows (A) the accumulation of HIF-1α, leading to transcriptional activation of genes involved in the hypoxic response, such as erythropoietin and VEGF. (B) Under normal oxygen conditions, GIF-1α is hydroxylated, recognized by VHL, ubiquitinated, and cleaved by the proteasome, preventing transcriptional activation.

DETAILED DESCRIPTION

The following is a detailed description to assist a person skilled in the art to practice the present invention. Specialists in the art can make modifications and variations in the described embodiments, without going beyond the essence and scope of this description. All publications, patent applications, patents, drawings and other specified references are incorporated herein in their entirety by reference, including WO 2013/106643 and US 2014-0356322.

Described herein are compositions that bind the E3 ubiquitin ligase protein complex. In particular, compositions are described that bind to Hippel-Lindau (VHL), the substrate-recognizing subunit of the E3 complex of the VCB ligase. In addition, the description presents bifunctional compounds, including them, and the corresponding methods of application for the implementation of ubiquitination and/or cleavage of the selected target protein. The description also provides a library of compounds described here.

The following terms are used to describe this invention.

Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which the invention belongs, using the term in the context of its use to describe this invention. The terminology used in the invention is only given to describe specific embodiments and does not limit the invention.

If a range of values is provided, it is understood that each intermediate value, up to tenths of a unit of the lowest limit, unless the context clearly indicates otherwise (for example, as in the case of a group containing the number of carbon atoms, where each number of carbon atoms falling within the range is represented), between the upper and lower limits of this interval, and any other specified or intermediate value in this specified interval, is included in the invention. The upper and lower limits of such smaller ranges may be independently included in the smaller ranges, are also covered by the invention, are also covered by the invention, subject to any particularly excluded limit in the specified range. If the specified range includes one or both of the limits, the ranges excluding both such included limits are included in the invention.

Terms in the singular used here and in the claims refer to one or more than one (because at least one) grammatical entity, unless the context clearly indicates otherwise. For example, "element" means one element or more than one element.

The phrase "and/or" in this specification and claims is to be understood as "either or both" of the elements thus combined, i.e. elements that are associated in some cases and separately present in others. The set of elements listed with "and/or" should be interpreted in the same way, i.e. "one or more" combined elements. Other elements other than those identified by the "and/or" condition may optionally be present, whether or not they are related to the specifically defined elements. Thus, as a non-limiting example, the expression "A and/or B" used in conjunction with an open term such as "comprising" may, in one embodiment, only refer to A (optionally including elements other than B) ; alternatively, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

In this specification and claims, "or" is to be understood as having the same meaning as "and/or" as defined above. For example, when separating the elements of a list, "or" or "and/or" should be interpreted as inclusive, i.e. including at least one, and also including more than one of the set or list of elements and, optionally, additional not listed elements. Only terms expressly meaning the opposite, such as "only one of" or "exactly one of" or, when used in the claims, "consisting of", refer to the inclusion of only one element from a set or list of elements. In general, the term " or" in this specification shall only be interpreted as indicating exclusive alternatives (i.e. "one or the other, but not both") if they are preceded by terms of exclusivity such as "one of two", "one of", "only one of" or "exactly one of".

In the claims, as well as in the description, all transitional phrases such as "comprising", "comprising", "carrying", "having", "comprising", "involving", "storing", "consisting of" and the like are understood as open, i.e. means including, but not limited to. Only the transition phrases "consisting of" and "consisting essentially of" must be closed or semi-closed transition phrases, respectively, as set out in the US Patent Office's Patent Examining Manual, Section 2111.03.

In this description and claims, the phrase "at least one" in relation to a list of one or more elements is understood to mean at least one element selected from any or more elements in the list of elements, but optionally including at least , one of every single element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows the optional presence of elements other than those specified in the list of elements to which the phrase "at least one" refers, related or unrelated to the specified elements. Thus, as a non-limiting example, "at least one of A and B" (or equivalently "at least one of A or B" or equivalently "at least one of A and/ or B") may refer, in one embodiment, to at least one, optionally including more than one, A, in the absence of B (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, in the absence of A (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

It should also be understood that in certain methods described herein that include more than one step or act, the order of the steps or act of the method is not necessarily limited to the order in which the steps or acts of the method are specified, unless the context clearly indicates otherwise.

The terms "co-administration" and "co-administered" or "combination therapy" refer to simultaneous administration (administration of two or more therapeutic agents at the same time) and separate administration (administration of one or more therapeutic agents at a time other than administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent, preferably in effective amounts, simultaneously. In certain preferred aspects, one or more of the compounds described herein is co-administered in combination with at least one additional bioactive agent, especially including an anticancer agent. In particularly preferred aspects, co-administration of the compounds results in a synergistic effect and/or therapy, including an anti-cancer effect.

, и двойная связь, и одинарная связь представлены в контексте показанного соединения.The term "compound" in this specification, unless otherwise indicated, refers to any specific chemical compound described herein and includes its tautomers, regioisomers, geometric isomers and, if applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as its pharmaceutically acceptable salts and derivatives (including prodrugs), if applicable, in the context. When used in context, the term compound generally refers to a single compound, but may also include other compounds such as stereoisomers, regioisomers, and/or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of the described compounds. The term also refers, in context, to prodrugs of compounds that can be modified to improve administration and delivery of the compounds to the site of action. It should be noted that when describing compounds, multiple substituents and variables associated with them, among others, are described. The person skilled in the art will appreciate that the molecules described herein are stable compounds, as generally described below. If the connection is shown

, both the double bond and the single bond are presented in the context of the compound shown.

The term "patient" or "subject" is used in the specification to describe an animal, preferably a human or a companion animal, to which treatment, including prophylactic treatment, is provided with compositions in accordance with this invention. For the treatment of infections, conditions, or disease states that are specific to a particular animal, such as a human, the term patient refers to that particular animal, including a domestic animal such as a dog or cat, or a farm animal such as a horse, cow, sheep, etc. .d. In general, in this invention, the term patient refers to a human unless otherwise indicated or clear from the context in which the term is used.

The term "effective" is used to describe the amount of a compound, composition, or component that, when applied in the context of the intended use, produces the desired result. The term effective includes all other terms of effective amount or effective concentration, which are described or used in this application.

The term "VCB E3 Ubiquitin ligase", "Hippel-Lindau (or VHL) E3 Ubiquitin ligase", "VHL", or "Ubiquitin ligase", which are commonly used interchangeably unless the context otherwise indicates, is used to describe the binding site of the target enzyme(s) of ubiquitin ligase fragments as described herein , i.e. in the bifunctional (chimeric) compounds described here. VCB E3 is a protein that, in combination with the E2 ubiquitin-conjugating enzyme, causes the attachment of ubiquitin to lysine on the target protein; E3 ubiquitin ligase acts on target protein substrates for cleavage by the proteasome. Thus, E3 ubiquitin ligase, alone or in combination with the E2 ubiquitin conjugating enzyme, is responsible for the transfer of ubiquitin to target proteins. In general, ubiquitin ligase is involved in polyubiquitination such that the secondary ubiquitin is attached to the primary; the tertiary joins the secondary, and so on. Polyubiquitination marks proteins for cleavage by the proteasome. However, there are some ubiquitination events that are limited to mono-ubiquitination, in which only one ubiquitin is added by a ubiquitin ligase to a substrate molecule. Mono-ubiquitinated proteins are not exposed to the proteasome for cleavage, instead their cellular location or function can be altered, for example, through the binding of other proteins that have domains capable of binding ubiquitin. Other complicating points, various lysines on ubiquitin, can be affected by E3 to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

As used herein, a fragment that binds an E3 ubiquitin ligase or a component thereof, eg VHL, is referred to as a ubiquitin ligase binding fragment or "ULM".

The term "target protein moiety" or PTM is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest and places/presents that protein or polypeptide adjacent to a ubiquitin ligase such that cleavage of the protein or polypeptide can occur. ubiquitin ligase. Non-limiting examples of small molecule target protein binding moieties include Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting aryl hydrocarbon receptor (AUR), among many others. The compositions described below represent some of the members of these and other types of small molecular weight target proteins. When ULM is combined with a target protein-binding moiety ('PTM'), the target protein is ubiquitinated and/or cleaved by the proteasome (see FIG. 1).

As stated above, the description refers to the surprising and unexpected discovery that the E3 ubiquitin ligase protein ubiquitinates the target protein once it and the target protein are placed next to the bifunctional PROTAC compound, which binds the E3 ubiquitin ligase protein or component thereof and the target protein. Therefore, the description provides such compounds that bind E3 ubiquitin ligase proteins, as well as PROTAC bifunctional compounds containing them.

Compounds and compositions

Described herein are compounds useful in regulating the activity of a protein. The compounds contain a binding fragment of the ubiquitin pathway protein (preferably for ubiquitin ligase, alone or in combination with an E2 ubiquitin conjugating enzyme that is responsible for the transfer of ubiquitin to target proteins) as described here. Preferably, the E3 binding fragment of the ubiquitin ligase is a small molecule (ie, not peptide-based). In certain aspects and embodiments, a binding fragment of a ubiquitin pathway protein is chemically linked, via a bond or via a chemical linker, to a protein targeting fragment, where the ubiquitin ligase binding fragment recognizes a ubiquitin ligase and the targeting fragment recognizes a target protein, and where the ubiquitin ligase protein binding fragment is combined with a directional fragment.

In one aspect, the disclosure provides ubiquitin ligase binding compounds (ULMs) capable of binding E3 ubiquitin ligase, eg, VHL, as described below. In certain embodiments, ULM links VHL.

In an additional aspect, this invention relates to a compound of the structure: L-ULM, where L is a linker group and ULM is a binding fragment of the ubiquitin ligase. In certain embodiments, the ULM is coupled directly or via a chemical linker to the PTM.

In another aspect, the specification provides compounds that contain a PTM group of general structure: ULM-L-PTM, where ULM is an E3 ubiquitin ligase, e.g., VHL, a binding moiety, PTM is a chemical moiety (protein targeting moiety) that binds with a target protein or polypeptide that is ubiquitinated by a ubiquitin ligase and chemically linked directly to the ULM group or through a linker group L, which may be a bond or a chemical linker. In certain embodiments, the PTM is alternatively a ULM' group, which is also an E3 ubiquitin ligase binding moiety, which may be the same as or different from the ULM group, directly or through a linker group, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof. In certain embodiments, at least one of ULM and ULM' (if present) is combined with PTM, PTM', or a combination thereof directly (bond) or via a chemical linker.

In certain aspects of the invention, where PTM is a ULM' group, the compound resembles a dimeric compound, where both ends of the compound contain a ubiquitin ligase binding moiety, as also described here.

Although the ULM group and the PTM group may be covalently linked to the linker group via any group that is suitable and stable with respect to the chemistry of the linker, in certain embodiments, and as described in more detail below, the linker may be independently covalently linked to the ULM group and the PTM group via amide, ester, thioether, keto group, carbamate (urethane), carbon or ether, each of these groups can be introduced anywhere on the ULM group and PTM group to obtain maximum binding of the ULM group on the ubiquitin ligase and the PTM group on the cleavable target protein . (It should be noted that in certain aspects where the PTM group is a ULM group, the target protein for cleavage may be the ubiquitin ligase itself). In certain aspects, the linker may be linked to an optionally substituted alkyl, alkylene, alkene, or alkyne group, aryl group, or heterocyclic group on ULM and/or PTM groups.

In an additional aspect, the description presents a library of compounds. The library contains more than one compound, where each composition is a ULM, as described here.

In a further aspect, the specification provides a library of compounds of formula A-B, wherein A is a ubiquitin pathway protein-binding fragment or ULM (preferably an E3 ubiquitin ligase fragment as described herein) and B is a protein-binding molecular library member or PTM, where A is linked (preferably , via a linker group) with B, and wherein the ubiquitin pathway protein linking fragment recognizes a ubiquitin pathway protein, in particular E3 ubiquitin ligase. In a specific embodiment, the library contains a specific ubiquitinated recognition fragment for VHL for E3 ubiquitin ligase (binding fragment of the ubiquitin pathway protein, as described here) with arbitrary target protein binding elements (eg, a chemical compound library). As such, the target protein is not predetermined and the method can be used to determine the activity of a putative protein binding element and its pharmacological value as a target for ubiquitin ligase digestion.

In any of the aspects or variants described herein, ULM and, if present, ULM', each is independently a chemical structure group:

where R ^1' is an optionally substituted C ₁ -C ₆ alkyl group, optionally substituted with -(CH ₂ ) _n OH, optionally substituted with -(CH ₂ ) _n SH, optionally substituted with (CH ₂ ) _n -O-(C ₁ -C ₆ ) an alkyl group optionally substituted with a (CH ₂ ) _n -WCOCW-(C ₀ -C ₆ ) alkyl group containing the epoxy moiety of WCOCW, where each W is independently an H or C ₁ -C ₃ alkyl group optionally substituted with -(CH ₂ ) _n COOH optionally substituted with -(CH ₂ ) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted with -(CH ₂ ) _n NHC(O)-R ₁ , optionally substituted with -(CH ₂ ) _n C(O)-NR ₁ R ₂ optionally substituted with -(CH ₂ ) _n OC(O)-NR ₁ R ₂ , -(CH ₂ O) _n H optionally substituted with -(CH ₂ ) _n OC(O) -(C ₁ -C ₆ alkyl), optionally substituted with -(CH ₂ ) _n C(O)-O-(C ₁ -C ₆ alkyl), optionally substituted with -(CH ₂ O) _n COOH, optionally substituted with -(OCH ₂ ) _n O-(C ₁ -C ₆ alkyl) optionally substituted with -(CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl) optionally substituted with -(OCH ₂ ) _n NHC(O)- R ₁ , optionally substituted with -(CH ₂ O) _n C(O)-NR ₁ R ₂ , -(CH ₂ CH ₂ O) _n H, optionally substituted with -(CH ₂ CH ₂ O) _n COOH, optionally substituted with -(OCH ₂ CH ₂ ) _n O-(C ₁ -C ₆ alkyl) optionally substituted with -(CH ₂ CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl) optionally substituted with -(OCH ₂ CH ₂ ) _n NHC(O)-R ₁ , optionally substituted with -(CH ₂ CH ₂ O) _n C(O)-NR ₁ R ₂ , optionally substituted with -SO ₂ R _S , optionally substituted with S(O) _RS , NO ₂ , CN or halogen (F, Cl, Br, I, preferably F or Cl);

R ₁ and R ₂ are each independently an H or C ₁ -C ₆ alkyl group which may be optionally substituted with one or two hydroxyl groups or up to those halogen groups (preferably fluorine);

R _S is a C ₁ -C ₆ alkyl group, optionally substituted with an aryl, heteroaryl or heterocyclic group, or -(CH ₂ ) _m NR ₁ R ₂ group,

X and X' are each independently C═O, C═S, -S(O), S(O) ₂ , (preferably X and X' are both C═O);

R ^2' is an optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w alkyl group optionally substituted with -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w NR _1N R _2N group optionally substituted with -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -Aryl optionally substituted with -(CH ₂ ) _n - (C=O) _u (NR ₁ ) _v (SO ₂ ) _w -Heteroaryl optionally substituted with -(CH ₂ ) _n -(C=O) _v NR ₁ (SO ₂ ) _w -Heterocycle optionally substituted with -NR ¹ - (CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl optionally substituted with -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted with -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted with -NR ¹ - (CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -Aryl optionally substituted with -NR ¹ -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -Heteroaryl or optionally substituted -NR ¹ -(CH ₂ ) _n -(C=O) _v NR ₁ (SO ₂ ) _w -Heterocycle optionally substituted with -X ^{R 2'} -alkyl group; optionally substituted -X ^R2' -Aryl group; optionally substituted with -X ^R2' -heteroaryl group; optionally substituted with -X ^R2' -heterocyclic group; optionally substituted;

R ^3' is optionally substituted alkyl, optionally substituted with -(CH ₂ ) _n -(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted with -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -C(O)NR ₁ R ₂ , optionally substituted with -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -Aryl optionally substituted with -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -Heteroaryl optionally substituted with -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -Heterocycle optionally substituted with -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl optionally substituted with -NR ¹ -( CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w - NR _1N R _2N , optionally substituted with -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N optionally substituted with -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -Aryl optionally substituted with -NR ¹ -( CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -Heteroa Ryl optionally substituted with -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -Heterocycle optionally substituted with -O-(CH ₂ )n-(C=O) _u ( NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted with -O-(CH ₂ )n-(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted with -O- (CH ₂ )n-(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted with -O-(CH ₂ )n-(C=O) _u ( NR ₁ ) _v (SO ₂ ) _w -Aryl, optionally substituted with -O-(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -Heteroaryl or optionally substituted with -O-(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycle; -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -alkyl group optionally substituted with -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -( V) n'-Aryl group optionally substituted with -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _{n' -Heteroaryl} group optionally substituted with -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -heterocyclic group optionally substituted with -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -alkyl group, optionally substituted with -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -Aryl group optionally substituted with -(CH ₂ ) _n -N(R _1' )(C= O) _m' -(V) _n' -Heteroaryl group optionally substituted with -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -Heterocyclic group optionally substituted with -X ^R3' is an alkyl group; an optionally substituted -X ^R3' -Aryl group; optionally substituted with -X ^R3' -heteroaryl group; an optionally substituted -X ^R3' -heterocyclic group; optionally substituted;

where R _1N and R _2N are each independently H, C ₁ -C ₆ alkyl which is optionally substituted with one or two hydroxyl groups and up to three halogen groups, or optionally substituted with -(CH ₂ ) _n -Aryl, -(CH ₂ ) _n -Heteroaryl or -(CH ₂ ) _n -Heterocyclic group;

V is O, S or NR ₁ ;

R ₁ is as described above;

R ¹ and R _1' are each independently H or C ₁ -C ₃ alkyl;

X ^R2' and X ^R3' are each independently optionally substituted -CH ₂ ) _n -, -CH ₂ ) _n -CH(X _v )=CH(X _v )-(cis or trans), -CH ₂ ) _n -CH ≡CH-, -(CH ₂ CH ₂ O) _n - or C ₃ -C ₆ cycloalkyl group, where X _v is H, halogen or C ₁ -C ₃ alkyl group, which is optionally substituted;

each m is independently 0, 1, 2, 3, 4, 5, 6;

each m' is independently 0 or 1;

each n is independently 0, 1, 2, 3, 4, 5, 6;

each n' is independently 0 or 1;

each u is independently 0 or 1;

each v is independently 0 or 1;

each w is independently 0 or 1; and

where any or more of R ^1' , R ^2' , R ^3' , X and X' of ULM is optionally modified to covalently bond to the PTM group via a linker group if PTM is not ULM' or if PTM is ULM' , any or more of R ^1' , R ^2' , R ^3' , X and X' of each ULM and ULM' is optionally modified to be covalently linked to another, directly or through a linker group, or a pharmaceutically acceptable salt, stereoisomer thereof , solvate or polymorph.

In any of the aspects or embodiments described, each ULM, and if present, ULM', is independently a chemical structure group:

where each of R ^1' , R ^2' and R ^3' are as described above, and X is C=O, C=S, -S(O) group or S(O) ₂ group, more preferably C= about the group, and

where any or more of R ^1' , R ^2' and R ^3' are optionally modified so as to be associated with a linker group that is further covalently linked to the PTM group, if PTM is not ULM', or if PTM is ULM', any or several of R ^1' , R ^2' , R ^3' from each ULM and ULM' are optionally modified to be covalently linked to the other, directly or via a linker group, or

or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

In any of the described aspects or variants, each ULM, and if present, ULM', is independently a chemical structure:

where any or more of R ^1' , R ^2' and R ^3' are optionally modified so as to be associated with a linker group that is further covalently linked to the PTM group, if PTM is not ULM', or if PTM is ULM', any or several of R ^1' , R ^2' , R ^3' each of ULM and ULM' are optionally modified to be covalently bonded to the other directly or via a linker group, or

or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

In other preferred aspects of the invention, R ^1' is preferably a hydroxyl group or a group that can be metabolized to a hydroxyl or carboxyl group such that the compound is a prodrug of the active compound. Typical preferred R ^1' groups include, for example, -(CH ₂ ) _n OH, (CH ₂ ) _n -O-(C ₁ -C ₆ )alkyl group, -(CH ₂ ) _n COOH, -(CH ₂ O) _n H optionally substituted with -(CH ₂ ) _n OC(O)-(C ₁ -C ₆ alkyl) or optionally substituted with -(CH ₂ ) _n C(O)-O-(C ₁ -C ₆ alkyl), where n is 0 or 1. If R ^1' is or contains a carboxylic acid group, a hydroxyl group, or an amine group, a hydroxyl group, a carboxylic acid group, or an amine (each of which may be optionally substituted), can be further chemically modified to form a covalent bond with the linker group to which the PTM group is linked (including the ULM'group);

X and X', if present, are preferably C=O, C=S, -S(O) group or S(O) ₂ group, more preferably C=O group;

R ^2' is preferably optionally substituted with -NR ¹ -T-Aryl, optionally substituted with -NR ¹ -T-Heteroaryl, or optionally substituted with -NR ¹ -T-Heterocycle, where R ¹ is H or CH ₃ , preferably H, and T is an optionally substituted -(CH ₂ ) _n - group, where each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halo, an amino acid side chain as described herein, or a C ₁ -C ₃ alkyl group, preferably with one or two methyl groups which may be optionally substituted; and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T can also be -(CH ₂ O) _n - group, -(OCH ₂ ) _n - group, -( CH ₂ CH ₂ O) _n - group, -(OCH ₂ CH ₂ ) _n - group, all of these groups are optionally substituted.

Preferred aryl groups for R ^2' include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, wherein the phenyl group is optionally substituted with a linker group to which a PTM group (including a ULM' group) is attached, halogen (preferably F or Cl), amine , monoalkyl- or dialkylamine (preferably dimethylamine), F, Cl, OH, COOH, C ₁ -C ₆ alkyl, preferably CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN group (each of which may be substituted at the ortho, meta and/or para positions of the phenyl ring, preferably para), an optionally substituted phenyl group (the phenyl group itself is optionally substituted with a linker group attached to the PTM group, including the ULM' group) and/or, at at least one of F, Cl, OH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN groups (in the ortho, meta and/or para positions of the phenyl ring, preferably para) , a naphthyl group which may be optionally substituted, optionally optionally substituted heteroaryl, preferably optionally substituted isoxazole, including methyl-substituted isoxazole, optionally substituted oxazole, including methyl-substituted oxazole, optionally substituted thiazole, including methyl-substituted thiazole, optionally substituted isothiazole, including methyl-substituted isothiazole, optionally substituted pyrrole, including methyl-substituted pyrrole, optionally substituted imidazole, including methylimidazole, optionally substituted benzimidazole or methoxybenzimidazole, optionally substituted oximidazole or methyloxymidazole, optionally substituted diazole group, including methyldiazole group, optionally substituted triazole group, including methyl-substituted triazole group, optionally substituted pyridine group, including halo- (preferably, F) or methyl-substituted pyridine a group or an oxapyridine group (wherein the pyridine group is bonded to the phenyl group by an oxygen) optionally substituted with furan, not necessarily substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3 or 4-azaindolizine), optionally substituted quinoline, optionally substituted with a chemical structure group:

where S ^c is CHR ^SS , NR ^URE or O;

R ^HET is H, CN, NO ₂ , halo (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic groups -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably , C ₁ -C ₃ alkyl);

R ^SS is H, CN, NO ₂ , halo (preferably F or Cl) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted with O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted with -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups );

R ^URE is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each of these groups optionally substituted with one or two hydroxyl groups, or up to three halogens, preferably fluoro groups, or an optionally substituted phenyl group, an optionally substituted heteroaryl or an optionally substituted heterocycle, preferably, for example, piperidine, morpholine, pyrrolidine, tetrahydrofuran);

R ^PRO is H, optionally substituted with C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine , furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably methyl or halo, preferably F or Cl), benzofuran , indole, indolizine, azaindolizine;

R ^PRO1 and R ^{PRO2 are} each independently H, optionally substituted with a C ₁ -C ₃ alkyl group, or together form a keto group; and

each n is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), or

optionally substituted heterocycle, preferably tetrahydrofuran, tetrahydrothiene, piperidine, piperazine or morpholine (when substituted each is preferably substituted with methyl or halogen (F, Br, Cl), each of which may be optionally substituted with a linker group to which a PTM group is attached (including ULM' group).

