RU2805523C2 - Compounds targeting tau protein and related use thereof - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound having the chemical structure ULM-L-PTM, or a pharmaceutically acceptable salt thereof, wherein ULM has the chemical structure represented by structure (aa), where R_14a is either H or C_1-6 alkyl; R₉ is H; R₁₀ is H, ethyl, isopropyl, tert-butyl or sec-butyl; R₁₁ is structure (b) or (c); R₁₂ is H; R₁₃ is either C_1-6 alkyl or C_1-6 alkylcarbonyl; R₁₅ is selected from H, structures (d) and (e); dotted line indicates the site of attachment of L; or ULM has the chemical structure represented by (a), where W is either CH₂ or C=O; each X is O; Z is O; G is H; Q₁ , Q₂ , Q₃ and Q₄ represent a carbon atom C, substituted by the group R'; A is H; R is selected from -CONR'R”, -OR', -NR'R”, -CR'R”-, -CR'NR'R”-, -Cl, -F, -Br, -I, -CF₃, -CN, -NR'CONR'R”, -CONR'COR”, -CO₂R', -C(C=N-OR')R”, -CR'=CR'R”, -CCR' or -OCF₃; R' and R” are H; is a bond that may or may not provide a stereospecific configuration; n is either 1, 2, 3 or 4; PTM is represented by a chemical structure selected from the group shown in the claims, and where R¹, R² and R³ independently represent H or optionally substituted with 1-3 halogens C_1-6alkyl; and R⁷, R⁸ , R⁹ and R¹⁰, each represents either 1 or 2 substituents independently selected from H, C_1-6alkyl, C_1-6haloalkyl, halogen or cyano; and L is represented by the formula -(A)_q- where A is a group connected to either an ULM or PTM fragment; and q is an integer from 1 to 19, where A is selected from CR^L1R^L2, O, NR^L3, CO, CR^L1=CR^L2, C≡, cyclopropyl, cyclobutyl, bicyclopentyl, oxetanyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, and cyclopropyl, cyclobutyl, bicyclopentyl, oxetanyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl are optionally substituted with either 1 or 2 R ^L1 ; each of R^L1, R^L2 and R^L3 is independently selected from H, halo, C_1-8alkyl, OH, CN, CF₃, CHF₂ and CH₂F. The invention relates to a pharmaceutical composition containing an effective amount of a compound of the invention and a pharmaceutically acceptable carrier for use in the treatment of a disease or disorder associated with tau protein.

EFFECT: obtaining compounds for use in the treatment of a disease or disorder associated with a tau protein.

19 cl, 1 dwg, 2 tbl

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[1] The present invention claims benefit from U.S. Provisional Patent Application No. 62/415,830, filed November 1, 2016, which is incorporated herein by reference in its entirety.

INCLUSION BY REFERENCE

[2] US Patent Application Serial No. 15/230354, filed August 5, 2016; and US Patent Application Serial No. 62/406888, filed October 11, 2016; and US Patent Application Serial No. 14/686640, filed April 14, 2015, published as US Patent Application Publication No. 2015/0291562; and US Patent Application Serial No. 14/792414, filed July 6, 2015, published as US Patent Application Publication No. 2016/0058872; and US Patent Application Serial No. 14/371956, filed July 11, 2014, published as US Patent Application Publication No. 2014/0356322; and US Patent Application Serial No. 15/074820, filed March 18, 2016, published as US Patent Application Publication No. 2016/0272639, are incorporated herein by reference in their entirety. In addition, all sources referenced herein are incorporated herein by reference in their entirety.

BACKGROUND OF THE ART

1. Field of technology to which the invention relates

[3] The present description relates to bifunctional compounds that are useful for modifying intracellular ubiquitination and subsequent destruction of target polypeptides and proteins, in particular tau protein. The compounds of the present invention place the target protein/polypeptide in close proximity to a ubiquitin ligase to effect ubiquitination and degradation (and inhibition) of tau protein.

2. Additional information

[4] Most small molecule drugs bind enzymes or receptors in dense and well-defined pockets. On the other hand, targeting protein-protein interactions using small molecules is notoriously difficult due to their large contact surface and the involvement of fine grooves or flat contact surfaces. E3 ubiquitin ligases (of which hundreds are known in humans) confer substrate specificity for ubiquitination and are therefore more attractive therapeutic targets than conventional proteasome inhibitors due to their specificity for certain protein substrates. Designing ligands for E3 ligases has proven difficult, partly due to the fact that they must disrupt protein-protein interactions. However, recent developments have made it possible to obtain specific ligands that bind to such ligases. For example, since the discovery of nutlins, the first small molecule E3 ligase inhibitors, additional compounds that target E3 ligases have been reported, but the field remains underdeveloped.