является

или

группой,In certain preferred aspects

is

or

group,

where R ^PRO and n are as described above.

Preferred heteroaryl groups for R ^2' include optionally substituted quinoline (which may be attached to a pharmacophore or substituted on any carbon atom in the quinoline ring), optionally substituted indole, optionally substituted indolizine, optionally substituted azaindolizine, optionally substituted benzofuran, including optionally substituted benzofuran, optionally substituted isoxazole, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted thiophene, optionally substituted pyridine (2-, 3 or 4-pyridine), optionally substituted imidazole, optionally substituted pyrrole, optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted oxymidazole or chemical structure group:

where S ^c is CHR ^SS , NR ^URE or O;

R ^HET is H, CN, NO ₂ , halo (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably , C ₁ -C ₃ alkyl);

R ^SS is H, CN, NO ₂ , halo (preferably F or Cl) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted with O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted with -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups );

R ^URE is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each optionally substituted with one or two hydroxyl groups, or up to up to three halogen, preferably fluoro groups, or an optionally substituted heterocycle, e.g. piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

Y ^C is N or CR ^YC where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted with O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic groups -C≡CR _a where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl), each of which may be optionally substituted by a linker group to which a PTM group (including ULM' group) is attached.

Preferred heterocyclic groups for R ^2' include tetrahydrofuran, tetrahydrothien, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane or thian, each of which may be optionally substituted, or a group with the chemical structure:

или

, предпочтительно,

или

группу,

or

, preferably

or

group,

where R ^PRO is H, optionally substituted with C ₁ -C ₆ alkyl or optionally substituted aryl, heteroaryl or heterocyclic group;

R ^PRO1 and R ^{PRO2 are} each independently H, optionally substituted with a C ₁ -C ₃ alkyl group, or together form a keto group, and

each n is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1), where each group may be optionally substituted with a linker group to which a PTM group (including a ULM' group) is attached.

Preferred R ^2' substituents for use in accordance with this invention also include specifically (and without limitation to certain described compounds) R ^2' substituents that are found in the identified compounds described here (which include certain compounds that are described in this description and on the accompanying drawings). Each of these R ^2' substituents can be used in combination with any number of R ^3' substituents, which are also described here.

R ^3' preferably optionally substituted -T-Aryl, optionally substituted -T-Heteroaryl, optionally substituted -T-Heterocycle, optionally substituted -NR ¹ -T-Aryl, optionally substituted -NR ¹ -T-Heteroaryl or optionally substituted -NR ¹ -T-Heterocycle, where R ¹ is H or C ₁ -C ₃ alkyl group, preferably H or CH ₃ , T is optionally substituted -(CH ₂ ) _n - group, where each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halo, a C ₁ -C ₃ alkyl group, or an amino acid side chain as described herein, preferably methyl, which may be optionally substituted; and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T can also be -(CH ₂ O) _n - group, -(OCH ₂ ) _n - group, -( CH ₂ CH ₂ O) _n - group, -(OCH ₂ CH ₂ ) _n - group, each of which is optionally substituted.

Preferred aryl groups for R ^3' include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, wherein the phenyl or naphthyl group is optionally substituted with a linker group to which a PTM group (including a ULM' group) is attached and/or a halogen (preferably F or Cl), amine, monoalkyl- or dialkylamine (preferably dimethylamine), amido group (preferably -(CH ₂ ) _m -NR ₁ C(O)R ₂ group, where m, R ₁ and R ₂ are as described above) , halogen (often F or Cl), OH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ , CN or S(O) ₂ R _S group ( _RS is a C ₁ -C ₆ alkyl group optionally substituted with aryl , a heteroaryl or heterocyclic group, or a -(CH ₂ ) _m NR ₁ R ₂ group), each of which may be substituted at the ortho, meta and/or para positions of the phenyl ring, preferably para-), or Aryl (preferably , phenyl), heteroaryl or heterocycle. Preferably, said substituent phenyl group is an optionally substituted phenyl group (i.e., the substituent phenyl group itself is preferably substituted with at least one of F, Cl, OH, SH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ , CN or a linker group to which is attached a PTM group (including ULM' group), where the substitution is in the ortho-, meta- and/or para-positions of the phenyl ring, preferably para-), naphthyl group, which may be optionally substituted as described above with optionally substituted heteroaryl (preferably optionally substituted isoxazole, including methyl-substituted isoxazole, optionally substituted oxazole, including methyl-substituted oxazole, optionally substituted thiazole, including methyl-substituted thiazole, optionally substituted pyrrole, including methyl-substituted pyrrole, optionally substituted imidazole, including methylimidazole, benzimidazole or methoxybenzylimidazole, oximidazole or methyloximidazole, optional an optionally substituted diazole group, including a methyldiazole group, an optionally substituted triazole group, including a methyl-substituted triazole group, a pyridine group, including a halogen- (preferably, F) or methyl-substituted pyridine group, or an oxapyridine group (wherein the pyridine group is bonded to the phenyl group by an oxygen atom), or optionally substituted heterocycle (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane or thian. Each aryl, heteroaryl or heterocyclic group may be optionally substituted with a linker group to which a PTM group is attached (including a ULM' group).

Preferred heteroaryl groups for R ^3' include optionally substituted quinoline (which may be attached to the pharmacocore or substituted on any carbon atom of the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3 or 4- azaindolizine) optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably , methyl and/or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably 1,2,3-triazole substituted with methyl group, triisopropylsilyl group optionally substituted with -(CH ₂ ) _m -OC ₁ -C ₆ alkyl group or optionally substituted -(CH ₂ ) _m -C(O)-OC ₁ -C ₆ alkyl group), optionally substituted pyridine (2-, 3 or 4-pyridine) or a group of chemical structure:

where S ^c is CHR ^SS , NR ^URE or O;

R ^HET is H, CN, NO ₂ , halo (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably , C ₁ -C ₃ alkyl);

R ^SS is H, CN, NO ₂ , halo (preferably F or Cl) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted with O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted with -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups );

R ^URE is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each optionally substituted with one or two hydroxyl groups, or up to up to three halogen, preferably fluoro groups, or an optionally substituted heterocycle, e.g. piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

Y ^C is N or CR ^YC where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted with O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl) Each of these heteroaryl groups may optionally be substituted with a linker group to which a PTM group (including a ULM' group) is attached.

Preferred heterocyclic groups for R ^3' include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane and thian, each of which may be optionally substituted, or a group with the chemical structure:

или

.

or

.

или

группу;Preferably,

or

group;

where R ^PRO is H, optionally substituted with C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl or halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

R ^PRO1 and R ^{PRO2 are} each independently H, optionally substituted with a C ₁ -C ₃ alkyl group, or together form a keto group, and

each n is 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), where each of these heterocyclic groups may be optionally substituted with a linker group to which a PTM group (including a ULM' group) is attached.

Preferred R ^3' substituents for use in accordance with this invention also include specifically (and without limitation to certain described compounds) R ^3' substituents that are found in the identified compounds described here (which include certain compounds that are described in this description and the accompanying drawings). Each of these R ^3' substituents can be used in combination with any number of R ^2' substituents, which are also described here.

In certain alternative preferred elements, R ^2' is an optionally substituted -NR ₁ -X ^R2' -alkyl group, -NR ₁ -X ^R2' -aryl group; optionally substituted -NR ₁ -X R2 ^' -HET, optionally substituted -NR ₁ -X ^R2' -Aryl-HET or optionally substituted -NR ₁ -X R2 ^' -HET-Aryl;

where R ₁ is H or C ₁ -C ₃ alkyl group (preferably H);

X ^R2' is optionally substituted -CH ₂ ) _n -, -CH ₂ ) _n -CH(X _v )=CH(X _v )- (cis or trans), -CH ₂ ) _n -CH≡CH-, -( CH ₂ CH ₂ O) _n - or C ₃ -C ₆ cycloalkyl group;

where X _v is H, halogen or C ₁ -C ₃ alkyl group, which is optionally substituted with one or two hydroxyl groups or up to three halogen groups;

Alkyl is an optionally substituted C1- _C10 alkyl (preferably C1- _C6 alkyl) group (in certain preferred embodiments, _the alkyl group is terminated with a halo group, often Cl or Br);

Aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); and

HET is optionally substituted with oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, benzofuran, lysine, indole, indole, quinoline (if substituted, each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably methyl or halo, preferably F or Cl) or a group with the chemical structure:

where S ^c is CHR ^SS , NR ^URE or O;

R ^HET is H, CN, NO ₂ , halo (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably , C ₁ -C ₃ alkyl);

R ^SS is H, CN, NO ₂ , halo (preferably F or Cl) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted with O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted with -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups );

R ^URE is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each optionally substituted with one or two hydroxyl groups, or up to up to three halogen, preferably fluoro groups, or an optionally substituted heterocycle, eg piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C is N or CR ^YC where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted with O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^PRO is H, optionally substituted with a C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine , furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably methyl or halo, preferably F or Cl), benzofuran , indole, indolizine, azaindolizine;

R ^PRO1 and R ^{PRO2 are} each independently H, optionally substituted with a C ₁ -C ₃ alkyl group, or together form a keto group, and

each n is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1). Each of these groups may optionally be substituted with a linker group to which a PTM group (including a ULM' group) is attached.

In certain alternative preferred embodiments of this invention, R ^3' is an optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -R ^S3' group optionally substituted with -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -R ^S3' group optionally substituted with -X ^R3' -alkyl group, optionally substituted with -X ^R3' -Aryl group; an optionally substituted -X ^R3' -HET group, an optionally substituted -X ^R3' -Aryl-HET group, or an optionally substituted -X ^R3' -HET-Aryl group;

where R ^S3' is an optionally substituted alkyl group (C ₁ -C ₁₀ preferably C ₁ -C ₆ alkyl), optionally substituted with an Aryl group or a HET group;

R _1' is H or a C ₁ -C ₃ alkyl group (preferably H);

V is O, S or NR _1' ;

X ^R3' is -(CH ₂ ) _n -, -(CH ₂ CH ₂ O) _n -, -CH ₂ ) _n -CH(X _v )=CH(X _v )- (cis or trans), -CH ₂ ) _n -CH≡CH- or C ₃ -C ₆ cycloalkyl group, all optionally substituted;

if X _v is H, halogen or a C ₁ -C ₃ alkyl group which is optionally substituted with one or two hydroxyl groups or up to three halogen groups;

Alkyl is an optionally substituted C ₁ -C ₁₀ alkyl (preferably C ₁ -C ₆ alkyl) group (in certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br);

Aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); and

HET is optionally substituted with oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, benzofuran, lysine, indole, indole, quinoline (if substituted, each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably methyl or halo, preferably F or Cl), or a group with the chemical structure:

where S ^c is CHR ^SS , NR ^URE or O;

R ^HET is H, CN, NO ₂ , halo (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably , C ₁ -C ₃ alkyl);

R ^SS is H, CN, NO ₂ , halo (preferably F or Cl) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted with O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted with -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups );

R ^URE is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₀ -C ₆ alkyl), each optionally substituted with one or two hydroxyl groups, or up to up to three halogen, preferably fluoro groups, or an optionally substituted heterocycle, eg piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C is N or CR ^YC where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted with O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^PRO is H, optionally substituted with C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine , furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably methyl, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

R ^PRO1 and R ^{PRO2 are} each independently H, optionally substituted with a C ₁ -C ₃ alkyl group, or together form a keto group;

each n is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1);

each m' is 0 or 1; and

each n' is 0 or 1;

wherein each of said compounds, preferably on alkyl, aryl or Het groups, is optionally substituted with a linker group to which a PTM group (including a ULM' group) is attached.

In alternative embodiments, R ³ ' is -(CH ₂ ) _n -Aryl, -(CH ₂ CH ₂ O) _n -Aryl, -(CH ₂ ) _n -HET or -(CH ₂ CH ₂ O) _n -HET;

where Aryl is phenyl which is optionally substituted with one or two substituents, wherein said substituents are preferably selected from -(CH ₂ ) _n OH, C ₁ -C ₆ alkyl which is itself optionally substituted with CN, halogen (up to those halo groups), OH, - (CH ₂ ) _n O(C ₁ -C ₆ )alkyl, amine, mono- or dt-(C ₁ -C ₆ alkyl)amine, where the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halogen ( preferably, F, Cl) groups, or

said Aryl group is substituted with -(CH ₂ ) _n OH, -(CH ₂ ) _n -O-(C ₁ -C ₆ )alkyl, -(CH ₂ ) _n -O-(CH ₂ ) _n -(C ₁ -C ₆ ) alkyl, -(CH ₂ ) _n -C (O) (C ₀ -C ₆ ) alkyl, - (CH ₂ ) _n -C (O) O (C ₀ -C ₆ ) alkyl, - (CH ₂ ) _n -OC(O)(C ₀ -C ₆ )alkyl, amine, mono- or di-(C ₁ -C ₆ alkyl)amine, where the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halogen ( preferably, F, Cl) groups, CN, NO ₂ , optionally substituted with -(CH ₂ ) _n -(V) _m' -CH ₂ ) _n -(V) _m' -(C ₁ -C ₆ )alkyl group, - (V) _m' -(CH ₂ CH ₂ O) _n -R ^PEG group, where V is O, S or NR _1' , R _1' is H or C ₁ -C ₃ alkyl group (preferably H) and R ^PEG is an H or C ₁ -C ₆ alkyl group which is optionally substituted (including optional substitution with a carboxyl group), or said Aryl group is optionally substituted with a heterocycle, including a heteroaryl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, ox imidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine, (if substituted, each is preferably substituted with C ₁ -C ₃ an alkyl group, preferably methyl, or a halo group, preferably F or Cl), or a group with the chemical structure:

where S ^c is CHR ^SS , NR ^URE or O;

R ^HET is H, CN, NO ₂ , halo (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably , C ₁ -C ₃ alkyl);

R ^SS is H, CN, NO ₂ , halo (preferably F or Cl) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted with O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted with -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups );

R ^URE is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₀ -C ₆ alkyl), each optionally substituted with one or two hydroxyl groups, or up to up to three halogen, preferably fluoro groups, or an optionally substituted heterocycle, eg piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C is N or CR ^YC where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted with O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^PRO is H optionally substituted with C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or a heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine , furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably methyl, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

R ^PRO1 and R ^{PRO2 are} each independently H, optionally substituted with a C ₁ -C ₃ alkyl group, or together form a keto group;

HET is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothien, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with C ₁ -C ₃ alkyl group, preferably methyl, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine or a chemical structure group:

where S ^c is CHR ^SS , NR ^URE or O;

R ^HET is H, CN, NO ₂ , halo (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably , C ₁ -C ₃ alkyl);

R ^SS is H, CN, NO ₂ , halo (preferably F or Cl) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted with O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted with -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups );

R ^URE is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₀ -C ₆ alkyl), each optionally substituted with one or two hydroxyl groups, or up to up to three halogen, preferably fluoro groups, or an optionally substituted heterocycle, eg piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C is N or CR ^YC where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F) optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (eg CF ₃ ), optionally substituted with O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted acetylenic group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^PRO is H, optionally substituted with C ₁ -C ₆ alkyl, or optionally substituted with aryl, heteroaryl, or a heterocyclic group;

R ^PRO1 and R ^{PRO2 are} each independently H, optionally substituted with a C ₁ -C ₃ alkyl group, or together form a keto group;

each m' is independently 0 or 1; and

each n is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1),

wherein each of said compounds, preferably on said Aryl or HET groups, is optionally substituted with a linker group to which a PTM group (including a ULM' group) is attached.

In other embodiments, preferred compounds include compounds of the chemical structure:

where R ^1' is OH or a group that is metabolized in the patient or subject to OH;

R ^2' is -NH-CH ₂ -Aryl-HET (preferably phenyl directly linked to a methyl thiazole);

R ^3' is -CHR ^CR3' -NH-C(O)-R ^3P1 group or -CHR ^CR3' -R ^3P2 group;

where R ^CR3' is a C ₁ -C ₄ alkyl group, preferably methyl, isopropyl or tert-butyl;

группой (группа этилового эфира, предпочтительно, мета-замещена на фенильной части), морфолиногруппой (связанной с карбонилом в положении 2- или 3-;R ^3P1 is C ₁ -C ₃ alkyl (preferably methyl) optionally substituted with an oxetane group (preferably methyl substituted, -(CH ₂ ) _n OCH ₃ group, where n is 1 or 2 (preferably 2), or

a group (an ethyl ester group, preferably meta-substituted on the phenyl moiety), a morpholino group (linked to the carbonyl at the 2- or 3- position;

группой;R ^3P2 is

group;

Aryl is phenyl;

HET is an optionally substituted thiazole or isothiazole; and

R ^HET is H or halo (preferably H);

or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, wherein each of said compounds is optionally substituted with a linker group to which a PTM group (including a ULM' group) is attached.

In certain aspects, bifunctional compounds contain a ubiquitin E3 ligase binding moiety (ULM), where ULM is a chemical structure group:

where each R ₅ and R ₆ is independently OH, SH or optionally substituted alkyl, or R ₅ , R ₆ and the carbon atom to which they are attached form a carbonyl;

R ₇ is H or optionally substituted alkyl;

E is a bond, C=O or C=S;

G is a bond, optionally substituted with alkyl, -COOH or C=J;

J is O or NR ₈ ;

R ₈ is H, CN, optionally substituted alkyl or optionally substituted alkoxy;

;M is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, or

;

each R ₉ and R ₁₀ is independently H; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, linked ULM disulfide, optionally substituted heteroaryl or haloalkyl; or R ₉ , R ₁₀ and the carbon atom to which they are attached form an optionally substituted cycloalkyl;

;R ₁₁ is optionally substituted heterocycle, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

;

R ₁₂ is H or optionally substituted alkyl;

R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate,

each R ₁₄ is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl;

R ₁₅ is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl;

each R ₁₆ is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy;

each R ₂₅ is independently H or optionally substituted alkyl; or both R ₂₅ groups may together form an oxo or optionally substituted cycloalkyl group;

R ₂₃ is H or OH;

Z ₁ , Z ₂ , Z ₃ and Z ₄ are independently C or N; and

o is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

In certain embodiments, the ULM is coupled to the target protein fragment (PTM) directly via a bond or via a chemical linker (L).

In certain embodiments, G is C=J, J is O, R ₇ is H, each R ₁₄ is H, and o is 0.

.In certain embodiments, G is C=J, J is O, R ₇ is H, each R ₁₄ is H, R ₁₅ is an optionally substituted heteroaryl, and o is 0. In other instances, E is C=O and M is

.

и M является

.In certain embodiments, E is C=O, R ₁₁ is an optionally substituted heterocycle, or

and M is

.

и R₁₁ является

или

, каждый R₁₈ независимо является галогеном, необязательно замещенным алкокси, циано, необязательно замещенным алкилом, галогеналкилом или галогеналкокси; и p равен 0, 1, 2, 3 или 4.In certain embodiments, E is C=O, M is

and R ₁₁ is

or

, each R ₁₈ is independently halogen, optionally substituted with alkoxy, cyano, optionally substituted with alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4.

In certain embodiments, ULM and, if present, ULM', are each independently a chemical structure group:

, где G является C=J, J является O, R₇ является Н, каждый R₁₄ является Н, o равен 0, R₁₅ является

и R₁₇ является Н, галогеном, необязательно замещенным циклоалкилом, необязательно замещенным алкилом, необязательно замещенным алкенилом и галогеналкилом. В других случаях, R₁₇ является алкилом (например, метилом) или циклоалкилом (например, циклопропилом). В определенных вариантах, ULM сопряжен с PTM прямо через связь или через химический линкер.

where G is C=J, J is O, R ₇ is H, each R ₁₄ is H, o is 0, R ₁₅ is

and R ₁₇ is H, halo, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, and haloalkyl. In other cases, R ₁₇ is alkyl (eg, methyl) or cycloalkyl (eg, cyclopropyl). In certain embodiments, the ULM is coupled to the PTM directly via a bond or via a chemical linker.

In other embodiments, ULM and, if present, ULM', are each independently a chemical structure group:

, где G является C=J, J является O, R₇ является Н, каждый R₁₄ является Н, o равен 0 и R₁₅ выбирают из группы, включающей:

where G is C=J, J is O, R ₇ is H, each R ₁₄ is H, o is 0 and R ₁₅ is selected from the group consisting of:

,

,

where R ₃₀ is H or optionally substituted alkyl.

In certain embodiments, the ULM is coupled to the PTM directly via a bond or via a chemical linker.

In other embodiments, ULM and, if present, ULM', are each independently a chemical structure group:

,

,

и R₁₁ выбирают из группы, включающей:where E is C=O, M is

and R ₁₁ is selected from the group consisting of:

и

.

and

.

In certain embodiments, the ULM is coupled to the PTM directly via a bond or via a chemical linker.

, где E является C=O, R₁₁ является

и M является

;In other embodiments, a compound of the chemical structure,

where E is C=O, R ₁₁ is

and M is

;

where q is 1 or 2;

;R ₂₀ is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or

;

R ₂₁ is H or optionally substituted alkyl; and

R ₂₂ is H, optionally substituted alkyl, optionally substituted alkoxy or haloalkyl. In certain embodiments, the ULM is coupled to the PTM directly via a bond or via a chemical linker.

In any of the above options, R ₁₁ is selected from the group consisting of:

In certain embodiments, R ₁₁ is selected from the group consisting of:

In certain embodiments, ULM (or, if present, ULM') is a chemical structure group:

;

;

where X is O or S

Y is H, methyl or ethyl

R ₁₇ is H, methyl, ethyl, hydroxymethyl or cyclopropyl;

M is optionally substituted heteroaryl, optionally substituted aryl, R ₉ is H;

R ₁₀ is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl.

.R ₁₁ is optionally substituted heteroaromatic, optionally substituted heterocyclic, optionally substituted aryl, or

.

and R ₁₂ is H or optionally substituted alkyl;

R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate.

In some embodiments, ULM and, if present, ULM', are each independently a chemical structure group:

where Y is H, methyl or ethyl

R ₉ is H;

R ₁₀ is isopropyl, t-butyl, sec-butyl, cyclopentyl or cyclohexyl;

R ₁₁ is optionally substituted amide, optionally substituted isoindolinone, optionally substituted isooxazole, optionally substituted heterocycles.

In other preferred embodiments of the invention, ULM and, if present, ULM', are each independently a chemical structure group:

where R ₁₇ is methyl, ethyl or cyclopropyl; and

R ₉ , R ₁₀ and R ₁₁ are as defined above. In other cases, R ₉ is H; and

R ₁₀ is H, alkyl or cycloalkyl (preferably isopropyl, t-butyl, sec-butyl, cyclopentyl or cyclohexyl).

In any of the aspects or variants described herein, ULM (or, if present, ULM') may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. In addition, in any of the aspects or variants described herein, the ULM (or, if present, the ULM') may be coupled to the PTM directly via a bond or via a chemical linker.

In certain aspects of the invention, the ULM fragment is selected from the group consisting of:

The term "independently" is used to indicate that a variable that is applied independently varies from application to application.

The term "alkyl" in the context means a linear, branched or cyclic fully saturated hydrocarbon radical or alkyl group, preferably C ₁ -C ₁₀ , more preferably C ₁ -C ₆ , alternatively, C ₁ -C ₃ alkyl group, which may be optionally substituted . Examples of alkyl groups include methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl and cyclohexyl, among others. In certain embodiments, the alkyl group is terminated with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, the compounds of this invention may be used for covalent bonding with dehalogenase enzymes. These compounds usually contain a side chain (often linked via a polyethylene glycol group) that is at the end of an alkyl group that has a halogen substituent (often chlorine or bromine) on the far ring, giving the compound containing such a moiety a covalent bond to the protein.