[5] One E3 ligase with promising therapeutic potential is the tumor suppressor of Hippel-Lindau disease (VHL), the substrate recognition subunit of the E3 ligase complex VCB, which also consists of elongins B and C, Cul2 and Rbx1. The major substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that increases gene expression such as the proangiogenic growth factor VEGF, and the cytokine erythropoietin, which induces red blood cell production in response to low oxygen levels. The first small molecule Hippel-Lindau (VHL) protein ligands binding to the substrate recognition subunit of E3 ligase were prepared and crystal structures were obtained indicating that the compound mimics the binding mechanism of the transcription factor HIF-1α, the major substrate of VHL.

[6] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologues are highly conserved among organisms ranging from plants to humans, highlighting its physiological importance. Cereblon is part of an E3 ubiquitin ligase complex with DNA damage binding protein 1 (DDB1), cullin 4A (CUL4A), and regulator of cullin 1 (ROC1). This complex carries out the ubiquitination of a number of other proteins. Through a mechanism that is not yet fully understood, ubiquitination of target proteins by cereblon leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates a number of developmental processes, such as the formation of limbs and the otic vesicle. The net result is that this ubiquitin ligase complex is essential for limb growth in embryos. In the absence of cereblon, DDB1 forms a complex with DDB2, which functions as a DNA-binding protein.

[7] Tau protein is a protein expressed in large quantities in the central nervous system, primarily found in nerve cells, although other cells of the central nervous system express tau protein at lower levels. In a healthy neuron, tau protein binds to microtubules and regulates microtubule stability, which is important for axon growth and neuronal plasticity. With pathological changes, tau protein molecules are not able to stabilize microtubules and tend to form insoluble aggregates. Once tau protein forms insoluble aggregates in cells, cellular dysfunction occurs, axonal transport is impaired, and neuronal loss results. The accumulation of abnormal tau protein aggregates in neurons is an important pathological feature in many neurodegenerative disorders, including Alzheimer's disease. In some pathological conditions, tau protein aggregation leads to the formation of paired helical filaments (PHF), straight filaments (SF) and/or neurofibrillary tangles (NFT). Accumulation of PHF and NFT in neurons directly correlates with microtubule dysfunction and neuronal degeneration. Neurons containing PHF, SF, and or tau NFTs activate a variety of cellular mechanisms in an attempt to rid the cell of abnormal protein aggregates.

[8] More recent studies suggest that instead of large insoluble filaments, soluble tau oligomers may play a more important role in the onset and progression of the disease to the development of PHF- or NFT-induced neurotoxicity. Oligomeric tau molecules can act as seeds for native tau aggregation, thereby promoting neurotoxic tau aggregation. A growing body of evidence suggests that tau protein aggregates can be transferred from one cell to another through propagation in a prion-like manner.

[9] Alterations in tau protein and the resulting dysfunction and extensive neuronal loss have long been associated with several neurodegenerative diseases, now collectively called tauopathies.

[10] The term “tauopathy” or “tauopathies” as used herein refers to a class of neurodegenerative diseases associated with the pathological aggregation of tau protein into neurofibrillary or gliofibrillary tangles in the human brain. Examples of tauopathies include, but are not limited to, AD, Down syndrome, frontotemporal lobar dementia (FTLD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP).

[11] Because of its pathological significance in many neurodegenerative diseases, tau protein is an important therapeutic target. Prevention of tau protein aggregation is emerging as a potential strategy for the treatment of tau protein-associated neurodegenerative disorders. To date, great efforts have been made to identify the molecular mechanisms of tau protein aggregation and to find therapeutic agents to arrest the progression of neurodegeneration.

[12] Tau aggregation inhibitors, which have shown promise in preclinical studies, have been ineffective in recent clinical trials for the treatment of various tauopathies. Therefore, there is a need in the art for effective treatments for diseases and conditions that are associated with tau protein aggregation in neurodegenerative disorders such as tauopathies.

SHORT DESCRIPTION

[13] The present invention describes bifunctional compounds, including compositions containing them, the function of which is to recruit endogenous proteins to E3 ubiquitin ligase for ubiquitination and subsequent destruction, and methods of using them. In particular, the present invention provides bifunctional or chimeric proteolytic targeting compounds (PROTACs) that find use as modulators of targeted ubiquitination and degradation of tau protein aggregates. In addition, the description provides methods of using effective amounts of the compounds described herein to treat or alleviate disease conditions caused by the accumulation or aggregation of tau proteins, such as tauopathies. Such diseases or disorders include, without limitation, neurological or neurodegenerative disorders.