The term "alkenyl" refers to linear, branched or cyclic C ₂ -C ₁₀ (preferably C ₂ -C ₆ ) hydrocarbon radicals containing at least one C=C bond.

The term "alkynyl" refers to linear, branched or cyclic C ₂ -C ₁₀ (preferably C ₂ -C ₆ ) hydrocarbon radicals containing at least one C≡C bond.

The term "alkylene", when used, refers to a -(CH ₂ ) _n - group (n is an integer 0-6) which may be optionally substituted. If substituted, the alkylene group is preferably substituted with one or more methylene groups with a C ₁ -C ₆ alkyl group (including a cyclopropyl group or a t-butyl group), but may also be substituted with one or more halo groups, preferably 1 to 3 halo groups or one or two hydroxyl groups, O-(C ₁ -C ₆ alkyl) groups, or amino acid side chains as described herein. In certain embodiments, the alkylene group may be substituted with a urethane or alkoxy group (or other group) that is also substituted with a polyethylene glycol chain (1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) that is substituted (preferably but not exclusively, at the far end of the polyethylene glycol chain) with an alkyl chain substituted with one halogen group, preferably chlorine. In other embodiments, the alkylene (often methylene) group may be replaced by an amino acid side chain such as a naturally occurring or artificial amino acid side group, e.g., alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine , phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine.

The term "unsubstituted" means substituted with only hydrogen atoms. The range of carbon atoms that includes C ₀ means that the carbon atom is absent and replaced by H. Thus, the range of carbon atoms C ₀ -C ₆ includes carbon atoms 1, 2, 3, 4, 5 and 6 and for C ₀ instead of carbon worth H.

The term "substituted" or "optionally substituted" means independently (i.e., if there is more than one substituent, each substituent is independent of other substituents) one or more substituents (independently up to five substituents, preferably up to three substituents, often 1 or 2 substituents per moieties in a compound according to this invention, and may include substituents which may themselves be substituted) at the carbon (or nitrogen) position anywhere in the molecule in context, and includes, as substituents, hydroxyl, thiol, carboxyl, cyano (C ≡N), nitro (NO₂), a halogen (preferably 1, 2 or 3 halogens, especially on an alkyl, especially a methyl group, e.g. trifluoromethyl), an alkyl group (preferably C_one-C_ten, more preferably C_one-C₆), aryl (especially phenyl and substituted phenyl, e.g. benzyl or benzoyl), alkoxy (preferably C_one-C₆ alkyl or aryl, including phenyl and substituted phenyl), thioether (C_one-C₆ alkyl or aryl), acyl (preferably C_one-C₆ acyl), ester, or thioether (so that the attachment is on the alkylene group and not on the ester functional group, which is preferably substituted with C_one-C₆ alkyl or aryl group), preferably C_one-C₆ alkyl or aryl, halogen (preferably F or Cl), amine (including five- or six-membered cyclic alkyleneamine, also including C_one-C₆ alkylamine or C_one-C₆ dialkylamine, where the alkyl groups may be substituted with one or two hydroxyl groups) or optionally substituted -N(C₀-C₆ alkyl)C(O)(O-C_one-C₆ alkyl) group (which may optionally be substituted with a polyethylene glycol chain to which is also attached an alkyl group containing one halogen, preferably chlorine substituent), hydrazine, amido, which is preferably substituted with one or two C_one-C₆ alkyl groups (including carboxamide which is optionally substituted with one or two C_one-C₆ alkyl groups), alkanol (preferably C_one-C₆ alkyl or aryl) or alkanoic acid (preferably C_one-C₆ alkyl or aryl). Substituents in accordance with this invention may include, for example, -SiR_oneR₂R₃ groups, where each R_one and R₂ such as described here, and R₃ is H or C_one-C₆ an alkyl group, preferably R_one, R₂, R₃ in this context are C_one-C₃ an alkyl group (including an isopropyl or t-butyl group). Each of the groups described above may be attached directly to the substitutable group or, alternatively, the substituent may be attached to the substitutable group (preferably in the case of an aryl or heteroaryl moiety) via an optionally substituted -(CH₂)_m- or alternatively, optionally substituted -(OCH₂)_m-, -(OCH₂CH₂)_m- or -(CH₂CH₂O)_m- a group which may be substituted by any or more of the substituents described above. Alkylene groups -(CH₂)_m- or -(CH₂)_ngroups or other chains, such as the ethylene glycol chains described above, may be substituted anywhere in the chain. Preferred substituents on alkylene groups include halo or C_one-C₆ (preferably C_one-C₃) alkyl groups which may be optionally substituted with one or two hydroxyl groups, one or two ether groups (O-C_one-C₆ groups), up to three halo groups (preferably F) or an amino acid side chain as described herein, and an optionally substituted amide (preferably a carboxamide substituted as described above) or urethane groups (often one or two C₀-C₆ alkyl substituents which may be further substituted). In certain embodiments, the alkylene group (often one methylene group) is substituted with one or two optionally substituted C_one-C₆ alkyl groups, preferably C_one-C_four alkyl groups, most commonly methyl or O-methyl groups, or an amino acid side chain as described herein. In the present invention, a moiety in the molecule may optionally be substituted with up to five substituents, preferably with up to three substituents. Most often, in the present invention, the parts that are substituted are substituted with one or more substituents.

The term "substituted" (each substituent is independent of the other substituent) also in the context of application means C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, amido, carboxamido, sulfone, including sulfonamide, keto, carboxy, complex C ₁ -C ₆ ether (oxyether or carbonyl ether), C ₁ -C ₆ keto, urethane -OC(O)-NR ₁ R ₂ or -N(R ₁ )-C(O)-OR ₁ , nitro, cyano and amine (especially including substituted C ₁ -C ₆ alkylene-NR ₁ R ₂ , mono- or di-C ₁ -C ₆ alkyl amines which may optionally be substituted with one or two hydroxyl groups). Each of these groups contains, unless otherwise indicated in the context, from 1 to 6 carbon atoms. In certain embodiments, preferred substituents include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH ₂ ) _m - (m and n in the context are 1, 2, 3, 4, 5 or 6), -S-, -S(O)-, SO ₂ - or -NH-C(O)-NH-, -(CH ₂ ) _n OH, -(CH ₂ ) _n SH, -(CH ₂ ) _n COOH, C ₁ -C ₆ alkyl, -(CH ₂ ) _n O-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n C (O) - (C ₁ -C ₆ alkyl), - (CH ₂ ) _n OC(O)-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n C(O)O-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n NHC(O) -R ₁ , -(CH ₂ ) _n C(O)-NR ₁ R ₂ , -(OCH ₂ ) _n OH, -(CH ₂ O) _n COOH, C ₁ -C ₆ alkyl, -(OCH ₂ ) _n O-(C ₁ -C ₆ alkyl), -(CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), -(OCH ₂ ) _n NHC(O)-R ₁ , -(CH ₂ O) _n C(O)-NR ₁ R ₂ , -S(O) ₂ -RS , _{-S(O)-R S ( RS} is C ₁ -C ₆ alkyl or -(CH ₂ ) _m -NR ₁ R ₂ group), NO ₂ , CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context in which the substituent is used. R ₁ and R ₂ , in the context, each is H or C ₁ -C ₆ alkyl group (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term "substituted" also means, in the chemical context of the compound being defined and the substituent used, an optionally substituted aryl or heteroaryl group, or an optionally substituted heterocyclic group, as described herein. Alkylene groups can also be substituted as described here, preferably with optionally substituted C ₁ -C ₆ alkyl groups (preferably methyl, ethyl or hydroxymethyl or hydroxyethyl to form a chiral center), side chain of an amino acid group as described here, amido group as described here , or a urethane group OC(O)-NR ₁ R ₂ group, where R ₁ and R ₂ such as described here, although many other groups can also be used as substituents. Various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents, and preferably 1 or 2 substituents. It should be noted that in some cases where a substitution is required at a particular position of the molecule in a compound (mainly due to valency) but no substitution is specified, the substituent is considered or understood to be H unless the context of the substitution suggests otherwise.

The term "aryl" or "aromatic" as used herein refers to a substituted (as described herein) or unsubstituted monovalent aromatic radical having one ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc. .) and may be linked to the compound of the invention at any available stable position of the ring(s) or as indicated on the chemical structure shown. Other examples of aryl groups in the context may include heterocyclic aromatic ring systems, "heteroaryl" groups containing one or more nitrogen, oxygen or sulfur atoms in the ring (monocyclic), such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., among others, which may be optionally substituted as described above. Heteroaryl groups which may be mentioned include nitrogen-substituted heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline , dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolysine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazolin, pyrimidine, phenanthroline, opyrazolidene, phenazoline, , pyrrolopyrimidine and pyridopyrimidine; sulfur-substituted aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles containing 2 or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, isothiazole, benzoxazole, benzothiazol, benzothiadiazol, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, among others, all of which are optionally substituted.

The term "substituted aryl" refers to an aromatic carbocyclic group containing at least one aromatic ring or a plurality of fused rings, at least one of which is aromatic, where the rings are substituted with one or more substituents. For example, the aryl group may contain substituent(s) selected from: -(CH ₂ ) _n OH, -(CH ₂ ) _n -O-(C ₁ -C ₆ )alkyl, -(CH ₂ ) _n -O-( CH ₂ ) _n -(C ₁ -C ₆ )alkyl, -(CH ₂ ) _n -C(O)(C ₀ -C ₆ )alkyl, -(CH ₂ ) _n -C(O)O(C ₀ - C ₆ )alkyl, -(CH ₂ ) _n -OC(O)(C ₀ -C ₆ )alkyl, amine, mono- or di-(C ₁ -C ₆ alkyl)amine, where the alkyl group of the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halogen (preferably F, Cl) groups, OH, COOH, C ₁ -C ₆ alkyl, preferably CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN groups (each of which may be substituted at the ortho, meta and/or para positions of the phenyl ring, preferably para-), an optionally substituted phenyl group (the phenyl group itself is preferably substituted with a linker group attached to a PTM group, including a ULM group), and /or at least one of F, Cl, OH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN groups (in the ortho, meta and/or para positions of the phenyl ring, preferably naphthyl group which may be optionally substituted, optionally substituted heteroaryl, preferably optionally substituted isoxazole, including methyl-substituted isoxazole, optionally substituted oxazole, including methyl-substituted oxazole, optionally substituted thiazole, including methyl-substituted thiazole, optionally substituted isothiazole, including methyl-substituted isothiazole, optionally substituted pyrrole, including methyl-substituted pyrrole, optionally substituted imidazole, including methylimidazole, optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oximidazole or methyloxymidazole, optionally substituted diazole group, including methyldiazole group, optionally substituted triazole group, including methyl, optionally triazole group substituted pyridine group, including a halogen- (preferably, F) or methyl-substituted pyridine group, or an oxapyridine group (wherein the pyridine i group is linked to the phenyl group by oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3 or 4-azaindolizine), optionally substituted quinoline, and combinations thereof.

"Carboxyl" means a group -C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl where generic substituents have the meanings identical to the definitions of the corresponding groups defined here.

The term "heteroaryl" or "hetaryl" may mean, but is not limited to, an optionally substituted quinoline (which may be attached to the pharmacocor or substituted on any carbon atom of the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indolizine, an optionally substituted azaindolizine (2, 3 or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and/or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably 1,2,3-triazole substituted with methyl group, triisopropylsilyl group, optionally substituted -(CH ₂ ) _m -OC ₁ -C ₆ alkyl group or optionally substituted -(CH ₂ ) _m -C(O)-OC ₁ -C ₆ alkyl group), optionally substituted pyridine (2-, 3 or 4-pyridine).

The terms "caralkyl" and "heteroarylalkyl" refer to groups which contain both an aryl or heteroaryl, respectively, and an alkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl ring system as defined above.

The term "arylalkyl" as used herein refers to an aryl group as defined above attached to an alkyl group as defined above. The arylalkyl group is attached to the parent molecule via an alkyl group, where the alkyl group contains from one to six carbon atoms. The aryl group in the arylalkyl group may be substituted as defined above.

The term "heterocycle" refers to a cyclic group that contains at least one heteroatom, such as N, O or S, and may be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties are relegated to the definition of heterocycle depending on the context in which they are used. Exemplary heteroaryl groups are described above.

Exemplary heterocycles include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, and others.

Heterocyclic groups may be optionally substituted with a radical selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, hydroxyaminoacyl, azido, cyano, halogen , hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycle, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -aryl, oxo (═O) and -SO ₂ -heteroaryl. Such heterocyclic groups may have a single ring or multiple fused rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolysine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl and the like, as well as heterocycles containing N-alkoxy nitrogen . The term "heterocycle" also includes bicyclic groups in which any of the heterocyclic rings is fused to a benzene ring or a cyclohexane ring or other heterocyclic ring (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, and the like).

The term "cycloalkyl" may mean, but is not limited to, monovalent groups derived from monocyclic or polycyclic alkyl groups or cycloalkanes as defined herein, for example, saturated monocyclic hydrocarbon groups containing three to twenty ring carbon atoms, including but not limited to , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The term "substituted cycloalkyl" may mean, but is not limited to, a monocyclic or polycyclic alkyl group and is substituted with one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, where these related groups of substituents have the same meaning as the definitions of the corresponding groups given in the description.

The term "hydrocarbyl" means a compound which contains carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic, and includes aryl groups, alkyl groups, alkenyl groups and alkynyl groups.

Typical linkers

-A ₁ -...-Aq-, where A ₁ is a group that links a fragment selected from the group including ULM, PTM and a combination thereof, with an Aq linker or directly to a fragment selected from the group including ULM, PTM and a combination thereof .

In certain embodiments, the compounds described herein include one or more PTMs chemically linked or conjugated to one or more ULMs or ULM's via a chemical linker (L). In certain embodiments, the linker group L is a group containing one or more covalently linked structural units A (for example, -A _{1 ...} A _q -), where A ₁ is a group connected to at least one ULM, PTM or their combination. In certain embodiments, q is an integer greater than or equal to 0. In certain embodiments, q is equal to an integer greater than or equal to 1.

In certain embodiments, for example, where q is greater than 2, A _q is a group that is connected to the ULM or ULM' fragment and A ₁ and A _q are connected via A units (number of such A units: q-2).

In certain embodiments, for example, where q is 2, A _q is a group that is connected to A ₁ and ULM or ULM' fragment.

In certain embodiments, for example, where q is 1, the structure of the linker group L is -A ₁ - and A ₁ is a group that is connected to the ULM or ULM' fragment and the PTM fragment.

In additional embodiments, q is an integer from 1 to 100, 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 up to 20 or from 1 to 10.

In certain embodiments, A ₁ - A _q are each independently a bond, CR ^L1 R ^L2 , O, S, SO, SO ₂ , NR ^L3 , SO ₂ NR ^L3 , SONR ^L3 , CONR ^L3 , NR ^L3 CONR ^L4 , NR ^L3 SO ₂ NR ^L4 , CO, CR ^L1 =CR ^L2 , C≡C, SiR ^L1 R ^L2 , P(O)R ^L1 , P(O)OR ^L1 , NR ^L3 C(=NCN)NR ^L4 , NR ^L3 C(= NCN), NR ^L3 C(=CNO ₂ )NR ^L4 , C _3-11 cycloalkyl optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, C _3-11 heterocyclyl optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, aryl optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, heteroaryl optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, wherein R ^L1 or R ^L ₂ can each independently be linked to other A groups to give a cycloalkyl and/or heterocyclyl moiety, which may be further substituted with 0-4 R ^L5 groups;

where R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are each independently H, halo, C _1-8 alkyl, OC _1-8 alkyl, SC _1-8 alkyl, NHC _1-8 alkyl, N(C _{1 -8} alkyl) ₂ , C _3-11 cycloalkyl, aryl, heteroaryl, C _3-11 heterocyclyl, OC _1-8 cycloalkyl, SC _1-8 cycloalkyl, NHC _1-8 cycloalkyl, N(C _1-8 cycloalkyl) ₂ , N (C _1-8 cycloalkyl) (C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P (O) (OC _1-8 alkyl) (C _1-8 alkyl), P(O)(OC _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH=CH(C _1-8 alkyl), C(C _1-8 alkyl)=CH(C _1-8 alkyl ), C(C _1-8 alkyl)=C(C _1-8 alkyl) ₂ , Si(OH) ₃ , Si(C _1-8 alkyl) ₃ , Si(OH)(C _1-8 alkyl) ₂ , COC _1-8 alkyl, CO ₂ H, halogen, CN, CF ₃ , CHF ₂ , CH ₂ F, NO ₂ , SF ₅ , SO ₂ NHC _1-8 alkyl, SO ₂ N (C _1-8 alkyl) ₂ , SONHC _1-8 alkyl, SON(C _1-8 alkyl) ₂ , CONHC _1-8 alkyl, CON(C _1-8 alkyl) ₂ , N(C _1-8 alkyl)CONH(C _1-8 alkyl), N (C _1-8 alkyl)CON(C _1-8 alkyl) ₂ , NHCONH(C _1-8 alkyl), NHCON(C _1-8 alkyl) ₂ , NHCONH ₂ , N(C _1-8 alkyl)SO ₂ NH (C _1-8 alkyl) , N (C _1-8 alkyl) SO ₂ N (C _1-8 alkyl) ₂ , NH SO ₂ NH (C _1-8 alkyl), NH SO ₂ N (C _1-8 alkyl) ₂ , NH SO ₂ NH ₂ .

или

группы;In certain embodiments, A is independently selected from a bond (i.e., absent), -(CH ₂ ) _i -O, -(CHR) _i -O, (CR ₂ ) _i -O, -(CH ₂ ) _i -S , -(CH ₂ ) _i -NR, -S, -S(O), -S(O) ₂ , -OP(O)OR, -SiR ₂ , (CH ₂ ) _i -X ₁ Y ₁ groups, where X ₁ Y ₁ form an amide group or a urethane group, an ester or thioether group, or

or

groups;

each R is independently H or C ₁ -C ₃ alkyl, an alkanol group, or a heterocycle (including a water-soluble heterocycle, preferably a morpholino, piperidine, or piperazine group to promote aqueous solubility of the linker group);

each Y is independently a bond, O, S, or N-R; and

each i is independently 0 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6; 1, 2, 3, 4 or 5.

группойIn preferred aspects, A is

group

;

или

;where each D is independently a bond (missing),

;

or

;

j is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5;

k is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5; preferably k is 1, 2, 3, 4 or 5;

m' is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15 , 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5;

n is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5;

X ¹ is O, S or NR, preferably O;

Y is as described above; and CON is a linking group (which may be a bond) that links A ₁ to A _q if present in the linker group.

In preferred aspects, CON is a bond (none), a heterocycle, including a water-soluble heterocycle such as piperazinyl, or another group or group wherein X ² is independently O, S, NR ₄ , OP(O)OR, SiR ₂ , -CC, cycloalkyl, heterocyclyl, S(O), S(O) ₂ , -S(O) ₂ O, -OS(O) ₂ or OS(O) ₂ O;

X ³ is O, S, CHR ₄ , NR ₄ ; and

R ⁴ is an H or C ₁ -C ₃ alkyl group optionally substituted with one or two hydroxyl groups, or a pharmaceutically acceptable salt, enantiomer or stereoisomer thereof.

In alternative preferred aspects, CON is a group or an amide group.

In another aspect, the linker may be asymmetric or symmetrical.

группой или амидной группой.In alternative preferred aspects, CON is

group or amide group.

In alternative preferred aspects, the linker group is an optionally substituted (poly)ethylene glycol containing from 1 to about 100 ethylene glycol units, from about 1 to about 50 ethylene glycol units, from 1 to about 25 ethylene glycol units, from about 1 to 10 ethylene glycol units, from 1 to about 8 units of ethylene glycol and 1 to 6 units of ethylene glycol, 2 to 4 units of ethylene glycol. In certain embodiments, the linker is optionally substituted; those. contains chemical groups located inside or on the PEG linker. In a certain additional embodiment, the PEG linker is substituted with an alkyl, alkylene, aromatic group, or aryl group, such as phenyl, benzyl, or a heterocyclyl group, or an amino acid side chain, and optionally contains optionally substituted O, N, S, P, or Si atoms.

In certain embodiments, the linker (L) is selected from the group consisting of:

Although the ULM group and the PTM group (including the ULM' group) can be covalently linked to the linker group via any group that is suitable and stable to the chemistry of the linker, in preferred aspects of the invention the linker is independently covalently linked to the ULM group and the PTM group (including the ULM' group ), preferably via an amide, ester, thioether, keto group, carbamate (urethane) or ether, each of which can be inserted anywhere on the ULM group and the PTM group (including the ULM' group) to obtain maximum binding of the ULM group on the ubiquitin ligase and PTM groups on the target protein to be cleaved. (It should be noted that in certain aspects where the PTM group is a ULM' group, the cleavage target protein is the ubiquitin ligase itself). In certain preferred aspects, the linker may be linked to an optionally substituted alkyl, alkylene, alkene or alkyne group, aryl group, or heterocyclic group on ULM and/or PTM groups.

Typical structures with sites for linkers

In an additional embodiment, particularly preferred compounds in accordance with this invention can be identified according to any or more of the chemical structures shown in figure 19:

группой,Where any or more of R _1PC , R _2PC , R _3PC , R _4PC , R _5PC , R _6PC , R _7PC , R _8PC , R _9PC , R _10PC , R _11PC , R _12PC , R _13PC and R _14PC is

group,

является нацеливающим на белок фрагментом, илиwhere L is a linker group and

is a protein-targeting moiety, or

their pharmaceutically acceptable salt, stereoisomer, solvate or polymorph.

группой и другие группы R_1PC, R_2PC, R_3PC, R_4PC, R_5PC, R_6PC, R_7PC, R_8PC, R_9PC, R_10PC, R_11PC, R_12PC, R_13PC и R_14PC независимо являются H или CH₃ группой, часто H.In preferred embodiments, no more than two R _1PC , R _2PC , R _3PC , R _4PC , R _5PC , R _6PC , R _7PC , R _8PC , R _9PC , R _10PC , R _11PC , R _12PC , R _13PC and R _14PC are

group and the other groups R _1PC , R _2PC , R _3PC , R _4PC , R _5PC , R _6PC , R _7PC , R _8PC , R _9PC , R _10PC , R _11PC , R _12PC , R _13PC and R _14PC are independently H or CH ₃ group, often H.

Certain preferred embodiments relate to ULM compounds of the chemical structure:

where R _7PC and R _10PC each independently is -[L-PTM] group or H; or

their pharmaceutically acceptable salt, stereoisomer, solvate or polymorph. Preferably, either R _7PC or R _10PC is a -[L-PTM] group and the other is R _7PC or R _10PC is H.

In other preferred embodiments, the compound has the chemical structure:

where R _7PC, R _11PC, R _12PC, R _13PC and R _14PC each independently is a -[L-PTM] group or H; or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. Preferably one of R _7PC , R _11PC , R _12PC , R _13PC and R _14PC is a -[L-PTM] group and the other groups are H, or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

In other preferred embodiments, the compound has the chemical structure:

where R _4PC , R _7PC , R _11PC , R _12PC , R _13PC and R _{14PC are} each independently a -[L-PTM] group or H; or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. Preferably, any of R _4PC , R _7PC or one of R _11PC , R _12PC , R _13PC and R _14PC is a -[L-PTM] group and other groups are H; or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

In other embodiments, the ULM compound has the chemical structure:

where R _3PC , R _7PC , R _11PC , R _12PC , R _13PC and R _{14PC are} each independently a -[L-PTM] group or H; or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. Preferably, one of R _3PC , R _7PC , R _11PC , R _12PC , R _13PC and R _14PC is a -[L-PTM] group and the other groups are H; or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

In other preferred embodiments, the compound has the chemical structure:

where R _7PC and R _9PC each independently is -[L-PTM] group or H; or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. Preferably, one of R _7PC and R _9PC is a -[L-PTM] group and the other group is H; or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

In the above embodiments, the linker group may be any of the linker groups described above, below, preferably a polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units. , from about 2 to 5 units of ethylene glycol, from about 2 to 4 units of ethylene glycol.

Typical PTMs.

In other aspects of the invention, the PTM group is a group that binds to target proteins. The targets of the PTM group are numerous and are selected from proteins that are expressed in cells, those that are at least part of the sequences found in the cells and can bind to the PTM group. The term "protein" includes oligopeptide and polypeptide sequences of sufficient length to allow binding of a PTM group in accordance with the present invention. Any protein in the eukaryotic system or microbial system, including virus, bacteria or fungi, is a target for ubiquitination mediated by the compounds of this invention. Preferably, the target protein is a eukaryotic protein. In certain aspects, the protein-binding moiety is a haloalkane (preferably a C ₁ -C ₁₀ alkyl group that is substituted with at least one halo group, preferably a halo group at the far end of the alkyl group (i.e. away from the linker or ULM group) that can covalently bind to the dehalogenase enzyme in a patient or in a diagnostic study.

PTM groups in accordance with this invention include, for example, any fragments that bind to a protein specifically (binds to a target protein) and includes the following non-limiting examples of small molecular weight fragments that target proteins: Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds bromodomain-containing proteins targeting human BET, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AUR), among others. The compositions described below represent some members of these ten types of small molecular weight fragments that bind target proteins. Such small molecular weight fragments that bind target proteins also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that can be targeted to target proteins. Such binding moieties are connected to the ubiquitin ligase binding moiety, preferably via a linker to place the target protein (to which the target protein moiety is bound) next to the ubiquitin ligase for ubiquitination and cleavage.

Any protein that can be linked to a protein targeting moiety or PTM group and be attacked or cleaved by a ubiquitin ligase is a target protein of the invention. In general, target proteins may include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins related to integrated cell function, including proteins involved in catalytic activity, aromatase activity, locomotor activity, helicase activity, metabolic processes. (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, fat, carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including transporter protein activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translational regulator activity. Target proteins can include proteins from eukaryotes and prokaryotes, including humans for drug therapy, other animals, including domestic animals, microbes for targeting antibiotics and other antimicrobials and plants, and even viruses, among others.

In other embodiments, the PTM group is a haloalkyl group, wherein said alkyl group generally ranges in size from about 1 or 2 carbons to about 12 carbons in length, often from about 2 to 10 carbons in length, often from about 3 carbons to about 8 carbons in length, more often from about 4 carbons to about 6 carbons in length. Haloalkyl groups are usually linear alkyl groups (although branched alkyl groups may also be used) and are terminated with at least one halogen group, preferably a single halogen group, often a single chloride group. Haloalkyl PTM groups for use in accordance with this invention are preferably represented by the chemical structure -(CH ₂ ) _v -halo, where v is any integer from 2 to about 12, often from about 3 to about 8, more often from about 4 to about 6. Halogen can be any halogen, but preferably Cl or Br, more often Cl.

группа, где w равен от 0 до 3, предпочтительно, 1 или 2. Эта группа связывается селективно с рецепторами эстрогена и ее применяют для лечения заболеваний, которые модулированы через рецепторы эстрогена и, в частности, раков, таких как рак молочной железы, рак эндометрия, рак яичников и рак матки, среди прочих.In other embodiments, the PTM group is

a group where w is from 0 to 3, preferably 1 or 2. This group binds selectively to estrogen receptors and is used to treat diseases that are modulated through estrogen receptors and in particular cancers such as breast cancer, endometrial cancer , ovarian cancer, and uterine cancer, among others.

The present invention can be used to treat a variety of diseases and/or conditions, including any disease and/or condition in which proteins are dysregulated and where the patient would benefit from protein breakdown.

In another aspect, this invention relates to pharmaceutical compositions containing an effective amount of the compound presented above, in combination with a pharmaceutically acceptable carrier, additive or excipient and, optionally, an additional bioactive agent.

In alternative aspects, this invention relates to a method of treating a disease through cleavage of a protein or polypeptide through which the disease or condition is modulated, comprising administering to said patient or subject an effective amount of at least one compound as described above, optionally in combination with an additional bioactive agent. The method in accordance with this invention can be used to treat a wide variety of diseases or conditions, including cancer, through the introduction of an effective amount of at least one compound described here.

Protein targeting moieties according to the invention include, for example, haloalkanhalogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds; and compounds targeting the aryl hydrocarbon receptor (AUR). The compositions described below represent some of the members of these types of small molecule target protein binding moieties. Such target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target the protein of interest. The links below are incorporated herein by reference in their entirety.

Heat shock protein 90 inhibitors (HSP90) :

The HSP90 inhibitors used herein include, but are not limited to:

HSP90 inhibitors identified by Vallee, et al ., "Tricyclic Series of Heat Shock Protein 90 (HSP90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the HSP90 Molecular Chaperone (2011) J .Med.Chem.54 :7206, including

YKB

N-[4-(3H-IMIDAZO[4,5-C]PYRIDIN-2-YL)-9H-FLUOREN-9-YL]SUCCINAMIDE

группа присоединена через концевую амидную группу;Obtained where the linker group is L or

the group is attached through a terminal amide group;

2. HSP90 p54 inhibitor (derivatized):

p54

8-[(2,4-dimethylphenyl)sulfanyl]-3-pent-4-yn-1-yl-3H-purine-6-amine

группа присоединена через концевую ацетиленовую группу;Where is the linker group L or

the group is attached through a terminal acetylene group;

3. HSP90 inhibitors (modified) identified by Brough, et al ., "4,5-Diarylizoxazole HSP90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer", J.MED.CHEM. vol: 51, pag:196 (2008), including compound 2GJ (5-[2,4-DIHYDROXY-5-(1-METHYLETHYL)PHENYL]-N-ETHYL-4-[4-(MORPHOLIN-4-YLMETHYL) PHENYL]ISOXAZOLE-3-CARBOXAMIDE), having the structure:

группа присоединена через амидную группу (на амине или на алкильной группе амина;Derivatized, where the linker group is L or

the group is attached via an amide group (on an amine or on an alkyl group of an amine;

4. HSP90 inhibitors (modified) identified by Wright, et al ., Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms, Chem Biol. 2004 Jun;11(6):775-85, including the HSP90 inhibitor PU3 having the structure:

присоединена через бутильную группу; иWhere is the linker group L or

attached via a butyl group; and

группа присоединена через амидную группу). 5. HSP90 inhibitor Geldanamycin ((4E,6Z, 8S ,9S, 10E , 12S , 13R , 14S , 16R ) -13-hydroxy- 8,14,19 -trimethoxy-4,10 ,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1] (derivatized) or any of its derivatives (e.g. 17-alkylamino-17-desmethoxygeldanamycin ("17-AAG") or 17 -(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin ("17-DMAG")) (derivatized where the linker group is L or a

group is attached via an amide group).

II. Kinase and phosphatase inhibitors:

Kinase inhibitors as used herein include, but are not limited to:

Tyrosine kinase inhibitor derivative Erlotinib

группой, присоединенной через простую эфирную группу;Where is the linker group L or

a group attached through an ether group;

2. Kinase inhibitor Sunitanib (derivatized):

группой, присоединенной к пиррольной части);(derivatized where R is a linker group of L or

a group attached to the pyrrole moiety);

3. Kinase inhibitor Sorafenib (derivatized)

группой, присоединенной к фенильной части);(derivatized where R is a linker group of L or

a group attached to the phenyl moiety);

4. Kinase inhibitor Desatinib (derivatized)

, присоединенной к пиримидину);(derivatized where R is a linker group of L or

attached to pyrimidine);

Kinase inhibitor Lapatinib (derivatized)

группа присоединена через концевой метил сульфонилметильной группы;Derivatized, where the linker group is L or

the group is attached through the terminal methyl sulfonylmethyl group;

Kinase inhibitor U09-CX-5279 (derivatized)

группа присоединена через амин (анилин), карбоновую кислоту или амин альфа к циклопропильной группе, или циклопропильную группу;Derivatized, where the linker group is L or

the group is attached via an amine (aniline), carboxylic acid, or amine alpha to a cyclopropyl group, or a cyclopropyl group;

7. Kinase inhibitors identified by Millan, et al ., Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease, J.MED.CHEM . vol:54, pag:7797 (2011), including Y1W and Y1X kinase inhibitors (derivatized) having the structures:

1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea

группа присоединена, предпочтительно, через пропильную группу;Derivatized, where the linker group is L or

the group is attached, preferably through a propyl group;

1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a ]pyridin-6-yl]sulfanyl}benzyl)urea

группа присоединена, предпочтительно, либо через пропильную группу, либо через бутильную группу;Derivatized, where the linker group is L or

the group is attached, preferably through either a propyl group or a butyl group;

8. Kinase inhibitors identified in Schenkel, et al ., Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors J. Med. Chem., 2011, 54 (24), pp 8440-8450, including compounds 6TP and 0TP (derivatized) having structures:

4-amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamide

Thianopyridine 19

группа присоединена, предпочтительно, через концевую связь метиильной группы к амидной части;Derivatized, where the linker group is L or

the group is attached, preferably via the terminal bond of the methyl group, to the amide moiety;

0TR

4-amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamide

Thienopyridine 8

группа присоединена, предпочтительно, через концевую связь метильной группы к амидной части;Derivatized, where the linker group is L or

the group is attached, preferably through the terminal bond of the methyl group to the amide moiety;

9. Kinase inhibitors identified by Van Eis, et al ., "2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes", Bioorg. Med. Chem. Lett. 2011 Dec 15;21(24): 7367-72, including the 07U kinase inhibitor having the structure:

2-methyl-N~1~-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]propan-1,2-diamine

группа присоединена, предпочтительно, через вторичный амин или концевую аминогруппу;Derivatized, where the linker group is L or

the group is attached, preferably through a secondary amine or terminal amino group;

10. Kinase inhibitors identified by Lountos, et al ., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy", J.STRUCT.BIOL . vol:176, pag:292 (2011), including a YCF kinase inhibitor having the structure:

группа присоединена, предпочтительно, через простой эфир концевых гидроксильных групп;Derivatized, where the linker group is L or

the group is attached, preferably through an ether of terminal hydroxyl groups;

11. Kinase inhibitors identified by Lountos, et al ., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy", J.STRUCT.BIOL. vol:176, pag:292 (2011), including XK9 and NXP kinase inhibitors (derivatized) having structures:

N-{4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanhydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide

NXP

N-{4-[(1E)-N-carbamimidoylethanehydrazonoyl]phenyl}-1H-indole-3-carboxamide

группа присоединена, предпочтительно, через концевую гидроксильную группу (XK9) или гидразоновую группу (NXP);Derivatized, where the linker group is L or

the group is attached, preferably via a terminal hydroxyl group (XK9) or a hydrazone group (NXP);

группа присоединена, предпочтительно, через алифатическую аминовую группу); 12. Kinase inhibitor Afatinib (derivatized) ( N- [4-[(3-Chloro-4-fluorophenyl)amino]-7-[[( 3S )-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]- 4(dimethylamino)-2-butenamide) (derivatized, where the linker group is L or

the group is attached, preferably via an aliphatic amine group);

группа присоединена, предпочтительно, через метоксигруппу); 13. Kinase inhibitor Fostamatinib (derivatized) (disodium phosphate hexahydrate [6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro -4H-pyrido[3,2-b]-1,4-oxazin-4-yl]methyl) (derivatized where the linker group is L or

the group is attached, preferably via a methoxy group);

группа присоединена, предпочтительно, через метокси или простую эфирную группу); 14. Gefitinib kinase inhibitor (derivatized) ( N- (3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine) (derivatized, where the linker group is L or

the group is attached, preferably via a methoxy or ether group);

группа присоединена, предпочтительно, через циклопропильную группу); 15. Lenvatinib kinase inhibitor (derivatized) (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide) (derivatized, wherein the linker group is L or

the group is attached, preferably via a cyclopropyl group);

группа присоединена предпочтительно, через метокси или гидроксильную группу); и 16. Vandetanib kinase inhibitor (derivatized) ( N- (4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine) (derivatized, where the linker group L or

the group is attached preferably via a methoxy or hydroxyl group); and

17. Vemurafenib kinase inhibitor (derivatized) ({3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}propane acids)

группа присоединена, предпочтительно, через сульфонилпропильную группу);(derivatized, where the linker group is L or

the group is attached, preferably via a sulfonylpropyl group);

18. Gleevec kinase inhibitor (derivatized):

группы присоединен, предпочтительно, через амидную группу или через анилинаминовую группу);(derivatized where R is the linker group L or

group is attached, preferably through an amide group or through an anilinamine group);

Pazopanib kinase inhibitor (derivatized) (EGFR3 inhibitor):

группой, предпочтительно, присоединенной к фенильной части или через анилинаминовую группу);(derivatized where R is a linker group of L or

a group, preferably attached to the phenyl moiety or through an anilinamine group);

Kinase inhibitor AT-9283 (derivatized) aurora kinase inhibitor

группой, присоединенной, предпочтительно, к фенильной части);(where R is a linker group L or

a group attached, preferably to the phenyl moiety);

TAE684 kinase inhibitor (derivatized) ALK inhibitor

группой, присоединенной, предпочтительно, к фенильной части);(where R is a linker group L or

a group attached, preferably to the phenyl moiety);

Kinase inhibitor Nilotanib (derivatized) Abl inhibitor:

группой, присоединенной, предпочтительно, к фенильной части или анилинаминовой группе);(derivatized where R is a linker group of L or

a group attached, preferably to a phenyl moiety or an anilinamine group);

27. NVP-BSK805 kinase inhibitor (derivatized) JAK2 inhibitor

группой, присоединенной к фенильной части или диазольной группе);(derivatized where R is a linker group of L or

a group attached to a phenyl moiety or a diazole group);

28. Kinase inhibitor Crizotinib, a derivatized Alk inhibitor

группой, присоединенной к фенильной части или диазольной группе);(derivatized where R is a linker group of L or

a group attached to a phenyl moiety or a diazole group);

29. JNJ kinase inhibitor FMS (derivatized) inhibitor

группой, присоединенной, предпочтительно, к фенильной части);(derivatized where R is a linker group of L or

a group attached, preferably to the phenyl moiety);

Kinase inhibitor Foretinib (derivatized) Met inhibitor

группой, присоединенной к фенильной части или гидроксильной или простой эфирной группе на хинолиновой части);(derivatized where R is a linker group of L or

a group attached to the phenyl moiety or a hydroxyl or ether group on the quinoline moiety);

31. Allosteric inhibitor of protein tyrosine phosphatase PTP1B (derivatized):

группа, предпочтительно, присоединена на R, как указано.Derivatized, where the linker group is L or

the group is preferably attached to R as indicated.

SHP-2 tyrosine phosphatase domain inhibitor (derivatized):

группа присоединена, предпочтительно, на R.Derivatized, where the linker group is L or

the group is attached, preferably at R.

Inhibitor (derivatized) BRAF (BRAF ^V600E )/MEK:

группа присоединена, предпочтительно, на R.Derivatized, where the linker group is L or

the group is attached, preferably at R.

34 . ABL tyrosine kinase inhibitor (derivatized)

группы на пиперазиновой части).(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups on the piperazine moiety).

III. MDM2 inhibitors:

MDM2 inhibitors as used herein include, but are not limited to:

1. MDM2 inhibitors identified in Vassilev, et al ., In vivo activation of the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol:303, pag:844-848 (2004) and Schneekloth, et al ., Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908, including (or additionally) the compounds nutlin-3, nutlin-2 and nutlin-1 (derivatized) as described below, and all their derivatives and analogues:

группа присоединена, предпочтительно, на метоксигруппе или в качестве гидроксильной группы)(derivatized where the linker group is L or

the group is attached, preferably on a methoxy group or as a hydroxyl group)

группа присоединена, предпочтительно, на метоксигруппе или гидроксильной группе);(derivatized where the linker group is L or

the group is attached, preferably on a methoxy group or a hydroxyl group);

группа присоединена через метоксигруппу или в качестве гидроксильной группы); и(derivatized where the linker group is L or

the group is attached via a methoxy group or as a hydroxyl group); and

Trans-4-iodine-4'-boranyl-chalcone

группа присоединена линкерная группа L или

группа присоединена группа присоединена через гидроксигруппу);(derivatized where the linker group is L or the linker group is L or

group attached linker group L or

a group is attached a group is attached via a hydroxy group);

IV. Compounds targeting human BET bromodomain-containing proteins :

группы, например:Compounds targeting human BET bromodomain-containing proteins include, but are not limited to, target-related compounds as described below, where "R" is the site for attaching the linker group L or

groups, for example:

one.

JQ1, Filippakopoulos et al. Selective inhibition of BET bromodomains. Nature (2010)

2.

I-BET, Nicodeme et al. Supression of Inflammation by a Synthetic Histone Mimic. Nature (2010). Chung et al. Discovery and Characterization of Small Molecule Inhibitors of the BET Family Bromodomains. J. Med Chem. (2011).

3.

Hewings et al. 3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands. J. Med. Chem. (2011) 54 6761.

four.

I-BET151, Dawson et al. Inhibition of BET Recruitment to Chromatin as an Efective Treatment for MLL-fusion Leukemia. Nature (2011).

(where R, in each case, means the point of attachment, for example, the linker group L or -(L-ULM) group).

v. HDAC inhibitors :

HDAC inhibitors (derivatized) include, but are not limited to:

one.

Finnin, M.S. et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188-193 (1999).

группы); и(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups); and

группа присоединена через гидроксильную группу); 2. Compounds defined by formula (I) of PCT WO0222577 ('DEACETILASE INHIBITORS') (derivatized where the linker group is L or

the group is attached via a hydroxyl group);

VI. Human lysine methyltransferase inhibitors :

Human lysine methyltransferase inhibitors include, but are not limited to:

one.

Chang et al. Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat Struct Mol Biol (2009) vol. 16(3)pp. 312-7

группы);(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups);

2.

Liu F, Chen X, Allali-Hassani A, et al. Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a. J Med Chem

группы);(derivatized, where ʺRʺ indicates a potential site of attachment of the linker group L or

groups);

группа присоединена через гидрокси или аминогруппы); и 3. Azacitidine (derivatized) (4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1 H )-one) (derivatized, where the linker group is L or

the group is attached via hydroxy or amino groups); and

группа присоединена через простую эфирную или гидроксигруппы или на аминогруппе). 4. Decitabine (derivatized) (4-amino-1-(2-deoxy-bD-erythropentofuranosyl)-1,3,5-triazin-2(1 H )-one) (derivatized, where the linker group is L or

the group is attached through an ether or hydroxy group or on an amino group).

VII. Angiogenesis inhibitors :

Angiogenesis inhibitors include, but are not limited to:

1. GA-1 (derivatized) and its derivatives and analogs having structures and binding to linkers as described in Sakamoto, et al ., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, Mol Cell Proteomics 2003 Dec;2 (12):1350-8;

группой, как описано у Rodriguez-Gonzalez, et al., Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer, Oncogene (2008) 27, 7201-7211;2. Estradiol (derivatized), which may be linked to a linker group L or

group as described in Rodriguez-Gonzalez, et al. , Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer, Oncogene (2008) 27, 7201-7211;

группой как описано у Sakamoto, et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, Mol Cell Proteomics 2003 Dec; 2(12):1350-8; и3. Estradiol, testosterone (derivatized) and related derivatives, including, but not limited to, DHT and its derivatives and analogues, having structures and binding to the linker group L or

group as described in Sakamoto, et al. , Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, Mol Cell Proteomics 2003 Dec; 2(12):1350-8; and

группой, как описано у Sakamoto, et al., Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation Proc Natl Acad Sci USA. 2001 Jul 17;98(15):8554-9 и патенте США № 7,208,157.4. Ovalicin, fumagillin (derivatized) and their derivatives and analogues, having structures and binding to the linker group L or

group as described in Sakamoto, et al., Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation Proc Natl Acad Sci USA . 2001 Jul 17;98(15):8554-9 and US Pat. No. 7,208,157.

VIII. Immunosuppressive compounds :

Immunosuppressive compounds include, but are not limited to:

группе как описано у Schneekloth, et al., Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation, J. AM. CHEM. SOC. 2004, 126, 3748-3754;1. AP21998 (derivatized), having the structure and binding to the linker group L or

group as described in Schneekloth, et al ., Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation, J. AM. CHEM. SOC. 2004, 126, 3748-3754;

группа должна быть связана, например, с любым из гидроксилов) и дипропионат беклометазона (дериватизированный, где линкерная группа или

связана, например, с пропионатом);2. Glucocorticoids (eg, hydrocortisone, prednisone, prednisolone, and methylprednisolone) (derivatized, where the linker group is L or

the group must be linked to, for example, any of the hydroxyls) and beclomethasone dipropionate (derivatized, where the linker group or

associated, for example, with propionate);

группа может быть связана, например, с любым из концевых гидроксилов);3. Methotrexate (derivatized, where the linker group or

the group may be linked, for example, to any of the terminal hydroxyls);

группа может быть связана, например, на любой из бутильных групп);4. Cyclosporine (derivatized, where the linker group or

the group may be linked, for example, to any of the butyl groups);

группа может быть связана, например, на одной из метоксигрупп); и5. Tacrolimus (FK-506) and rapamycin (derivatized, where the linker group is L or

the group may be linked, for example, to one of the methoxy groups); and

группа может быть связана, например, на одной из изопропильных групп).6. Actinomycins (derivatized, where the linker group is L or

the group may be linked, for example, on one of the isopropyl groups).

IX. Compounds targeting the aryl hydrocarbon receptor (AUR) :

Compounds that target the aryl hydrocarbon receptor (AUR) include, but are not limited to:

группой, как показано у Lee, et al., Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem Volume 8, Issue 17, pages 2058-2062, November 23, 2007); b1. Apigenin (derivatized to bind to a linker group L or

group as shown in Lee, et al., Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem Volume 8, Issue 17, pages 2058-2062, November 23, 2007); b

связана), описанные в Boitano, et al., Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells, Science 10 September 2010: Vol. 329 no. 5997 pp. 1345-1348.2. SR1 and LGC006 (derivatized such that the linker group L or

related) described in Boitano, et al ., Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells, Science 10 September 2010: Vol. 329 no. 5997 pp. 1345-1348.

x. Compounds that target the RAF receptor (kinase):

PLX4032

PLX4032

группы).(derivatized, where ʺRʺ indicates the place to attach the linker group L or

groups).

XI. Compounds targeting FKBP

группы).(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups).

XII. Compounds targeting the androgen receptor (AR)

1. RU59063 androgen receptor ligand (derivatized)

группы).(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups).

2. SARM ligand (derivatized) androgen receptor

группы).(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups).

3. Androgen receptor ligand DHT (derivatized)

группы).(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups).

MDV3100-like ligand (derivatized)

группу;where R is a linker group L or

group;

ARN-509-like ligand (derivatized)

группу;where R is a linker group L or

group;

Hexahydrobenzisoxazoles

группу;where R is a linker group L or

group;

Tetramethylcyclobutanes

группу;where R is a linker group L or

group;

XIII. Compounds targeting the estrogen receptor (ER) ICI-182780

1. Estrogen receptor ligand

группы).(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups).

Compounds targeting the thyroid hormone receptor (RTH)

Thyroid hormone receptor ligand (derivatized)

группы и MOMO означает метоксиметоксигруппу).(derivatized, where ʺRʺ means the point of attachment of the linker group L or

group and MOMO means methoxymethoxy).

XV. Compounds targeting HIV protease

HIV protease inhibitor (derivatized)

группы). См. J. Med. Chem. 2010, 53, 521-538.(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups). See J. Med. Chem. 2010 , 53, 521-538.

HIV protease inhibitor

группы). См. J. Med. Chem. 2010, 53, 521-538.(derivatized, where ʺRʺ indicates a potential site of attachment of the linker group L or

groups). See J. Med. Chem. 2010 , 53, 521-538.

XVI. Compounds targeting HIV integrase

HIV integrase inhibitor (derivatized)

группы). См. J. Med. Chem. 2010, 53, 6466.(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups). See J. Med. Chem. 2010 , 53, 6466.

2 . HIV integrase inhibitor (derivatized)

группы). См. J. Med. Chem. 2010, 53, 6466.(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups). See J. Med. Chem. 2010 , 53, 6466.