[14] Thus, in one aspect, the present invention provides compounds that function to recruit endogenous proteins, such as tau proteins, to E3 ubiquitin ligases for ubiquitination and degradation.

[15] In any of the embodiments, the connections have the following general structure:

[16] In certain embodiments, the compounds have the following general structure (A):

[17] In certain embodiments, the compounds have the following general structure (B):

wherein PTM is a protein targeting fragment, ULM is an E3 ubiquitin ligase targeting fragment, including but not limited to VLM (VHL ligase complex binding fragment) and CLM (cereblon ligase complex binding fragment), and L is a linker, such as a bond or chemical linker moiety. One skilled in the art will appreciate that the bifunctional compounds described herein can be synthesized such that the number and position of the corresponding functional moieties can be varied as needed.

[18] In certain embodiments, the PTMs of structure (A) are ligands that bind to tau protein as well as the VHL E3 ubiquitin ligase complex.

[19] In certain embodiments, the PTMs in structure (B) are ligands that bind to tau proteins as well as the CLM of the E3 ubiquitin ligase complex.

[20] In certain embodiments, the compounds described herein contain multiple ULMs, multiple PTMs, multiple chemical linkers, or a combination thereof. In a further aspect, the disclosure provides therapeutic compositions comprising an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. Therapeutic compositions modulate protein degradation in a patient or subject, such as an animal such as a human, and may be used to treat or alleviate disease states or conditions that are modulated by protein degradation. In certain embodiments, the therapeutic compositions described herein can be used to promote the destruction of proteins of interest to treat or alleviate a disease, such as a neuronal disease. In yet another aspect, the present invention provides a method for causing ubiquitination/degradation of a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described herein comprising a ULM and a PTM, which may be joined via a linker moiety described later herein, wherein the ULM is linked to the PTM and wherein the ULM recognizes a ubiquitin pathway protein, such as a ubiquitin ligase. , such as an E3 ubiquitin ligase, more preferably VLM and CLM, and the PTM recognizes a target protein (TBM) such that when a target protein (e.g., tau protein) is placed in close proximity to a ubiquitin ligase, degradation of the target protein will occur, thus , leads to the destruction of the target protein, suppressing its effects and controlling protein levels. In another aspect, the target protein is tau protein. The present invention provides for the treatment of a disease state or condition by controlling protein levels, i.e. by reducing the level of a given protein (such as tau protein) in the patient's cells by destroying it.

[21] Specifically, PTMs are molecules that bind to tau protein (TBM), and ULMs are molecules that bind to the VHL E3 ubiquitin ligase complex and/or the CLM of the E3 ubiquitin ligase complex, with the following general structure:

[22] The PTM (protein targeting moiety) included in the PROTAC of the present invention is represented by the general formulas I, II, III, IV, V, VI, VII, VIII, XI, X and XI:

Where

each of A, B, C, D, E and F is independently selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring, an optionally substituted 4-7 membered cycloalkyl or heterocycloalkyl, wherein contact between the rings indicates ring condensation; And

L _PTM is selected from a bond, alkyl, alkenyl or alkynyl, optionally interrupted by one or more rings (i.e. cycloalkyl, heterocycloalkyl, aryl or heteroaryl) or one or more functional groups, which may include -O-, -S-, - NR ¹ _PTM - (where R ¹ _PTM is selected from H or alkyl), -N=N-, -S(O)-, -SO ₂ -, -C(O)-, -NHC(O)-, -C (O)NH-, -NHSO ₂ -, -NHC(O)NH-, -NHC(O)O, -OC(O)NH-, wherein said functional group may optionally be located at either end of the linker (i.e. directly adjacent to rings A, B, C, D, E or F).

[23] The above aryl and heteroaryl rings may be optionally substituted with 1-3 substituents, each independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl and cyano, where said alkyl and alkenyl groups may be further substituted.

[24] In any aspect or embodiment described herein, at least one of A, B, C, F, or combinations thereof is selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings.

[25] In certain embodiments of the present invention, PTM is represented by formula I and/or II, wherein A, B, and C are 5- or 6-membered fused aryl or heteroaryl rings, L _PTM is selected from bond or alkyl, and D is selected from 6-membered aryl, heteroaryl or heterocycloalkyl, wherein A, B, C and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl or cyano.

[26] In other embodiments, PTM is represented by formula III and/or IV, wherein A, B, and C are 5- or 6-membered fused aryl or heteroaryl rings, L _PTM is selected from a bond or alkyl, and D and E are 5- or 6-membered fused aryl or heteroaryl rings, and wherein A, B, C, D and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl or cyano.