XVII. Compounds targeting HCV protease

HCV protease inhibitors (derivatized)

группы).(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups).

XVIII. Compounds targeting Acylprotein thioesterase-1 and -2 (APT1 and APT2)

APT1 and APT2 inhibitor (derivatized)

группы). См. Angew. Chem. Int. Ed. 2011, 50, 9838 -9842, где(derivatized, where ʺRʺ means the point of attachment of the linker group L or

groups). See Angew. Chem. Int. Ed. 2011 , 50, 9838-9842, where

связывает ULM группу с PTM группой, как описано здесь.L is a linker group, as described here, and a specified ULM group, as described here, such that

links the ULM group to the PTM group, as described here.

The term "target protein" is used to describe a protein or polypeptide which is the target for binding to a compound of the invention and cleaving with a ubiquitin ligase. Such small molecule binding groups for target proteins also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target the target protein. Such linking groups are linked to ULM groups via L linker groups.

Pharmaceutical compositions

In an additional aspect, the description provides therapeutic or pharmaceutical compositions containing an effective amount of at least one of the compounds described herein, one ULM, at least one PROTAC, and combinations thereof. Pharmaceutical compositions containing an effective amount of at least one difunctional compound according to this invention and optionally one or more of the other compounds described herein, all in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive or excipient, are another aspect of the description.

In certain embodiments, the compositions contain pharmaceutically acceptable salts, in particular acid or base addition salts of the compounds as described herein. Acids which are useful in the preparation of pharmaceutically acceptable acid addition salts of the above basic compounds include those which form non-toxic acid addition salts, ie. salts containing pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate , methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e. 1,1'-methylenebis-(2-hydroxy-3-naphthoate)], among others.

Pharmaceutically acceptable base addition salts can also be used to prepare pharmaceutically acceptable salts of the compounds or derivatives. Chemical bases that can be used to prepare pharmaceutically acceptable base salts of compounds that are acidic in nature include those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, salts derived from pharmacologically acceptable cations such as alkali metal (eg, potassium and sodium) and alkaline earth metal (eg, calcium, zinc, and magnesium) cations, ammonium addition salts, and water-soluble amine such as N-methylglucamine-(meglumine) and lower alkanolammonium, and other basic salts of pharmaceutically acceptable organic amines, among others.

The compounds described herein, in certain embodiments, can be administered in one or more unit doses by the oral, parenteral, or topical route. Administration of the active compound may vary from continuous (intravenous infusion) to multiple oral administrations per day (e.g., P.R.S.), and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include an agent for penetration enhancement), buccal, sublingual and suppository administration, among other routes of administration. Enteric-coated oral tablets can also be used to improve the bioavailability of compounds by the oral route. The most effective dosage form will depend on the pharmacokinetics of the particular agent chosen and on the severity of the disease in the patient. The administration of the compounds of this invention as sprays, sprays or aerosols for intranasal, intratracheal or pulmonary administration can also be used. Therefore, this invention also relates to pharmaceutical compositions containing an effective amount of a compound according to this invention, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. The compounds of this invention may be administered in immediate release, intermediate release, or delayed or controlled release forms. Forms with delayed or controlled release, preferably administered orally, but also in the form of suppositories and transdermal or other topical forms. Intramuscular injections in the form of liposomes can also be used to control or slow down the release of the compound at the injection site.

Compositions in accordance with this invention may be formulated in the usual manner using one or more pharmaceutically acceptable carriers, and may also be administered in controlled release formulations. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, propylene glycol and lanolin.

The compositions described herein may be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injections or infusions. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

Sterile injectable forms of the described compositions may be aqueous or oily suspensions. These suspensions may be formulated according to methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Suitable vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as a solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and their glyceride derivatives are used for injection as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. Such oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant such as Ph. Helv or similar alcohol.

The pharmaceutical compositions described herein may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. In tablets for oral administration, useful carriers typically include lactose and cornstarch. Lubricants such as magnesium stearate are also commonly added. For oral administration in the form of capsules, useful diluents include lactose and dried corn starch. If aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. Certain sweetening, flavoring or coloring agents may also be added if desired.

Alternatively, the pharmaceutical compositions described herein may be administered in the form of rectal suppositories. They can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions described herein may also be administered topically. Suitable topical formulations are easily prepared for each of these areas or organs. Local administration to the lower intestinal tract may be in the form of rectal suppositories (see above) or in the form of a suitable enema. Topically acceptable transdermal patches may also be used.

For topical administration, pharmaceutical compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Vehicles for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, a polyoxypropylene compound, an emulsifying wax, and water. In certain preferred aspects, the compounds may be enclosed in a stent that is surgically implanted in a patient to inhibit or reduce the likelihood of occlusion occurring in the stent in the patient.

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

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably as solutions in isotonic, pH adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

Pharmaceutical compositions in accordance with this invention can also be administered by nasal spray or inhalation. Such compositions are prepared by methods well known in the art of pharmaceutical formulations and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The amount of a compound in a pharmaceutical composition according to the invention that can be combined with a carrier to form a unit dosage form varies depending on the host and the disease being treated, the specific route of administration. Preferably, the compositions should be formulated to contain from about 0.05 milligrams to about 750 milligrams or more, more preferably from about 1 milligram to about 600 milligrams, and even more preferably from about 10 milligrams to about 500 milligrams of the active ingredient, alone or in combination with at least one other compound according to the invention.

It should also be understood that the specific dosage and treatment regimen for a particular patient will depend on a variety of factors, including the potency of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of elimination, combination of drugs, and opinion. treating physician and the severity of the specific disease or condition being treated.

A patient or subject in need of treatment with compounds of this invention may be treated by administering to the patient (subject) an effective amount of a compound of this invention, including pharmaceutically acceptable salts, solvates, or polymorphs thereof, optionally in a pharmaceutically acceptable carrier or diluent, alone or in combination with other known erythropoiesis stimulating agents as described herein.

These compounds may be administered by any suitable route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, including transdermally, in liquid, cream, gel or solid form, or as an aerosol.

The active compound is incorporated in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired indication without causing serious toxic effects in the patient being treated. The preferred dose of active compound for all of the conditions herein is from about 10 ng/kg to 300 mg/kg, preferably from 0.1 to 100 mg/kg per day, more preferably from 0.5 to about 25 mg per kilogram of body weight. body of the recipient / patient per day. Typical local dose is 0.01-5% wt./mass. in a suitable medium.

The compound is usually administered in any suitable unit dosage form, including, but not limited to, a form containing less than 1 mg, from 1 mg to 3000 mg, preferably from 5 to 500 mg of the active ingredient per dosage form. A convenient oral dose is about 25-250 mg.

The active ingredient is preferably administered to achieve peak plasma concentrations of the active compound of about 0.00001-30 mM, preferably about 0.1-30 μM. This can be achieved, for example, by intravenous injection of a solution or composition of the active ingredient, optionally in a saline or aqueous medium, or administered as a bolus of the active ingredient. Oral administration is also suitable for obtaining effective plasma concentrations of the active agent.

The concentration of the active compound in the drug composition depends on the absorption, distribution, inactivation and rate of excretion of the drug, as well as other factors known to the person skilled in the art. It should also be noted that the dose values also vary depending on the severity of the relieved condition. It is also understood that, for any particular subject, particular dosing regimens will need to be adjusted over time according to individual need and the professional judgment of the person administering or supervising the administration of the compositions presented herein, and that the concentration ranges presented herein are exemplary only and do not limit the scope or practice of the claimed compositions. The active ingredient may be administered once or may be divided into multiple smaller doses for administration at different time intervals.

Oral compositions typically include an inert diluent or edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For purposes of oral therapeutic administration, the active compound or prodrug thereof may be mixed with excipients and administered in the form of tablets, lozenges or capsules. Pharmaceutically compatible binding agents and/or adjuvants may be included as part of the composition.

Tablets, pills, capsules, lozenges or the like may contain any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, tragacanth or gelatin; a filler such as starch or lactose, a dispersing agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange. If the unit dosage form is a capsule, it may contain, in addition to the above material, a liquid carrier such as a fixed oil. In addition, unit dosage forms may contain various other materials that modify the physical form of the dosage form, such as coatings of sugar, shellac, or enteric agents.

The active compound, or a pharmaceutically acceptable salt thereof, may be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetener, and certain preservatives, colors, and flavors.

The active compound, or pharmaceutically acceptable salts thereof, may also be mixed with other active materials that do not interfere with the desired effect, or with materials that complement the desired effect, such as erythropoietin stimulating agents, including EPO and darbapoetin alfa, among others. In certain preferred aspects of the invention, one or more compounds of the invention are co-administered with another bioactive agent, such as an erythropoietin-stimulating agent or wound healing agent, including an antibiotic, as described herein.

Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical administration may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and tonicity adjusting agents such as sodium chloride or dextrose. Parenteral preparations may be enclosed in ampoules, disposable syringes or reusable glass or plastic vials.

For intravenous administration, the preferred carriers are saline or phosphate buffered saline (PBS).

In one embodiment, the active compounds are provided with carriers that will protect the compound from rapid clearance from the body, such as in controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such compositions are obvious to those skilled in the art.

Liposomal suspensions may also be pharmaceutically acceptable carriers. They can be obtained by methods known to those skilled in the art, for example, as described in US patent No. 4,522,811 (which is incorporated here by reference in full). For example, liposome compositions can be prepared by dissolving suitable fats (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, aracadoylphosphatidylcholine and cholesterol) in an organic solvent which is then evaporated to form a thin film of dried fat on the surface of the container. An aqueous solution of the active compound is placed in a container. The container is then shaken by hand to release the lipid material from the sides of the container and to disperse the fat aggregates to form a liposome suspension.

The term "pharmaceutically acceptable salt" is used in this specification to describe, where applicable, a salt of one or more of the described compounds, which is provided to increase the solubility of the compound in the gastric juice of the patient's gastrointestinal tract to promote the dissolution and bioavailability of the compounds. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium, among other bases and acids well known in the pharmaceutical art. Salts of sodium and potassium are particularly preferred as neutralizing salts of phosphates in accordance with this invention.

The term "pharmaceutically acceptable derivative" is used in the specification to describe any pharmaceutically acceptable prodrug (such as ester, amide, other prodrug groups) which, when administered to a patient, yields, directly or indirectly, a given compound or an active metabolite of a given compound.

Therapeutic ways.

The terms "treat", "treatment", and "treatment", etc. as used herein, refers to any act of benefit to a patient to whom these compounds may be administered, including the treatment of any disease or condition that is modulated through the protein to which these compounds bind. Diseases or conditions, including cancer, that can be treated with the compounds of this invention are listed above.

In another aspect, the specification provides a method for identifying a target protein associated with a given cell function. The method includes incubating a cell with a composition from a library of the present invention; tracking a given cell function; identifying a composition that alters a given cell function; identifying a target protein that binds to the identified composition, wherein the target protein is associated with the desired cell function.

In another aspect, the specification provides a method for identifying a target protein associated with a given cell function. The method includes incubating the cell with a pool of units from the library of the present invention; tracking a given cell function; identifying the gender of units that changes the cell's predetermined function; identifying a target protein that binds to the identified composition, wherein the target protein is associated with the desired cell function.

In another aspect, the specification provides a method for ubiquitinating/cleaving a target protein in a cell. The method includes administering a bifunctional composition comprising a ubiquitin pathway protein binding fragment and a specific fragment, preferably linked via a linker portion as described herein, where the ubiquitin pathway protein binding fragment is conjugated to a specific fragment, and where the ubiquitin pathway protein binding fragment recognizes the ubiquitin pathway protein ( ubiquitin ligase, preferably E3 ubiquitin ligase) and a specific fragment recognizes the target protein such that cleavage of the target protein occurs when the target protein is placed near the ubiquitin ligase, resulting in cleavage/inhibition of the action of the target protein and control of protein levels. The control of protein levels provided by the present invention provides treatment for a disease or condition that is modulated through a target protein by lowering the level of that protein in a patient's cell.

In another aspect, the description provides a method of treating or preventing, in a patient in need thereof, a disease or condition modulated through a protein, wherein cleavage of the protein has a therapeutic effect on that patient, wherein the method comprises administering to the patient in need an effective amount of a compound according to the present invention. invention, optionally in combination with another bioactive agent. A disease or condition is a disease caused by a microbial agent or other exogenous agent such as a virus, bacterium, fungus, protozoan or other microbes, or may be a disease that is caused by overexpression of a protein resulting in the disease and/or condition.

Target proteins that can be associated with the target protein fragment and cleaved by the ligase to which the ubiquitin ligase binding fragment is associated include structural proteins, receptors, enzymes, cell surface proteins, proteins associated with integrated cell function, including proteins associated with catalytic activity, aromatase activity, locomotor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, fat, carbohydrate), receptor activity, cell motility, membrane synthesis, cell communication, regulation of biological processes, cell development, cell differentiation c, stimulus response, behavioral proteins, non-specific cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including transporter protein activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity. Target proteins may include proteins from eukaryotes and prokaryotes, including microbes, viruses, fungi, and parasites, including human microbes, viruses, fungi, and parasites, among others, as targets for drug therapy, other animals, including domestic animals, microorganisms to determine targets for antibiotics and other antimicrobials, and plants and even viruses, among others.

More specifically, a variety of therapeutic targets for human therapy provide protein targets to which a fragment of a target protein can be linked and incorporated into the compounds of this invention. These include proteins that can be used to restore function in a variety of polygenic diseases including, for example, B7,1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase Type 5, PDE IV phosphodiesterase type 4, PDE I, PDE II, PDE III, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide synthase (NO), cyclooxygenase 1, cyclooxygenase 2, 5HT receptors, dopamine receptors, G proteins, i.e. . Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, trypanosomal GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and the like, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MLR), protein P-glycoprotein (and BMLR), tyrosine kinases, CD23, CD124, p56 lck tyrosine kinase, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channels , MASE, VLA-4 integrin, selectins, CD40/CD40L, nevokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase 3C, rhinovirus protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinases, vascular endothelial growth factor, oxytocin receptor, inhibitor microsomal transport protein, bile acid transport inhibitor, 5-alpha reductase inhibitors, angiotensin 11 glycine receptor, glycine receptor, norepinephrine reuptake receptor, endothelin receptors, neuropeptide Y and receptor, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyl transferases, geranylgeranyltransferase, TrkA a receptor for GFNT, amyloid beta, Flk-IIKDR tyrosine kinase, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibitor, cytosolic phospholipase A2 and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride ion transporter ion channel, acetylcholinesterase, voltage-gated sodium channel protein, ryanodine receptor, and chloride ion transporter channels. Other target proteins include acetyl-CoA carboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, and enolpyruvylshikimate phosphate synthase.

Haloalkanehalogenase enzymes are another target for the specific compounds of this invention. Compounds of the invention that contain chloralkane peptide binding moieties (C ₁ -C ₁₂ , often around C ₂ -C ₁₀ alkyl halo groups) can be used to inhibit and/or cleave haloalkane halogenase enzymes that are used in fusion proteins or related diagnostic proteins, such as described in PCT/US 2012/063401 filed December 6, 2011 and published as WO 2012/078559 June 14, 2012, the entire content of which is incorporated here by reference.

These different protein targets can be used in screens that identify parts of a compound that bind to proteins, and by incorporating the part into the compounds of the present invention, the level of protein activity can be altered for a therapeutic end result.

The term "disease or condition" is used to describe any disease or condition where there is protein dysregulation (i.e., an increase in the amount of protein expressed in a patient) and where cleavage of one or more proteins in a patient may be a useful therapy or symptom relief in a patient in need of such. In certain cases, the disease or condition may be treated.

Diseases or conditions that may be treated using the compounds of this invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliopathy, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease , mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth amyotrophy, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter's syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease , (PKD1) or 4 (PKD2) Prader-Willi syndrome, drepanocytic anemia, Tay-Sachs disease, Turner syndrome.

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

Other diseases or conditions that may be treated with the compounds of this invention include aceroplasminemia, type II achondrogenesis, achondroplasia, acrocephaly, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, Coley's adenomatous polyposis, ALL dehydratase deficiency, adenylose succinate lyase deficiency, adrenogenital syndrome, adrenoleodystrophy, ALL-D porphyria, ALL dehydratase deficiency, alkaptonuria, Alexander's disease, alkaptonuric ochronosis, alpha-1 antitrypsin deficiency, alpha-1-proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Ahlström's syndrome, Alexander's disease, amelogenesis imperfecta , ALL dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse angiokeratoma of the trunk, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, dermatorhexis (Evers-Danlos syndrome # arthrochalasia), ataxia-telangi ectasia, Rett's syndrome, primary pulmonary hypertension, Sandhoff's disease, type II neurofibromatosis, Beer-Stevenson syndrome, Mediterranean fever, familial, Benjamin's syndrome, beta thalassemia, bilateral acoustic neurofibromatosis (type II neurofibromatosis), Leiden factor V thrombophilia, Bloch syndrome Sulzberger (pigment incontinence), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ulrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion disease, Birt-Hogg-Dube syndrome, brittle bone disease (osteogenesis imperfecta), syndrome big toe (Rubinstein-Taibi syndrome), bronze diabetes/bronze cirrhosis (hemochromatosis), bulbospinal muscular atrophy (Kennedy disease), Burger-Grutz syndrome (lipoprotein lipase deficiency), CGM chronic granulomatosis, campomelic dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome ), cat's cry syndrome, VOSP (congenital absence of the vas deferens), cardiofaci Caylor syndrome (CBAVD), EP (erythropoietic uroporphyria), cystic fibrosis, congenital hypothyroidism, chondrodystrophic syndrome (achondroplasia), otospiglomegaepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome , (familial adenomatous polyposis), erythropoietic uroporphyria, congenital heart disease, methemoglobinemia/congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, collagenosis, velocardiofascial syndrome, Cooley's anemia (beta thalassemia), copper storage disease (Wilson's disease), Menkes syndrome (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial dysarthrosis (Crowson syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Kurschmann-Batten-Steinert disease (myotonic dystrophy), Beer-Stevenson syndrome, primary hyperoxaluria, spondyloepimetaphyseal dysplasia (according to Strud Vick), muscular dystrophy, Duchenne and Becker disease (DBMD), Usher syndrome, degenerative nerve diseases including de Grushy syndrome and Dejerine-Sottas syndrome, developmental disorders, spinal dystrophic muscular atrophy type V, androgen insensitivity syndrome, globoid cell leukodystrophy (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, erythroid 5-aminolevulinate synthetase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedrich's ataxia, familial recurrent polyserositis, hemochromatosis , familial sensory neuropathy, primary pulmonary hypertension (PLH), fibrocystic disease of the pancreas, fragile X syndrome, galactosemia, genetic disorders of the brain, congenital giant cell hepatitis (hemochromatosis of the newborn), Gronblad-Strandberg syndrome (el astic pseudoxanthoma), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria ), hyperandrogenism, hypochondroplasia, hypochromic anemia, disorders of the immune system, including X-linked severe combined immunodeficiency syndrome, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney disease, including hyperoxaluria , Klinefelter syndrome, Knist dysplasia, lacunar dementia, Langer-Saldino achondrogenesis, ataxia-telangiectasia, Lynch syndrome, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Knist dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome , cystic fibrosis, Menke's syndrome, multiple neurophysi bromatosis, Nancy-Insley syndrome, Nancy-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyotssal fibrous osteodysplasia (McCune-Albright syndrome), syndrome Peutz-Jeghers, Prader-Labhart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford syndrome), progressive chorea, chronic hereditary Huntington's disease (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PEP (pseudoxanthoma elastica), RB (retinoblastoma), Recklinghausen's disease (type I neurofibromatosis), recurrent polyserositis, retinal disorders , retinoblastoma, Rett's syndrome, RFALS type 3 Ricker's syndrome, Riley-Day, Roussy-Levy syndrome, severe achondroplasia with developmental delay and acanthokeratodermia (TAZRAD), Li-Fraumeni syndrome, sarcoma-breast-leukemia-adrenal syndrome (MALS), tuberous sclerosis (tuberous sclerosis), SDAT, congenital EDS (congenital spondyloepiphyseal dysplasia), stradwick sED (spondyloepileptic dysplasia, strudwick), csed (congenital spondyloepileptic dysplasia) SEMD, stradwick disease (spondyloepimethphyseal dysplasia, stradwick), schprintzen syndrome, skin pigmentation disorders, smith-lemli-opitz syndrome, south african genetic porphyria ( mixed porphyria), hereditary afferent spastic palsy, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta thalassemia, thyroid disease, tomacular neuropathy (hereditary compression neuropathy), Trever-Col syndrome lens, triple X syndrome (triple X syndrome), trisomy 21 (Down syndrome), trisomy X, FHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Ahlström syndrome), Wrolick disease, Waardenburg syndrome, Warburg syndrome - Sjo-Fledelius, Weissenbacher-Sweimüller syndrome, Wolff-Hirschhorn syndrome, Wolff's periodic disease, Weissenbacher-Sweimüller syndrome, and xeroderma pigmentosum, among others.

The term "cancer" is used herein to describe pathological processes that cause the formation and growth of cancerous or malignant neoplasms, ie. abnormal tissue that grows as cells proliferate, often faster than normal tissue, and continues to grow after stimulation that initiates the cessation of new growth. Malignancies show partial or complete lack of structural organization and functional coordination with normal tissue and most invade surrounding tissues, metastasize to multiple sites, and are likely to recur after excision attempts, and cause death in the patient if not adequately treated. Exemplary cancers that may be treated in accordance with the present invention, alone or in combination with at least one additional anticancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular and renal cell carcinomas, bladder, colon cancer , breast, cervix, colon, esophagus, head, kidneys, liver, lungs, neck, ovaries, pancreas, prostate and stomach; leukemia; benign and malignant lymphomas, especially Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors and meningiosarcoma schwannomas; colon cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer , melanoma; carcinosarcoma, Hodgkin's disease, Wilms tumor and teratocarcinomas. Additional cancers that can be treated using the compounds of this invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, T adult-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.

The term "co-administration" or "combination therapy" means that at least two compounds or compositions are administered to a patient simultaneously, such that effective amounts or concentrations of each of the two or more compounds can be found in the patient at a given point in time. Although the compounds of this invention may be co-administered to a patient at the same time, the term includes the administration of two or more agents at the same time or at different times, provided that effective concentrations of all co-administered compounds or compositions are found in the patient at a given point in time.

In an additional aspect, the specification provides combination therapies comprising an effective amount of a compound described herein with an additional bioactive agent. The term "bioactive agent" is used to describe an agent, other than the compound described herein, which is used in combination with these compounds as an agent with biological activity to facilitate the intended therapy, inhibition and/or prevention/prophylaxis for which these compounds are used. Preferred bioactive agents for use in accordance with this invention include agents that have a pharmacological effect similar to that for which these compounds are used or administered, and include, for example, anticancer agents, antiviral agents, especially anti-HIV and anti-HCV agents, antimicrobial agents, antifungal agents, etc. In certain embodiments, the compound described herein, the additional bioactive agent, or both are present in effective amounts or, in certain embodiments, synergistically effective amounts.

The term "additional anti-cancer agent" is used to describe an anti-cancer agent that can be combined with the compounds of this invention for the treatment of cancer. These agents include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258 , GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, EGFR inhibitor, EGFR TK inhibitor, aurorakinase inhibitor, PIK modulator 1, Bcl-2 inhibitor, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, EGFR TK inhibitor, IGFR-TK inhibitor, anti-HGF antibody, PI3 kinase inhibitors, AKT inhibitor, JAK/STAT inhibitor, checkpoint inhibitor -1 or 2, focal adhesion kinase inhibitor, MAP kinase (mek) inhibitor, VEGF trap antibody, pemetrexed, erlotinib, dazatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab , edoteracin, tetrandrin, rubitecan, tesmilifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cileng itide, hymatecan, IL13-PE38QQR, INO 1001, IPdR ₁ KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5- yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, tofemifene citrate, anastrozole, exemestane, letrozole, DEZ(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR -258); 3-[5-(methylsulfonylpiperadinemethyl)indolyl]quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly10] acetate (pyro-Glu-His-Trp-Ser-Tyr-D- Ser(But)-Leu-Arg-Pro-Azgly-NH ₂ [C ₅₉ H ₈₄ N ₁₈ O ₁₄ -(C ₂ H ₄ O ₂ ) _X , where x=1-2.4], goserelin acetate, leuprolide acetate , triptorelin pamoate, hydroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB -569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib;amiphostine, NVP-LAQ824, suberoyl analide, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, ep irubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleyevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, nioclutamido, mitotane oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, melphalan, uramustine, estramustine, altretamine, floxuridine, 5 -deoxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neofastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin- 12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitoxy, gefitinib, bortezimibe, paclitaxel, creamless y paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxy tamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584 VX-745 PD 184352 Rapamycin , wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony stimulating factor, prednisone, cetuximab, granulocyte macrophage colony stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transetic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, chlormethine, methylprednisolone, ibrithumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tocitumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwin asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, alprazepam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof.

The term "anti-HIV agent" or "additional anti-HIV agent" includes, for example, nucleoside reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., those that are not part of this invention), protease inhibitors, fusion inhibitors, among others, exemplary compounds of which include, for example, 3TC (Lamivudine), AZT (Zidovudine), (-)-FTC, ddI (Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC ( Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV (Delavirdin), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV (Nelfinavir), APV (Amprenavir), LPV (Lopinavir), fusion inhibitors such as T20, among others, Fuzeon and mixtures thereof, including anti-HIV compounds under clinical investigation or development.

Other anti-HIV agents that may be used for co-administration with the compounds of this invention include, for example, other NNRTIs (i.e., other than the NNRTIs of this invention) selected from the group consisting of nevirapine (BI- R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl- 3-furancarbothiamide), etravirine (TMC125), Trovirdin (Ly300046.HCl), MKC-442 (emivirine, coactinone), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC -127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II (Methyl 3',3'-dichloro-4',4'-dimethoxy-5',5'-bis(methoxycarbonyl)-6,6-diphenylhexenoate) , Methyl 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoate (analogue of Alkenyldiarylmethane, analog of Adam), 5Cl3PhS-2INDOLCONH2 (5- chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), Capravirine (AG-1549, S-1153), atevirdine (U-87201E), auryntricarboxylic acid (SD- 0953 45), 1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine (piperazine-1-pyridine-4-indolyl derivative), 1-[5- [[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine (piperazine-1-pyridine-5-indolyl derivative), 1-[3-(ethylamino)- 2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine, 1-[(6-Formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl] piperazine, 1-[[5-(Methylsulfonyloxy)-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, U88204E, Bis(2-nitrophenyl)sulfone (NSC 633001), Kalanolide A (NSC675451), Calanolide B, 6-Benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961, E-EBU, E-EBU-dm, E-EPSeU, E- EPU, Foscarnet (Foscavir), HEPT (1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M (1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl) thio)thymine), HEPT-S (1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine), Inophyllum P, L-737,126, Michellamine A (NSC650898), Michellamine B (NSC649324), Michellamine F, 6-(3,5-Dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-Dimethylbenzyl)-1-(ethyloxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC 648400), Oltipraz (4-Methyl-5-(pyrazinyl)-3H-1,2-dithiol-3-thione), N-{2-(2-Chloro-6-fluorophenethyl]-N'-(2 -thiazolyl)thiourea (PETT Cl, F derivative), N-{2-(2,6-Difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea (PETT derivative), N-{2-(2 ,6-Difluorophenethyl]-N'-[2-(5-methylpyridyl)]thiourea (PETT Pyridyl derivative), N-[2-(3-Fluorofuranyl)ethyl]-N'-[2-(5-chloropyridyl)] thiourea, N-[2-(2-Fluoro-6-ethoxyphenetyl)]-N'-[2-(5-bromopyridyl)]thiourea, N-(2-Phenethyl)-N'-(2-thiazolyl)thiourea ( LY-73497), L-697.639, L-697.593, L-697.661, 3-[2-(4,7-Difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pyridine-2(1H) -thione (2-pyridinone derivative), 3-[[(2-Methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pyridine-2(1H)-thione ( 2-Pyridinone 3pyride 3MeNH derivative), R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720, Supamine sodium, TBZ L, NSC 625487), Thiazoloisoindol-5-one, (+)(R)-9b-(3,5-Dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one, Tivirapine (R86183), UC-38 and UC-84, among others.

General approaches to synthesis

The general scheme for the synthesis of ULM derivatives is described below. Briefly, the compounds of this invention are synthesized according to the General Liquid Phase Synthesis Scheme (below) and/or General Scheme I, which relates to the liquid phase synthesis of the compounds of this invention. First, a hydroxy-protected carboxy-substituted (and protected) pyrrolidine compound is reacted with a carboxylic acid-containing reagent that introduces a carbonyl group on the amine of the pyrrolidine ring to form an amide group. Alternatively, the amine of the pyrrolidine may be protected and the carboxylic acid portion may be fused to the nucleophilic group on the dextrorotatory moiety to form the amide on the dextrorotatory portion of the pyrrolidine moiety. The left and right rotating moieties fused into the amine and carboxylic acid group of the pyrrolidine moiety, respectively, are preferably prepared in advance for condensing into the pyrrolidine group, but other approaches to introducing groups into the pyrrolidine group can be used. The individual components combined to form the ULM group can be made using blocking groups on the preferred functional groups on the ULM group, which can be removed to interact with and covalently bind the linker group that is generated to form the PTM moiety to which the moiety is already linked, the binding protein, or PTM group, or may be further subjected to interaction to obtain a covalent bond with a PTM group, which may also contain a ULM' group, as described here. Thus, a carboxylic acid containing a left-handed fragment can be condensed into an amine group of pyrrolidine, thereby obtaining an amide group with R ¹ a left-handed fragment, as shown below. To a carboxyl group, any number of nucleophilic (preferably amine-containing) dextrorotatory moieties (previously synthesized) can be condensed into a carboxyl group to form an amide group with an R ² dextrorotatory moiety as shown below. Obtaining pre-synthesized groups for condensation into the amine and/or carboxyl part of the pyrrolidine is easy. The solid phase synthesis method can also be used and includes methods similar to those used for liquid phase synthesis, the main difference is that the hydroxyl group can be associated with a solid support during other stages of the synthesis. The general synthetic methods apply to virtually all compounds of the present invention with minor modifications made in accordance with the state of the art in chemical synthesis, and are applied directly or adapted from the specific examples below.

Scheme 1. Liquid phase synthesis of UML derivatives in accordance with this invention

Liquid phase methods

Liquid phase chemistry is preferred by many due to library construction due to the wide range of organic reactions available for liquid phase synthesis, this technology has traditionally been adopted by most organic chemists and products in solution are easier to identify in standard drug target assays and characterize. A problem with liquid-phase synthesis of one molecule at a time is the final purification, which can be costly and slow. The first thing that is addressed is chromatography, as it usually works. In addition, problems associated with liquid phase chemistry become more complex when attempting to obtain tens or thousands of compounds to produce a library or a "book" for a library.

Numerous methods have been developed in the creation of compound libraries, resulting in the widespread use of large libraries of chemicals, making it easy to discover potential drugs. Creating chemical libraries that are free in solution is usually the goal of much of the pharmaceutical industry. This goal is driven by the nature of many drug targets and related research. It is also usually easier to create and use chemical libraries, but to create models of compounds in solution to form the basis of a chemical library. Thus, the advantages of solid phase synthesis methods are not usually fully realized in the context of current drug discovery efforts. The main reason for this is the interest, not in binding the compound to the drug target, but in demonstrating that the activity of the drug target is altered, which would normally require the free compound in solution. Other problems with solid phase compound libraries arise from problems caused by the potential influence of linker and steric effects on solid phase compounds.

Thus, methods for producing a compound that binds to target molecules are known in the art. Also, optimization of initially discovered compounds is well known in the art, where affinity is improved by pooling related compounds through a more selective combinatorial chemistry approach.

The present invention provides a mechanism to overcome these problems in the development of drugs and small molecules.

Addition of a ubiquitin ligase binding moiety (ULM)

At this point along the route of inventing the compounds of the present invention, the target protein-binding element of the compounds of the present invention has been identified. These optimal binding molecules are then subjected to further chemistry to add a ubiquitin ligase (ULM) binding moiety as described herein.

Protein level control

This invention also relates to a method for monitoring protein levels in a cell. It is based on the use of compounds according to the invention which are known to interact with a specific target protein such that in vivo cleavage of the target protein allows the amount of protein in the biological system to be controlled, preferably to a certain therapeutic benefit.

The following examples are used to help describe the invention, but should not be construed as limiting the invention in any way.

General methods of chemical synthesis

The following general methods of chemical synthesis are presented for the synthesis of many compounds in accordance with this invention, which are presented in table 2 Table of affinity above. Each method is presented with reference to a specific compound, the details of the synthesis of which are presented above. All numbered compounds can be synthesized relatively easily using direct methods, which are presented below. In certain cases, more synthetic details are provided for certain preferred embodiments in order to present this information so that it can serve as a template for the synthesis of a variety of other compounds as described here.

All reactions are carried out in oven-dried or flame-dried laboratory glassware equipped with a rubber membrane under positive nitrogen pressure unless otherwise noted. Air- and moisture-sensitive liquids are transferred through a syringe or cannula. THF is distilled off from sodium/benzophenone. Dichloromethane is distilled off from calcium hydride. Analytical thin layer chromatography (TLC) was carried out using glass plates pre-coated with silica gel (0.25 mm). TLC plates are visualized by exposure to UV light (UV) or KMnO ₄ . Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck) with the indicated solvents.

As an example, see the synthesis below for compound VL133:

Synthesis of VL133

(2S,4R)-4-hydroxy-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxylic acid

(2S,4R)-4-(tert-butoxy)-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxylic acid (124.9 mg, 0.4 mmol, 1 eq) dissolved in DCM (18 ml) at room temperature. Add TFA (2 ml, 10%) and the solution is stirred for 12 hours. It is then concentrated under reduced pressure and purified by column chromatography (4-20% MeOH/DCM) to give a yellow oil (99.7 mg, 0.39 mmol, 98%). ¹ H NMR (500 MHz, MeOD) δ 6.24 (s, 1H), 4.55-4.46 (m, 2H), 3.89 (d, J =28.3 Hz, 2H), 3, 77 (dd, J =10.9, 4.3 Hz, 1H), 3.62 (d, J =11.0 Hz, 1H), 2.36-2.22 (m, 4H), 2.10 (ddd, J =13.1, 8.0, 4.8 Hz, 1H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 175.33, 168.51, 167.61, 161.61, 105.28, 70.86, 59.33, 56.60, 38.78, 33.85 , 11.20. MS (ESI) 255.1 (M+H).

(2S,4R)-N-(4-(1H-pyrrol-3-yl)benzyl)-4-hydroxy-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxamide (VL133 )

(2S,4R)-4-hydroxy-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxylic acid (52.6 mg, 0.207 mmol, 1.3 eq), (4- (1H-pyrrol-3-yl)phenyl)methanamine (27.3 mg, 0.159 mmol, 1 eq), EDA (39.7 mg, 0.207 mmol, 1.3 eq) and HOBT (28 mg, 0.207 mmol, 1 3 eq) was dissolved in DMF (4.1 ml) and cooled to 4°C. DIPEA (0.083 ml, 0.477 mmol, 3 eq) is added and the solution is slowly warmed to room temperature. After 16 hours, the mixture was poured into half-saturated sodium chloride (aqueous) and extracted 3 times with EtOAc. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (1-10% 0.5N NH ₃ (MeOH)/DCM) gave an off-white solid (41.5 mg, 0.102 mmol, 64%). ¹ H NMR (400 MHz, DMSO) δ 8.40 (d, J =6.0 Hz, 1H), 7.52-7.39 (m, 2H), 7.22-7.12 (m, 3H ), 6.82-6.72 (m, 1H), 6.41 (d, J = 1.7 Hz, 1H), 6.24 (s, 1H), 5.17 (d, J = 3, 9 Hz, 1H), 4.31 (ddd, J =17.1, 13.7, 6.4 Hz, 4H), 3.88 (s, 2H), 3.75-3.65 (m, 1H ), 3.52-3.41 (m, 1H), 2.18 (d, J =18.0 Hz, 3H), 2.12-1.99 (m, 1H), 1.94-1, 85 (m, 1H). ¹³ C NMR (101 MHz, DMSO) δ 171.36, 166.69, 165.54, 159.38, 135.66, 134.68, 127.20, 124.21, 123.00, 118.86, 114.71, 105.22, 103.99, 68.61, 58.76, 55.18, 41.63, 38.27, 32.78, 11.00. MS (ESI) 431.5 (M+Na).

Other links are provided in the following articles and links cited here:

Buckley DL et al. J. Am. Chem. Soc 2012, 134, 4465-4468.

Van Molle I et al. A Chemistry & Biology 2012, 19 , 1300-1312

Buckley, D Angew. Chem. Int. Ed ., 2012 , 51, 11463-11467

Buckley, D. Let al. Angew. Chem. 2012 , 124, 11630-11634.

As an example, see below the synthesis of compound VL116:

Synthesis of VL116

(2S,4R)-4-(tert-butoxy)-1-(2-(3-methylisoxazol-5-yl)acetyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide

(2S,4R)-4-(tert-butoxy)-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidin-2-carboxylic acid (53.7 mg, 0.173 mmol, 1.3 eq) , (4-(4-methylthiazol-5-yl)phenyl)methanamine (27.2 mg, 0.133 mmol, 1 eq), EDA (33.2 mg, 0.173 mmol, 1.3 eq) and HOBT (23.4 mg, 0.173 mmol, 1.3 eq) are dissolved in DMF (3.5 ml) at 4°C. DIPEA (0.07 ml, 0.4 mmol, 3 eq) is added and the solution is slowly warmed to room temperature. After 19 hours the mixture was poured into brine and extracted four times with EtOAc. The organic layer is dried with sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (1-5% MeOH/DCM) gave a colorless oil (58.1 mg, 0.117 mmol, 88%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.67 (s, 1H), 7.42-7.27 (m, 5H), 6.06 (s, 1H), 4.69 (dd, J = 8.4, 2.6 Hz, 1H), 4.59-4.35 (m, 3H), 3.82-3.71 (m, 3H), 3.34 (dd, J =9.9, 6.3 Hz, 1H), 2.59-2.46 (m, 4H), 2.25 (s, 3H), 1.91 (dd, J =8.2, 4.4 Hz, 1H), 1.25-1.14 (m, 9H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 170.70, 167.35, 165.30, 160.24, 150.42, 148.59, 138.09, 131.74, 131.05, 129.66 , 127.85, 104.19, 74.48, 70.02, 59.12, 54.20, 43.25, 35.59, 33.49, 28.38, 16.19, 11.57 MS (ESI) 497.4 (M+H).

(2S,4R)-4-hydroxy-1-(2-(3-methylisoxazol-5-yl)acetyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VL116 )

(2S,4R)-4-(tert-butoxy)-1-(2-(3-methylisoxazol-5-yl)acetyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide (58.1 mg, 0.117 mmol) was dissolved in DCM (8 ml). Add TFA (2 ml, 20% vol./about.) and the solution is stirred for 12 hours at room temperature, after which it is concentrated under reduced pressure. Purification by column chromatography (1-10% 0.5N NH ₃ (MeOH)/DCM) gave a colorless oil (28.4 mg, 0.065 mmol, 56%). ¹ H NMR (400 MHz, MeOH) δ 8.87 (d, J =2.1 Hz, 1H), 7.50-7.34 (m, 4H), 6.23 (s, 1H), 4, 57 (t, J = 8.0 Hz, 1H), 4.54-4.38 (m, 3H), 3.93 (d, J = 2.4 Hz, 2H), 3.81 (dd, J =10.9, 4.3 Hz, 1H), 3.63 (dd, J =7.2, 5.5 Hz, 1H), 2.46 (d, J =8.8 Hz, 3H), 2 .33-2.20 (m, 4H), 2.10 (ddd, J =13.1, 8.2, 4.7 Hz, 1H). ¹³ C NMR (101 MHz, MeOH) δ 174.43, 168.71, 167.66, 161.58, 152.83, 149.04, 140.14, 133.39, 131.56, 130.43, 128.88, 105.39, 70.86, 60.78, 57.00, 43.65, 39.36, 33.96, 15.81, 11.22. MS (ESI) 441.3 (M+H).

As an example, see below the synthesis of compound VL 156:

Synthesis of VL156

1H-Imidazol-1-ylacetic acid (20.6 mg, 0.163 mmol, 1.3 eq), EDA (31.2 mg, 0.163 mmol, 1.3 eq) and HOBt (22 mg, 0.163 mmol, 1.3 eq) is dissolved in DCM (2.5 ml) and DMF (0.4 ml) at room temperature in a 1-drachm tube. After stirring for 15 minutes, DIPEA (0.055 ml, 0.313 mmol, 2.5 eq) was added followed by (2S, 4R )-4-( tert -butoxy) -N- (4-chlorobenzyl)pyrrolidine-2-carboxamide (38.9 mg, 0.125 mmol, 1 eq) after another 30 minutes. The mixture is stirred for 14 hours, then diluted with EtOAc and washed with brine. The organic layer is dried over sodium sulfate, filtered and condensed. Purification by column chromatography (1-10% MeOH/DCM) gave a white solid which was used immediately in the next step. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.65 (s, 1H), 7.28 (td, J =10.9, 8.4 Hz, 4H), 7.06 (d, J =43 .6 Hz, 2H), 4.99 (dd, J = 38.1, 17.1 Hz, 2H), 4.51 (t, J = 6.6 Hz, 2H), 4.35 (q, J =15.4 Hz, 2H), 3.86 (dd, J =10.2, 5.6 Hz, 1H), 3.45 (dd, J =10.3, 4.1 Hz, 1H), 2 .22-2.02 (m, 2H), 1.21 (d, J =13.8 Hz, 9H). MS (ESI) 419.7 (M+H).

The white solid is dissolved in DCM (9 ml) at room temperature. Add TFA (1 ml) and the mixture is stirred for 12 hours and condense. Purification by column chromatography (1-20% 0.5 N methanolic ammonia/DCM) gave a white solid (39.8 mg, 0.11 mmol, 88% over 2 steps. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.73 (s, 1H), 7.47 (d, J =16.9 Hz, 2H), 7.26 (s, 4H), 5.25 (dd, J =37.5, 16.9 Hz, 2H), 4.56 (t, J = 7.9 Hz, 2H), 4.44-4.27 (m, 2H), 3.82 (dd, J = 10.8, 4.1 Hz , 1H), 3.63 (d, J = 10.8 Hz, 1H), 2.36-2.22 (m, 1H), 2.07 (ddd, J = 13.1, 8.3, 4 .6 Hz, 1H) ¹³ C NMR (126 MHz, CD ₃ OD) δ 174.14, 166.34, 138.56, 138.20, 133.87, 129.97, 129.49, 124.55 , 121.47, 70.94, 61.00, 55.75, 51.33, 43.35, 39.21 MS (ESI) 364.8 (M+H).

As an example, see below the synthesis of compound VL 217:

Synthesis of VL217

(2 S ,four R )-four-( tert- butoxy)-1-(3-ethoxybenzoyl)- N -(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide

3-Ethoxybenzoic acid (13.3 mg, 0.08 mmol, 1 eq), EDA (16.9 mg, 0.088 mmol, 1.1 eq) and HOBt (11.9 mg, 0.88 mmol, 1.1 eq) was dissolved in DCM (0.8 ml) at room temperature. DIPEA ( 0.0279 mL, 0.16 mmol, 2 eq) was added followed by (2S, 4R )-4-( tert -butoxy) -N- (4-(oxazol-5-yl)benzyl)pyrrolidin- 2-carboxamide (33.0 mg, 0.096 mmol, 1.2 eq). The solution is stirred for 21 hours, then diluted with EtOAc and washed with 10% citric acid, saturated sodium bicarbonate and brine. The organic layer is dried over sodium sulfate, filtered and condensed. Purification by column chromatography (1-5% MeOH/DCM) gave a colorless oil (36.1 mg, 0.073 mmol, 92%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.61 (dd, J =16.6, 6.9 Hz, 3H), 7.38-7.27 (m, 4H), 6.98 (dd, J =16.0, 6.4 Hz, 3H), 4.92 (dd, J =8.3, 4.7 Hz, 1H), 4.48 (d, J =6.0 Hz, 2H), 4.43-4.31(m, 1H), 4.03(kv, J =7.0 Hz, 2H), 3.61(dd, J =10.9, 5.7 Hz, 1H), 3.31 (dd, J =10.9, 4.4 Hz, 1H), 2.73-2.55 (m, 1H), 2.05-1.92 (m , 1H), 1.40 (t, J =7.0 Hz, 3H), 1.13 (s, 9H). MS (ESI) 492.4 (M+H).

VL217

( 2S , 4R )-4-( tert -butoxy)-1-(3-ethoxybenzoyl) -N- (4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide (36.1 mg, 0.073 mmol, 1 eq) was dissolved in DCM (9 ml) at room temperature. Add TFA (1 ml) and the solution is stirred for 13 hours, then condense. Purification by column chromatography (1-10% MeOH/DCM) gave a colorless oil (22.9 mg, 0.053 mmol, 72%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.24 (d, J =12.0 Hz, 1H), 7.65 (dd, J =28.0, 8.3 Hz, 2H), 7, 47 (dd, J =18.8, 10.6 Hz, 3H), 7.23 (dd, J =9.4, 4.6, 4.1 Hz, 3H), 7.09-6.87 ( m, 2H), 4.75 (dd, J =9.6, 7.7 Hz, 1H), 4.48 (dd, J =49.7, 15.5 Hz, 3H), 4.06 (q , J = 7.0 Hz, 2H), 3.84 (dd, J = 11.5, 3.5 Hz, 1H), 3.44 (d, J = 11.5 Hz, 1H), 2.42 -2.29 (m, 1H), 2.21-2.05 (m, 1H), 1.36 (dt, J =24.0, 7.0 Hz, 3H). ¹³ C NMR (101 MHz, CD ₃ OD) δ 174.78, 172.66, 160.35, 153.14, 152.74, 140.85, 138.38, 130.66, 129.00, 127, 71, 125.62, 121.77, 120.50, 118.08, 114.30, 71.02, 64.71, 60.85, 59.82, 43.72, 39.32.

As an example, see below the synthesis of compound VL 219:

Synthesis of VL219

VL219

Dissolve 3-ethoxybenzoic acid (17 mg, 0.1 mmol, 1 equiv.) in 1 ml of 10:1 DCM:DMF and load EDA (25 mg, 0.13 mmol 1.3 equiv.) and HOBT (21 mg, 0.13 mmol, 1.3 equiv.). After 5 minutes of stirring, add (2S,fourR)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (31 mg, 0.095 mmol, 1 equiv.). After stirring for 18 h, the reaction mixture was diluted with 15 ml of EtOAc and washed with 25 ml of 10% aqueous citric acid and 25 ml of saturated NaHCO₃. The organic layer is dried with Na₂SO_four and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (DCM to 9% MeOH (0.5 N NH₃) in DCM) to give 25 mg (56% yield) of the product as a white solid. ^one H NMR (501 MHz, CD₃OD) δ 8.87 (s, 1H), 7.51-7.42 (m, 4H), 7.37 (t,J= 8.1, 1H), 7.23-7.14 (m, 2H), 7.05 (dd,J=2.2, 8.4, 1H), 4.79 (dd,J=7.7, 9.5, 1H), 4.63-4.40 (m, 3H), 4.08 (q,J=7.0, 2H), 3.86 (dt,J=3.8, 7.6, 1H), 3.47 (d,J=11.5, 1H), 2.47 (s, 3H), 2.36 (dd,J=7.6, 13.2, 1H), 2.14 (ddd,J=5.3, 10.2, 16.4, 1H), 1.41 (t,J=7.0, 3H); ¹³ C NMR (126 MHz, CD₃OD) δ 174.74, 172.64, 160.34, 152.78, 149.05, 140.21, 138.40, 133.39, 131.55, 130.65, 130.44, 128.83 , 120.49, 118.07, 114.32, 71.02, 64.71, 60.83, 59.81, 43.67, 39.30, 15.79, 15.06;TLC: (9:1 DCM:MeOH (0.5 N NH₃)) R _f =0.25;MSNR (IER) 466.1(M+H)⁺.

Method F includes methods C, D and E and is a general method that uses commercially available amines.

The following procedures are used for the synthesis and/or characterization of compounds in accordance with this invention:

Characterization and purification of compounds:

¹ H NMR (300 or 400 MHz) and ¹³ CNMR (100.6 MHz) spectra were recorded on Bruker spectrometers at rt with the peak of TMS or residual solvent as internal standard. Line or multiplet positions are given in (δ) and coupling constants (J) are given as absolute values in Hertz (Hz). The multiplicities in the ¹ H NMR spectrum are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), w or wide (extended).

LC-MS analytical data were collected on a Shimadzu LCMS-2020 with a mobile phase of 0.05% TFA in acetonitrile (A) and 0.05% TFA in HPLC water (B); 0.1% FA in acetonitrile (A) and 0.1% FA in HPLC water (B); acetonitrile (A) and 5 mM ammonium bicarbonate in HPLC water (B).

Shimadzu LCMS-2020 is equipped with LC-20AD or 30AD pumps, SPD-M20A PDA and Alltech 3300 ELSD. The system applies the following conditions for a run time of 2.0 minutes, 2.6 minutes, 3 minutes, 3.6 minutes, 5 minutes, or 5.6 minutes.

run 2.0 minutes: column Kinetex XB-C 18 100A, 2.6 µm, 3.0×50 mm. Flow rate 1.5 ml/min, run time 2.0 min and gradient profiles 0.01 min 10% A, 1.10 min 100% A, 1.60 min 100% A, 1.70 min 10% A, 2.00 min 10% A.

run 2.6 minutes: Shim-pack VP-ODS column, 2.2 µm, 3.0 x 50 mm. Flow rate 1.5 ml/min, run time 2.6 min and gradient profiles 0.01 min 5% A, 1.20 min 100% A, 2.20 min 100% A, 2.30 min 5% A, 2.60 min 5% A.

run 3.0 minutes: ACE UltraCore Super C18 column, 2.5 µm, 3.0 x 50 mm. Flow rate 1.5 ml/min, run time 3.0 min and gradient profiles 0.01 min 10% A, 2.00 min 95% A, 2.60 min 95% A, 2.70 min 10% A, 3.00 min 10% A.

run 3.6 minutes: Shim-pack VP-ODS column, 2.2 µm, 3.0×50 mm. Flow rate 1.5 ml/min, run time 3.6 min and gradient profiles 0.01 min 5% A, 2.20 min 100% A, 3.20 min 100% A, 3.30 min 5% A, 3.60 min 5% A.

run 5.0 minutes: ACE UltraCore Super C18 column, 2.5 µm, 3.0×50 mm. Flow rate 1.5 ml/min, run time 5.0 min and gradient profiles 0.01 min 10% A, 4.00 min 60% A, 4.70 min 60% A, 4.80 min 10% A, 5.00 min 10% A.

run 5.6 minutes: Shim-pack VP-ODS column, 2.2 µm, 3.0×50 mm. Flow rate 1.5 ml/min, run time 5.6 min and gradient profiles 0.01 min 5% A, 3.00 min 50% A, 5.00 min 50% A, 5.20 min 5% A, 5.60 min 5% A.

LCMS data is also collected on an Agilent infinity 1260 LC; Agilent 6230 TOF mass spectrometer. The analysis is carried out on a Poroshell 120 EC C18 column (50 mm x 3.0 mm ID, 2.7 µm sorbent diameter) at 45°C.

Applicable eluent:

A=0.1% v/v solution of formic acid in water.

B=0.1% v/v solution of formic acid in acetonitrile.

applied gradient:

Time (minutes) Flow rate (ml/min) %A %B 0 one 95 5 0.5 one 95 5 3.0 one one 99 4.0 one one 99 4.1 one 95 5 4.5 one 95 5

UV detection is an average signal from a wavelength of 210 nm to 350 nm, and the mass spectrum is recorded on a mass spectrometer using positive electrospray ionization.

Unless otherwise noted, all LC-MS data presented are results obtained with the instruments and methods described above. Unless otherwise indicated, all compounds were obtained in LC-MS purity >95%.

The following are the mobile phases and gradients used in the purification of compounds by mass directed autopreparative HPLC.

Mass directed autopreparative HPLC (formic acid modifier)

HPLC analysis is carried out on a Sunfire C18 column (150 mm x 30 mm ID, 5 µm sorbent diameter) at ambient temperature.

Solvents used:

A=0.1% v/v solution of formic acid in water.

B=0.1% v/v solution of formic acid in acetonitrile.

Mass directed autopreparative HPLC (trifluoroacetic acid modifier)

HPLC analysis is carried out on a Sunfire C18 column (150 mm x 30 mm ID, 5 µm sorbent diameter) at ambient temperature.

Solvents used:

A=0.1% v/v trifluoroacetic acid solution in water.

B=0.1% v/v trifluoroacetic acid solution in acetonitrile.

Mass Directed Autopreparative HPLC (Ammonium Bicarbonate Modifier)

HPLC analysis is carried out on an XBridge C18 column (150 mm x 30 mm ID, 5 µm sorbent diameter) at ambient temperature.

Solvents used:

A=10 mM ammonium bicarbonate in water adjusted to 10 with ammonia solution.

B=acetonitrile.

For each of the mass directed autopreparative purifications, regardless of the modifier used, the applied gradient depends on the retention time of the particular compound being purified, as recorded on the analytical LCM, and is as follows:

Time (minutes) Flow rate (ml/min) %A %B 0 40 99 one one 40 99 one ten 40 70 thirty eleven 40 one 99 fifteen 40 one 99

For compounds with an analytical LCMS retention time of 0.6 to 0.9 minutes, the following gradient is applied:

Time (minutes) Flow rate (ml/min) %A %B 0 40 85 fifteen one 40 85 fifteen ten 40 45 55 eleven 40 one 99 fifteen 40 one 99

For compounds with an analytical LCMS retention time of 0.9 to 1.2 minutes, the following gradient is applied:

Time (minutes) Flow rate (ml/min) %A %B 0 40 70 thirty one 40 70 thirty ten 40 fifteen 85 eleven 40 one 99 fifteen 40 one 99

For compounds with an analytical LCMS retention time of 1.2 to 1.4 minutes, the following gradient is applied:

Time (minutes) Flow rate (ml/min) %A %B 0 40 fifty fifty one 40 fifty fifty ten 40 one 99 eleven 40 one 99 fifteen 40 one 99

The UV determination is an average waveform from 210 nm to 350 nm, and the mass spectrum is recorded on a mass spectrometer using alternating scanning positive and negative electrospray ionization.

Preparative HPLC purification is also performed on a Waters® UV-Directed Purification System equipped with a 2545 Binary Gradient Module, 2767 Sample Manager and 2489 UV/visible Detector controlled by MassLynx V4.1 software. All purifications are performed using the following columns: Atlantis Prep T3 OBD Column, SunFire Prep C18 OBD Column and XBridge Prep Phenyl OBD Column. The mobile phases are water (with 0.1% TFA or 0.01% NH ₄ HCO ₃ ) and acetonitrile; All reagents used are HPLC grade. Flow rate 30 ml/min. After the 1:1000 columns, the sorbent LC flow splitter transfers part of the eluent to the UV detector. The electrospray source is set to 3.0 kV capillary voltage, 30 V cone voltage, source temperature 110°C, desolvation temperature 350°C, desolvation gas flow 600 l/h and cone gas flow 60 l/h. For the analyzer, the multiplier is set to 550 for preparative tuning.

By analogy with the above general synthetic methods and description, the following compounds are synthesized:

Example 1

(2S,4R)-N-(4-(4-bromothiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl )pyrrolidine-2-carboxamide;

Example 2

(2S,4R)-N-(4-(4-cyclopropylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl )pyrrolidine-2-carboxamide;

Example 3

(2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 4

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-vinylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 5

(2S,4R)-N-(4-(4-ethylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl )pyrrolidine-2-carboxamide;

Example 6

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 7

(2S,4R)-1-((S)-2-(7-chloro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 8

(2S,4R)-1-((S)-2-(7-fluoro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 9

((2S,4R)-1-((S)-2-(6-fluoro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5 -yl)benzyl)pyrrolidine-2-carboxamide;

Example 10

(2S,4R)-1-((R)-2-(6-fluoro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 11

(2S,4R)-1-((S)-2-(6-bromo-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 12

(2S,4R)-1-((S)-3,3-dimethyl-2-propionamidobutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide;

Example 13

(2S,4R)-1-((S)-2-butyramido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 14

(2S,4R)-1-((S)-3,3-dimethyl-2-pivalamidobutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 15

(2S,4R)-4-hydroxy-1-((S)-2-(7-methoxy-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 16

(2S,4R)-1-((S)-2-(5-fluoro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 17

(2S,4R)-1-((S)-2-(6-cyano-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 18

(2S,4R)-1-((S)-3,3-dimethyl-2-(3-methylbutanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 19

(2S,4R)-1-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin- 2-carboxamide;

Example 20

(2S,4R)-1-((S)-2-(3-cyclohexylpropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin- 2-carboxamide;

Example 21

(2S,4R)-1-((S)-3,3-dimethyl-2-(2-phenylacetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 22

(2S,4R)-4-hydroxy-1-((R)-2-(4-methylpentanamido)-3-(methylthio)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 23

(2S,4R)-N-(4-bromobenzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

Example 24

(2S,4R)-N-((S)-1-(4-bromophenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl )pyrrolidine-2-carboxamide;

Example 25

(2S,4R)-1-((S)-2-(5-bromo-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 26

(2S,4R)-1-((S)-2-(4-bromo-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 27

(2S,4R)-4-hydroxy-1-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide;

Example 28

(2S,4R)-1-((S)-3,3-dimethyl-2-(4-methylpentanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 29

(2S,4R)-1-((S)-2-benzamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide;

Example 30

(2S,4R)-4-hydroxy-1-((2S,3S)-3-methyl-2-(1-oxoisoindolin-2-yl)pentanoyl)-N-(4-(4-methylthiazol-5-yl )benzyl)pyrrolidine-2-carboxamide;

Example 31

(2S,4R)-4-hydroxy-1-((2S,3S)-3-methyl-2-(4-methylpentanamido)pentanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 32

(2S,4R)-1-((S)-2-cyclopentyl-2-(isopentylamino)acetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ;

Example 33

(2S,4R)-1-((S)-2-(4-fluoro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 34

(2S,4R)-1-((S)-2-(5-cyano-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 35

(2S,4R)-1-((S)-2-(4-cyano-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 36

(2S,4R)-1-((S)-2-(cyclohexanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2- carboxamide;

Example 37

(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-((R)-3-(methylthio)-2-(1-oxoisoindolin-2-yl )propanoyl)pyrrolidine-2-carboxamide;

Example 38

(2S,4R)-1-((S)-2-cyclopentyl-2-(1-oxoisoindolin-2-yl)acetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 39

(2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3 -methyl-2-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2-carboxamide

Example 40

(2S,4R)-N-(biphenyl-4-ylmethyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

Example 41

(2S,4R)-N-(4-(1H-pyrazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl )pyrrolidine-2-carboxamide;

Example 42

(2S,4R)-1-((S)-2-(7-bromo-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 43

(2S,4R)-1-((S)-2-(4-cyanobenzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin- 2-carboxamide;

Example 44

(2S,4R)-1-((S)-3,3-dimethyl-2-(3-phenylpropanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 45

(2S,4R)-4-hydroxy-1-((2S,3S)-3-hydroxy-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl )benzyl)pyrrolidine-2-carboxamide;

Example 46

(2S,4R)-4-hydroxy-1-(2-methyl-2-(1-oxoisoindolin-2-yl)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide;

Example 47

(2S,4R)-1-((S)-2-(7-cyano-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 48

(2S,4R)-4-hydroxy-1-((R)-3-mercapto-2-(1-oxoisoindolin-2-yl)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 49

(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-(1-(1-oxoisoindolin-2-yl)cyclopropanecarbonyl)pyrrolidin-2-carboxamide;

Example 50

(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-(1-(1-oxoisoindolin-2-yl)cyclopentanecarbonyl)pyrrolidine-2-carboxamide;

Example 51

(2S,4R)-4-hydroxy-1-((2S,3S)-3-hydroxy-2-(4-methylpentanamido)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 52

(2S,4R)-4-hydroxy-1-((R)-2-(4-methylpentanamido)-2-(thiophen-2-yl)acetyl)-N-(4-(4-methylthiazol-5-yl )benzyl)pyrrolidine-2-carboxamide;

Example 53

(2S,4R)-4-hydroxy-1-((S)-2-(5-(3-methoxyprop-1-ynyl)-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-N-(4 -(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 54

(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-(1-(1-oxoisoindolin-2-yl)cyclohexanecarbonyl)pyrrolidine-2-carboxamide;

Example 55

(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-(1-(1-oxoisoindolin-2-yl)cyclobutanecarbonyl)pyrrolidine-2-carboxamide;

Example 56

(2S,4R)-1-((S)-2-cyclohexyl-2-(4-methylpentanamido)acetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide;

Example 57

(2S,4R)-4-hydroxy-1-((S)-2-(5-(3-methoxypropyl)-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 58

(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-((R)-2-(1-oxoisoindolin-2-yl)-2-(thiophene -2-yl)acetyl)pyrrolidine-2-carboxamide;

Example 59

(2S,4R)-4-hydroxy-1-((R)-3-mercapto-2-(4-methylpentanamido)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide;

Example 60

(2S,4R)-4-hydroxy-1-((R)-3-(((S)-3-((2R,4S)-4-hydroxy-2-(4-(4-methylthiazole-5- yl)benzylcarbamoyl)pyrrolidin-1-yl)-2-(4-methylpentanamido)-3-oxopropyl)disulfanyl)-2-(4-methylpentanamido)propanoyl)-N-(4-(4-methylthiazol-5-yl) benzyl)pyrrolidine-2-carboxamide;

Example 61

(S)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)-4-oxopyrrolidine- 2-carboxamide;

Example 62

(2S,4S)-4-hydroxy-4-methyl-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5 -yl)benzyl)pyrrolidine-2-carboxamide;

Example 63

(2S,4R)-4-hydroxy-1-(3-methoxybenzoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 64

(2S,4R)-1-benzoyl-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 65

(2S,4R)-1-((S)-3,3-dimethyl-2-(1-oxoisoindolin-2-yl)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl )benzyl)pyrrolidine-2-carboxamide;

Example 66

(4R)-4-hydroxy-1-(3-methoxybenzoyl)-2-methyl-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 67

(4R)-2-ethyl-4-hydroxy-1-(3-methoxybenzoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 68

((2S,4R)-1-((S)-2-(4-chloro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5 -yl)benzyl)pyrrolidine-2-carboxamide;

Example 69

(2S,4R)-1-((S)-2-acetamido-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 70

(2S,4R)-1-((S)-2-(2-cyanobenzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin- 2-carboxamide;

Example 71

(2S,4R)-1-((S)-2-(3-cyanobenzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin- 2-carboxamide;

Example 72

(2S,4R)-4-hydroxy-1-((S)-2-(5-methoxy-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 73

(2S,4R)-1-((S)-2-(5-chloro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 74

(2S,4R)-1-((S)-2-(6-chloro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 75

N-((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1 -oxobutan-2-yl)-1-methylpiperidine-4-carboxamide;

Example 76

(2S,4R)-4-hydroxy-1-((S)-2-(3-(4-methoxyphenyl)propanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl )benzyl)pyrrolidine-2-carboxamide;

Example 77

(2S,4R)-4-hydroxy-1-((S)-2-(3-(3-methoxyphenyl)propanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl )benzyl)pyrrolidine-2-carboxamide;

Example 78

N-((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1 -oxobutan-2-yl)picolinamide;

Example 79

(2S,4R)-4-hydroxy-4-methyl-1-[(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine- 2-carboxylic acid;

Example 80

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(3-methylpyridin-4-yl)benzyl )pyrrolidine-2-carboxamide;

Example 81

(2S,4R)-4-hydroxy-N-(4-methoxybenzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

Example 82

(2S,4R)-N-(2-fluoro-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindoline-2 -yl)butanoyl)pyrrolidine-2-carboxamide;

Example 83

(2S,4R)-4-hydroxy-1-((S)-2-(3-(2-methoxyphenyl)propanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl )benzyl)pyrrolidine-2-carboxamide;

Example 84

N-((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1 -oxobutan-2-yl)nicotinamide;

Example 85

(2S,4R)-1-((S)-2-acetamidopropanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 86

(2S,4R)-1-(2-acetamidoacetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 87

(S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-1-oxopropan-2-yl acetate;

Example 88

(2S,4R)-4-hydroxy-1-(4-methoxy-2-methylbenzoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 89

(2S,4R)-1-(2-amino-3,3,3-trifluoropropanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 90

(2S,4R)-1-(2-acetamido-3,3,3-trifluoropropanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 91

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-morpholinobenzyl)pyrrolidine-2-carboxamide;

Example 92

(2S,4R)-4-hydroxy-N-(4-(1-methyl-1H-pyrazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindoline-2 -yl)butanoyl)pyrrolidine-2-carboxamide;

Example 93

(2S,4R)-N-(3-fluoro-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindoline-2 -yl)butanoyl)pyrrolidine-2-carboxamide;

Example 94

(2S,4R)-1-((2S,3S)-2-(6-fluoro-1-oxoisoindolin-2-yl)-3-methylpentanoyl)-4-hydroxy-N-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 95

(2S,4R)-4-hydroxy-1-(5-methoxy-2-methylbenzoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 96

(2S,4R)-4-hydroxy-N-(4-(1-methyl-1H-imidazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindoline-2 -yl)butanoyl)pyrrolidine-2-carboxamide;

Example 97

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(thiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 98

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(2-oxopyrrolidin-1-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 99

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)butanoyl)- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 100

(2S,4R)-N-(4-(1H-1,2,3-triazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindoline) -2-yl)butanoyl)pyrrolidine-2-carboxamide;

Example 101

(2S,4R)-N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindoline-2 -yl)butanoyl)pyrrolidine-2-carboxamide;

Example 102

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-(trifluoromethyl)thiazole-5- yl) benzyl) pyrrolidine-2-carboxamide;

Example 103

(2S,4R)-N-(4-(1,4-dimethyl-1H-imidazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindoline -2-yl)butanoyl)pyrrolidine-2-carboxamide;

Example 104

(2S,4R)-4-hydroxy-1-((2S,3S)-3-methyl-2-(phenethylamino)pentanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide;

Example 105

(2S,4R)-4-hydroxy-1-((2S,3S)-3-methyl-2-(1-phenylethylamino)pentanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 106

(2S,4R)-N-(4-(1,5-dimethyl-1H-imidazol-4-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindoline -2-yl)butanoyl)pyrrolidine-2-carboxamide;

Example 107

(2S,4R)-1-((S)-2-acetamidobutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 108

(2S,4R)-1-((S)-3,3-dimethyl-2-(N-methylacetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 109

(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-(3-phenoxyphenyl)pyrrolidine-2-carboxamide;

Example 110

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carbothioamide;

Example 111

(2S,4R)-4-hydroxy-1-((S)-2-(4-methoxy-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-methylbutanoyl)-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 112

(2S,4R,E)-N'-cyano-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboximidamide;

Example 113

(2S,4R)-N-(4-cyclopropylbenzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

Example 114

(2S,4R)-N-(4-cyclobutylbenzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

Example 115

(2S,4R)-N-(4-cyclopentylbenzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

Example 116

(2S,4R)-N-(4-cyclopentenylbenzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

Example 117

(2S,4R)-N-(4-cyclohexylbenzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

Example 118

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(tetrahydro-2H-pyran-4-yl )benzyl)pyrrolidine-2-carboxamide;

Example 119

(2S,4R)-4-mercapto-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 120

(2S,4R,E)-4-hydroxy-N'-methoxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboximidamide;

Example 121

2-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzylamino)methyl)pyrrolidin-1-yl)-3-methyl- 1-oxobutan-2-yl)isoindolin-1-one;

Example 122

tert-butyl (S)-1-((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2-ylamino)-1-oxopropan-2-ylcarbamate;

Example 123

(2S,4R)-1-((S)-2-((S)-2-aminopropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl)pyrrolidine-2-carboxamide;

Example 124

tert-butyl 2-((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-ylamino)-2-oxoethylcarbamate;

Example 125

(2S,4R)-1-((S)-2-(2-aminoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin- 2-carboxamide;

Example 126

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboximidamide;

Example 127

(2S,4R)-4-hydroxy-N-(4-(3-hydroxyoxetan-3-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl )pyrrolidine-2-carboxamide;

Example 128

((4R)-4-hydroxy-2-methyl-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide Isomer A;

Example 129

((4R)-4-hydroxy-2-methyl-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide Isomer B;

Example 130

(2S,4R)-1-((S)-2-acetamido-3-methylbutanthoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 131

((4R)-4-hydroxy-2-methyl-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide Isomer C;

Example 132

((4R)-4-hydroxy-2-methyl-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide Isomer D;

Example 133

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methyloxazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 134

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(N-methylacetamido)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide;

Example 135

(2S,4R)-4-hydroxy-1-(2-(3-methylisoxazol-5-yl)acetyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 136

(2S,4R)-4-hydroxy-N-(4-(isoxazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine -2-carboxamide;

Example 137

(2S,4R)-4-hydroxy-N-(4-(isoxazol-4-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine -2-carboxamide;

Example 138

(2S,4R)-4-hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide;

Example 139

(2S,4R)-4-hydroxy-1-((S)-2-(3-methylisoxazol-5-yl)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide;

Example 140

(2S,4R)-4-hydroxy-1-(2-methyl-2-(3-methylisoxazol-5-yl)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide;

Example 141

(2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide;

Example 142

(2S,4R)-4-hydroxy-4-methyl-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5 -yl)benzyl)pyrrolidine-2-carboxamide;

Example 143

(2S,4R)-4-hydroxy-1-(2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 144

(2S,4S)-4-hydroxy-4-(hydroxymethyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazole) -5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 145

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 146

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 147

(2S,3R,4S)-3,4-dihydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5 -yl)benzyl)pyrrolidine-2-carboxamide;

Example 148

(2S,4R)-1-((S)-2-acetamidopentanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 149

(2S,4R)-4-hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide;

Example 150

(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) )benzyl)pyrrolidine-2-carboxamide;

Example 151

(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl )benzyl)pyrrolidine-2-carboxamide;

Example 152

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methyloxazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 153

(2S,4R)-4-hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidin-2 -carboxamide;

Example 154

(2S,4R)-4-hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide ;

Example 155

(2S,4R)-4-hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ;

Example 156

(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-(4-(thiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 157

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(thiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 158

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(thiazole- 5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

Example 159

(2S,4R)-4-hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(thiazol-5-yl) phenyl)ethyl)pyrrolidine-2-carboxamide;

Example 160

(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-( thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

Example 161

(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-( 4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

Example 162

(2S,4R)-4-hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

Example 163

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

Example 164

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4- methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

Example 165

(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-( 4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

Example 166

(2S,4R)-4-hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methyloxazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

Example 167

(2S,4R)-4-hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(oxazol-5-yl) phenyl)ethyl)pyrrolidine-2-carboxamide;

Example 168

(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-( oxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

Example 169

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(oxazol- 5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

Example 170

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(3-methylisothiazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 171

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(3-methyl-1,2,4-thiadiazol-5-yl)butanoyl)-N-(4-(4 -methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 172

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)butanoyl)-N-(4-(4 -methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 173

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(5-methyl-4H-1,2,4-triazol-3-yl)butanoyl)-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 174

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)butanoyl)-N-(4-(4 -methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 175

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)butanoyl)-N-(4-(4 -methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 176

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(5-methylisoxazol-3-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 177

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(5-methylisothiazol-3-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 178

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(5-methyl-1,2,4-thiadiazol-3-yl)butanoyl)-N-(4-(4 -methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 179

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)butanoyl)-N-(4-(4 -methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 180

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(5-methyl-1H-pyrazol-3-yl)butanoyl)-N-(4-(4-methylthiazol-5 -yl)benzyl)pyrrolidine-2-carboxamide;

Example 181

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(5-methyl-1H-imidazol-2-yl)butanoyl)-N-(4-(4-methylthiazol-5 -yl)benzyl)pyrrolidine-2-carboxamide;

Example 182

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(5-methyloxazol-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 183

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(5-methylthiazol-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 184

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(4-methyloxazol-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 185

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methylthiazol-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 186

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(2-methyloxazol-4-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 187

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(2-methylthiazol-4-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide;

Example 188

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(2-methyl-1H-imidazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5 -yl)benzyl)pyrrolidine-2-carboxamide;

Example 189

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-phenylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

Example 190

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(pyridin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 191

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(pyridazin-3-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 192

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(pyridin-3-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 193

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(pyrazin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 194

(2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(pyrazin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

Example 195

(2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole -5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

Example 196

(2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-4-hydroxy-N-({4-[4-(hydroxymethyl)-1,3-thiazol-5-yl ]phenyl}methyl)pyrrolidine-2-carboxamide

Example 197

(2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,2,3 -thiadiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

Example 198

(2S,4R)-4-hydroxy-N-[(1S)-1-{4-[4-(hydroxymethyl)-1,2,3-thiadiazol-5-yl]phenyl}ethyl]-1-[( 2S)-3-methyl-2-(4-methyl-1H-imidazole-1-tl)butanoyl]pyrrolidine-2-carboxamide

Example 199

(2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3 -methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl]pyrrolidine-2-carboxamide

Example 200

(2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3 -methyl-2-(4-phenyl-1H-pyrazol-1-yl)butanoyl]pyrrolidine-2-carboxamide

Example 201

(2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3 -methyl-2-[4-(pyridin-3-yl)-1H-pyrazol-1-yl]butanoyl]pyrrolidine-2-carboxamide

Example 202

(2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3 -methyl-2-[4-(pyridin-3-yl)-1H-pyrazol-1-yl]butanoyl]pyrrolidine-2-carboxamide

Example 203

(2S,4R)-4-hydroxy-1-[(2S)-2-(4-methoxy-1H-pyrazol-1-yl)-3-methylbutanoyl]-N-[(1S)-1-[4- (4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

Example 204

(2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3 -methyl-2-[4-(pyridin-2-yl)-1H-pyrazol-1-yl]butanoyl]pyrrolidine-2-carboxamide

Example 205

(2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3 -methyl-2-(3-methyl-1,2-oxazol-5-yl)butanoyl]pyrrolidine-2-carboxamide

Example 206

(2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3 -methyl-2-(4-phenoxy-1H-pyrazol-1-yl)butanoyl]pyrrolidine-2-carboxamide

Example 207

(2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]propyl]-1-[(2R)-3 -methyl-2-(3-methyl-1,2-oxazol-5-yl)butanoyl]pyrrolidine-2-carboxamide

Example 208

(2S,4R)-4-hydroxy-1-[(2R)-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-{[4-(4-methyl -1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide

Exemplary Methods for Synthesizing PROTAC

Amide Coupling: Typical PROTAC Synthesis for ULM Groups with Free Amine

Mitsunobu Method: Generic PROTAC Synthesis for ULM with Free Hydroxyl Group

Suzuki Method: Typical Synthesis of PROTACs with Halogenated ULMs

Using the above methods and various other approaches well described in the literature, the following exemplary PROTAC compounds are prepared. (Table 3 and Table 4). The exemplary compounds in Table 3 and Table 4 are also analyzed for their ability to cleave BRD4 and AR. Thus, in certain embodiments, the description provides compounds, including compositions containing an effective amount of a compound or its derivative, analog or prodrug, in combination with at least one pharmaceutically acceptable carrier, another active agent, including a second PROTAC molecule, as described here, or a combination thereof. In additional embodiments, the description provides a method of treating a disease or condition in a patient in need thereof, comprising administering a composition containing an effective amount of a compound from the list below, where the composition is effective for treating or alleviating a symptom of the disease or condition.

Cellular analyzes:

1. Analysis of fluorescent polarization

The ability of VHL ligands to contend for the GIF 1 binding site on the VCB is determined through a competitive fluorescent polarization assay, as described by Buckley et al. JACS, 2012, 134, 4465-4468, WO 2013/106643 and US 2014-0356322, which are incorporated herein by reference in their entirety for any purpose.

2. Androgen Receptor ELISA Assay

Compounds are evaluated in this assay in LNCaP and/or VCaP cells using similar protocols. The protocols used for VCaP cells are described below. The androgen receptor ELISA assay is performed using a PathScan AP ELISA (Cell Signaling, cat. no. 12850) according to the following assay steps:

VCaP cells are seeded at 30,000 cells/well in a volume of 200 μl/well in VCaP assay medium [RPMI without phenol red (Gibco, cat. no. 11835-030); EBS purified on 5% activated carbon (treated with dextran) (Omega Scientific, cat. no. FB-04); Pen/Strep Life Technologies (Gibco, cat. no. 10378-016); 0.1 nM R1881 (Sigma cat. no. R0908) is added at the start of the assay, but not during the initial seeding of the cells in the plate) into Corning 3904 plates. Cells are grown for a minimum of 3 days.

First, the cells are injected with compounds diluted in 0.1% DMSO in a propylene plate according to the following protocol: (1) (i) prepare 1000x stock plate in DMSO; (ii) 20 mM stock diluted 1/6.7 DMSO (5 µl+28.3 µl DMSO)=3 mM in the H row; (iii) make serial dilutions at ½ log doses (10 µl PROTAC+20 µl DMSO) from row H to row B. Reverse row A for DMSO; (iv) 7 doses in total (final concentration in this 1000x plate 3 mM, 1 mM, 333 μM, 111 μM, etc.). (2) (i) get 10x the original plate in the environment; (ii) transfer 2.5 µl of 1000x stock solution to a new 10x stock plate (use a 12-channel pipette, start from A (DMSO control) to H. When 247.5 µl of medium is added to this plate, it will happen as 10× stock solution (iii) prepare medium + 1 nM R1881 to obtain 10× stock plate (iv) add 247.5 µl of medium with 1 nM R1881 to each well of 10× stock plate, mix.

Then 22 µl of 10x stock solution is added to the cells and incubated for 24 hours. 1x Cell Signaling cell lysis buffer (catalog no. 9803; comes with the kit) is prepared - get for 50 µl/well. Keep on ice. The medium is aspirated and 50 μl of 1x cell lysis buffer/well is added. Cells are placed on ice for 10 minutes. The solution is mixed, then transferred to a PCR plate and centrifuged at 4° C. for 10 minutes at 4000 rpm.

5 µl is transferred to a fresh plate (use immediately or freeze -80°C); add 115 µl of ELISA diluent (0.15 µg/ml-0.075 µg/ml; comes with PathScan ELISA kit).

Add 100 μl/well AP ELISA; cap and shake, 37°C for 2 h; pour, siphon, wash 4×200 μl ELISA wash buffer; add 100 μl/well Ab for determination of mouse AP; cap and shake, 37°C for 1 h; pour, siphon, wash with 4×200 µl ELISA wash buffer; add 100 µl/well of anti-mouse HRP Ab conjugated (supplied); cover with a lid and shake, 37°C for 30 min; bring the TMB reagent to RT; pour, siphon, wash with 4×200 µl ELISA wash buffer; pour out; add 100 µl of TMB, shake for 5 min, observe the color. Stop reagent is added when the color turns light blue. Add 100 µl stop solution; shake and read at 450 nM.

The development of prostate cancer in patients treated with anti-androgen therapy typically involves one of several mechanisms for improved androgen receptor (AR) signaling, including increased intratumoral androgen synthesis, increased AR expression, and AR mutations. PROTAC (PROteolysis TArgeting Chimera), which uses bifunctional molecules that simultaneously bind a chosen target and an E3 ligase, induce ubiquitination through induced proximity and cleavage of the abnormal target protein. Unlike traditional target inhibition, which is a competitive process, cleavage is a progressive process. As such, it is less susceptible to increases in endogenous ligand, target expression, or mutation in the target. Thus, this technology seems to be ideal for reversing the mechanisms of AR resistance in patients with prostate cancer.

PROTAC ARs cleave AR in LNCaP and VCaP cells with nM to pM activity and cause >85% reduction in AP concentration (D _max ). Cleavage is fast, 50% of AP is lost within 15 minutes, and maximum degradation occurs after 4 hours. The duration of AR shutdown is long, and AR recovery is not observed for more than a few days. The cleavage process in cells is specific because PROTACs with an inactive epimer for E3 ligase do not cleave AP. PROTAC ARs induce rapid apoptosis and cell death in VCaP cells. In LNCap and VCaP cellular systems, PROTAC ARs are antiproliferative under conditions where enzalutamide is inactive, such as elevated concentrations of the AR agonist R1881 and cells containing the AR ^F876L mutation. PROTAC ARs usually have t _1/2 values of several hours and bioavailability >50% after i.b. or p.k. injections. In mice, PROTAC ARs have shown in vivo activity, including seminal vesicle involution, reduction in prostate AP protein levels, and reduction in VCaP tumors.

The results presented in Table 3 are obtained using the androgen receptor ELISA assay described above, where the potency of the compounds is characterized by the highest percentage of androgen receptor cleavage (D _max ) obtained.

BDR4 Receptor ELISA Assay (Table 4)

22RV-1 cells are seeded at 30,000 cells/well in a volume of 75 μl/well in RPMI+10% EBS in 96-well plates and grown overnight at 37°C. Compounds are injected into cells at 4× concentration diluted in 0.4% DMSO; compounds are serially diluted 1:3 for an 8-point dose curve. 25 μl of the compound is added to the cells to a final concentration starting from 300 nM - 0.3 nM in 0.1% DMSO and incubated for 18 hours. The medium is aspirated, the cells are washed with 1x PBS and aspirated. Cells are lysed in 50 μl RIPA buffer (50 mM Tris pH8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. The plates are incubated on ice for 15 minutes, then centrifuged at 4° C. for 10 minutes at 4000 rpm. Add 50 μl of the purified lysate from the 96-well assay plate to a 96-well c-myc ELISA plate (Novex, Life Technologies, cat. no. KH02041). Reconstituted c-myc standard with standard dilution buffer; standard curve interval 333 pg/mL - 0 pg/mL diluted 1:2 for an 8-point dose curve. The rest of the analysis is carried out according to the protocol from the c-myc ELISA kit. The data is analyzed and plotted using the GraphPad Prism software.

Surface Plasmon Resonance Analysis

Surface plasmon resonance (SPR) experiments were carried out on a Biacore3000 (GE Healthcare). The His-tagged VHL protein is immobilized on a carboxymethylated dextran surface with nitriloacetic acid (NTA) to take advantage of NTA/Ni ²⁺ chelation. The resulting surface is equilibrated for more than three hours in a running buffer (Ambion 1×FRP buffer at pH 7/4, 0.005% Tween, 2% DMSO).

All compounds are prepared in 100% DMSO stock plates at 5 mM cut off in 3× serial dilutions. Compounds are transferred from the original plate to the assay plate and diluted in running buffer containing no DMSO. All compounds are tested at six concentrations with a final assay cut-off of 100 μM. Data analysis was carried out in Scrubber 2 (BioLogic software, Campbell, Australia). The control is subtracted and the data corrected for DMSO using the DMSO standard curve. All reported KD values represent the average of at least N=2 and are obtained by fitting to a minimum of five concentrations using a 1:1 fitting algorithm.

Below ( Table 1) shows the VHL inhibition data (i.e., IC ₅₀ , μM) of each example at various DMSO concentrations (i.e., 0.25% in DMSO, 1% in DMSO, and 10% in DMSO) in a fluorescent assay. polarization (FP).

Table 1. VHL inhibition data (ie, IC ₅₀ , μM) in a fluorescent polarization (FP) assay. Example No. VHL analysis of FP IC _fifty (µM) at various concentrations of test compounds in DMSO 0.25% in DMSO 1% in DMSO 10% in DMSO one 2.38 2.28 2 2.86 0.732 0.533 3 2.54 0.696 1.48 four 3.34 1.22 1.94 5 7.72 0.799 1.58 6 6.37 0.697 1.48 7 7.51 8.52 eight 3.04 0.619 1.33 9 1.28 0.309 0.498 ten ~6.73 295 eleven 1.56 0.542 0.0163 12 9.34 2.08 4.86 13 3.37 1.34 2.94 fourteen 7.15 4.63 13.3 fifteen 1.22 24.5 81.9 16 2.95 0.265 1.8 17 2.2 0.317 1.07 eighteen 5.5 0.855 2.72 19 3.77 0.937 1.65 twenty 4.96 1.05 1.15 21 5.69 0.392 1.49 22 6.25 8.29 23 1.14 2.51 6.04 24 1.39 8.65 28.0 25 2.38 1.33 1.67 26 2.94 0.941 0.441 27 ~1,569 3.04 8.31 28 4.47 2.21 3.6 29 2.42 0.905 1.85 thirty 2.27 0.572 0.859 31 3.22 1.28 2.11 32 2.22 1.15 3.36 33 1.94 0.539 1.08 34 2.12 0.66 1.18 35 2.05 0.509 1.3 36 6.54 3.55 5.48 37 1.9 20.6 7.41 38 2.19 0.758 1.09 39 0.958 0.699 1.63 40 17.5 2.36 3.92 41 7.28 1.19 3.05 42 4.95 15.7 43 0.906 1.2 44 0.385 0.465 45 ~32 472 46 19410 5103 47 0.178 0.339 48 3.77 4.7 49 244 fifty 235 51 56.6 1518 52 2.48 3.73 53 0.474 1.03 54 0.834 1.21 55 115 461 56 0.878 1.48 57 0.717 1.41 58 32.6 26.2 59 1.42 3.69 60 1.45 0.293 61 not active not active 62 not active not active 63 58.4 53.0 64 16.8 30.5 65 0.631 0.578 66 not active not active 67 not active not active 68 0.972 0.668 69 1.43 4.28 70 2.02 1.2 71 1.62 1.38 72 0.86 1.03 73 1.33 1.19 74 0.45 0.264 75 13.7 9.29 76 0.169 77 0.55 0.349 78 1.03 0.81 79 >100 >100 80 22.4 38.9 81 >49 371 82 1.64 1.58 83 0.626 0.32 84 1.24 1.46 85 28.9 21.2 86 151 225 87 384 263 88 20.4 39.2 89 60.6 139 90 45.2 47.9 91 >100 92 1.65 93 1.2 94 0.566 95 23.4 96 35.4 97 1.45 98 4.15 99 0.418 100 9.77 101 4.39 102 7.75 103 33.8 104 >10 105 37.7 106 14.2 107 64.6 108 33.5 109 6.67 110 21.6 111 0.859 112 >100 113 >10 114 47.3 115 15.8 116 3.9 117 15.5 118 330 119 not active 120 15.5 121 >100 122 2.18 123 4.23 124 1.11 125 1.64 126 79.5 112 127 406 128 >100 129 19.3 130 3.89 131 not active 132 1.69 133 1.64 134 12.7 135 19.2 136 5.59 137 13.1 138 2.38 139 65.4 140 157 141 0.0709 142 134 143 0.964 144 not active 145 0.1 146 17 147 12.4 148 6.2

Table 2 shows the VHL inhibition data (ie, Kd, μM) of the examples presented here in a surface plasmon resonance (SPR) assay.

Table 2. Affinity measured in SPR VHL for typical ULMs. Example No. SPR Kd (µM) 3 0.12 145 0.01 205 0.33 207 0.24 208 13.0

Digest data for exemplary PROTAC compounds according to the invention

Table 3 presents functional (D _max splitting) data for PROTAC AP, which covers the VHL ligands and analogs described here. D _max :+(D _max ≤25%); ++ (26%≤D _max ≤50%); +++ (51%≤D _max ≤70%); ++++ (71%≤D _max ).

Table 3. Split data for exemplary PROTAC APs Typical ULMs Structure _Dmax 202

+++ 202

+++ 203

+++ 203

++ 202

++

Table 4 presents functional (cMyc I _max ) data for BRD4 PROTAC, which covers the VHL ligands and analogs described here. cMyc I _max :+(I _max ≤25%); ++ (26%≤I _max ≤50%); +++ (51%≤I _max ≤70%); ++++ (71%≤I _max ).

Table 4. Cleavage Readouts for Typical Brd4 PROTACs Typical ULMs Structure _cMyc Imax 202

++++ 202

++++ 202

+++ 202

++++ 200

++++

The description, including examples and experimental data, demonstrates the efficacy and broad applicability of the PROTAC bifunctional compounds described herein to target any cleavage target protein. As presented here, PROTAC-mediated protein cleavage provides a mechanism to target "drug-resistant" pathological proteins that may not have been viable targets for traditional approaches.

The contents of all references, patents, patent applications pending and published patents cited in this description, are included here as links.

One of skill in the art will understand, or be able to ascertain by routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are included in the following claims. It is understood that the detailed examples and variations described herein are given by way of example for purposes of illustration only and should not be considered as limiting the invention. Various modifications or changes in light thereof may be suggested by those skilled in the art and are included within the spirit and content of this application and are considered to be included within the scope of the claims. For example, the relative amounts of ingredients may be varied to optimize the desired effects, additional ingredients may be added and/or similar ingredients may be substituted for one or more of the ingredients described. Additional advantageous features and functionality associated with the systems, methods and processes of the present invention will be apparent from the claims. Moreover, those skilled in the art will recognize, or be able to ascertain through routine experimentation, many equivalents to the specific embodiments of the invention described. Such equivalents are included in the claims.

Claims (79)

1. A bifunctional compound having a chemical structure: ULM-L-PTM, where (a) PTM is a targeting protein fragment, which is a small molecule that binds to an intracellular target protein; (b) L is the chemical linker group connecting the ULM and the specified PTM, where the chemical linker group is represented by the chemical structure -A ₁ -…-A _q -, where q is an integer from 1 to 20; each A is independently selected from CR ^L1 R ^L2 , O, NR ^L3 , CO, C _3-11 cycloalkyl optionally substituted with 1-6 R ^L1 groups, C _3-11 heterocyclyl optionally substituted with 1-6 R ^L1 groups, 6-membered aryl optionally substituted with 1-6 R ^L1 groups, and 5- or 6-membered heteroaryl optionally substituted with 1-6 R ^L1 groups; and R ^L1 , R ^L2 and R ^L3 are each independently H, halogen, C _1-8 alkyl, OC _1-8 alkyl, NHC _1-8 alkyl, N(C _1-8 alkyl) ₂ , OH, NH ₂ , CN or CF ₃ ; (c) ULM is the von Hippel-Lindau (VHL) E3 ubiquitin ligase (ULM) binding fragment having the chemical structure:

where E is C=O; G is C=O; M is

each R ₉ and R ₁₀ is independently H, optionally substituted with C _1-6 alkyl, optionally substituted with C _1-6 hydroxyalkyl or C _1-6 haloalkyl; R ₁₁ is an optionally substituted 5- or 6-membered heteroaryl, an optionally substituted 6-membered aryl, or

,

or

; each R ₁₈ is independently halo, C _1-6 alkoxy, cyano, or optionally substituted C _1-6 alkyl; and p from ULM means 0, 1, 2, 3, or 4; R ₁₂ is H or optionally substituted C _1-6 alkyl; R ₁₃ is H, optionally substituted C _1-6 alkyl, optionally substituted acetyl, or optionally substituted C _1-6 alkylcarbonyl, each R ₁₄ is independently H, C _1-6 haloalkyl or optionally substituted C _1-6 alkyl, where one R ¹⁴ is C _1-6 haloalkyl or optionally substituted C _1-6 alkyl; R ₁₅ is an optionally substituted 5- or 6-membered heteroaryl, an optionally substituted 6-membered aryl, or

; each R ₁₆ is independently halo, optionally substituted with C _1-6 alkyl, optionally substituted with C _1-6 haloalkyl, CN, or optionally substituted with C _1-6 haloalkoxy; o from ULM is 0, 1, 2, 3, or 4; each heteroaryl and heterocyclyl has 1-3 heteroatoms independently selected from O, N and S; and optionally substituted refers to optional substitutions by one or more members independently selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, =O, amino, amide, C _3-7 heterocycle, 6-membered aryl, CN , halogen, COOH, hydroxyl, C _1-6 ester, C _1-6 acyl and phenyl, or a pharmaceutically acceptable salt thereof, where (i) the target protein is selected from the group consisting of Ras, Raf, MEK, ERK pathways, estrogen receptor and androgen receptor; or (ii) PTM is a compound that targets human BET bromodomain-containing proteins, a compound that targets RAF, a compound that targets the estrogen receptor, a compound that targets the androgen receptor, or a compound that targets the epidermal growth factor receptor. 2. The compound according to claim 1, where R ₁₅ is selected from the group including:

. 3. The compound according to claim 1 or 2, where R ₁₁ is selected from the group including:

;

;

;

;

;

;

;

;

;

;

;

;

;

;

and

. 4. The compound according to claim 1, where R ₁₁ is selected from the group including:

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

. 5. The compound according to claim 1, where ULM has a chemical structure:

; where X is O or S; Y is methyl or ethyl R ₁₇ is H, methyl or ethyl; M is

; R ₉ is H; R ₁₀ is H or optionally substituted C _1-6 alkyl; R ₁₁ is an optionally substituted 5- or 6-membered heteroaryl,

or

, or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 1, where ULM is a group of the chemical structure:

, where Y is methyl or ethyl; R ₉ is H; R ₁₀ is isopropyl, t-butyl or sec-butyl; R ₁₁ is isoindolinonyl or isoxazolyl, where isoindolinonyl is optionally substituted halogen, C _1-6 alkoxy, cyano, C _1-6 alkyl, or C _1-6 haloalkyl, and where isoxazolyl is optionally substituted halogen, C _1-6 alkoxy, cyano, or C _1-6 alkyl; and R ₁₇ is alkyl. 7. The connection according to claim 1, where the ULM fragment is selected from the group including:

. 8. Connection according to any one of paragraphs. 1-7 wherein the target protein is selected from the group consisting of estrogen receptor and androgen receptor. 9. Connection according to any one of paragraphs. 1-7, where PTM is a compound that targets human BET bromodomain-containing proteins, a compound that targets the estrogen receptor, or a compound that targets the androgen receptor. 10. Pharmaceutical composition containing an effective amount of a compound according to any one of paragraphs. 1-9 in combination with a pharmaceutically acceptable carrier, additive or excipient, wherein the composition is effective to cleave an intracellular target protein, wherein (i) the target protein is an androgen receptor; or (ii) PTM is a compound that targets human BET bromodomain-containing proteins, or a compound that targets the androgen receptor. 11. The pharmaceutical composition of claim 10 wherein PTM is a compound that targets the androgen receptor. 12. The pharmaceutical composition of claim 10, wherein the PTM is a compound that targets human BET bromodomain-containing proteins. 13. A method for causing cleavage of an intracellular target protein in a cell, comprising: introducing an effective amount of a compound according to any one of paragraphs. 1-9 into a cell, wherein the compound is effective in cleaving an intracellular target protein in the cell, and wherein (i) the target protein is an androgen receptor; or (ii) PTM is a compound that targets human BET bromodomain-containing proteins, or a compound that targets the androgen receptor. 14. The method of claim 13 wherein the PTM is a compound that targets human BET bromodomain containing proteins. 15. The method of claim 13 wherein the PTM is an androgen receptor targeting compound. 16. A method of cleaving an intracellular target protein in a cell, comprising treating the cell with a composition containing an effective amount of a compound according to any one of paragraphs. 1-12, wherein the intracellular target protein is an androgen receptor or a protein containing a BET bromodomain and the compound cleaves the target protein. 17. The method of claim 16 wherein the intracellular target protein is an androgen receptor. 18. The method of claim 16 wherein the intracellular target protein is a BET bromodomain containing protein.

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