[27] In certain other embodiments of the present invention, PTM is represented by Formula I, wherein A is phenyl or a 6-membered heteroaryl ring, B is a 5-membered heteroaryl ring, C is phenyl or a 6-membered heteroaryl ring, L _PTM is is a bond, and D is a 6-membered heteroaryl or a 6-membered heterocycloalkyl ring, wherein each of A, B, C, and D is optionally independently substituted with alkyl, halogenalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, trifluoromethyl, or cyano, provided that the nitrogen atom in any of rings A, B, C and D is not directly attached to a heteroatom or to a carbon atom in L _PTM to which another heteroatom is directly attached.

[28] It should be understood that the general structures are illustrative and the corresponding fragments can be arranged in space in any desired order, number or configuration.

[29] In additional embodiments, the disclosure provides a bifunctional compound having a structure selected from the group consisting of compounds 1-330 (eg, a compound selected from Tables 1 and 2), a salt, a polymorph, and a prodrug thereof.

[30] In additional embodiments, the description provides a bifunctional compound having a structure selected from Table 1 or Table 2 (eg, a chemical structure selected from compounds 1-330), a salt, a polymorph, and a prodrug thereof.

[31] In another aspect, the description provides compositions containing the compounds described herein and a pharmaceutically acceptable carrier. In certain embodiments, the compositions are therapeutic or pharmaceutical compositions containing an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In certain embodiments, the therapeutic or pharmaceutical compositions contain an additional biologically active agent, for example, an agent effective for treating a neuronal disease.

[32] In any of the aspects or embodiments described herein, therapeutic compositions containing the compounds described herein may be in any suitable dosage form, such as solid or liquid, and capable of delivery by any suitable route, for example oral, parenteral, intravenous, intraperitoneal, subcutaneous, intramuscular, etc.

[33] In another aspect, the description provides methods for modulating tau protein, its ubiquitination and subsequent destruction in a subject, for example, in a cell, tissue in a mammal or human patient, the method comprising administering an effective amount of a compound described herein, or a composition containing an effective amount of the compound, to a subject, wherein the compound or composition containing the compound is effective in modulating the ubiquitination and degradation of tau protein in the subject.

[34] In yet another aspect, the description provides methods of treating or alleviating a symptom of a disease associated with tau protein activity in a subject, such as a cell, tissue in a mammal, or a human patient, the method comprising administering an effective amount of a compound described in herein, or a composition containing an effective amount of a given compound, to a subject in need thereof, wherein the compound or composition containing the compound is effective in treating or alleviating a symptom of a disease associated with tau protein activity in the subject. In certain embodiments, the disease being treated is a neurological or neurodegenerative disease, such as Alzheimer's disease, Parkinson's disease, dementia, etc.

[35] In a preferred embodiment, the subject is a human.

[36] In a further aspect, the description provides methods for identifying the effects of disruption of proteins of interest in a biological system using compounds of the present invention.

[37] Where applicable or unless specifically stated, any of the embodiments described herein are intended to be combined with any other one or more embodiments, although embodiments are described in various aspects herein inventions. Accordingly, the foregoing general applications are given by way of example only and are not intended to limit the scope of the present invention and the appended claims. Additional objects and advantages associated with the compositions, methods and processes of the present invention will be apparent to one skilled in the art in light of the claims, descriptions and examples. For example, various aspects and embodiments of the present invention can be used in numerous combinations, all of which are expressly contemplated herein. Such additional advantages, objects and embodiments are expressly included within the scope of the present invention. Publications and other materials used herein to highlight the prior art of the present invention and, in specific cases, to provide additional details regarding its implementation, are incorporated by reference.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[38] The accompanying drawings, which are included in and form a part of the specification, illustrate several embodiments of the present invention and, together with the description, serve to explain the teachings of the present invention. The graphics are intended to illustrate an embodiment of the present invention only and should not be construed as limiting the present invention. Additional objects, features and advantages of the present invention will become apparent from the following detailed description taken in conjunction with the accompanying drawings showing illustrative embodiments of the present invention in which:

[39] Figure 1 shows total tau protein levels in hippocampal homogenates. Data are shown as a scatterplot. Statistically significant differences between test treatment (TI) and vehicle control groups according to one-way ANOVA followed by Dunnett's multiple comparison test are indicated with an asterisk, ** p < 0.01, * p < 0.05 .

DETAILED DESCRIPTION

[40] The following detailed description is presented to assist one skilled in the art with respect to the practice of the present invention. Modifications and changes to the embodiments described herein may be made by those skilled in the art without departing from the spirit or scope of the present invention. All publications, patent applications, patents, figures and other sources mentioned herein are expressly incorporated by reference in their entirety.

[41] The present disclosure relates to the unanticipated and unexpected discovery that an E3ubiquitin ligase complex protein can mediate the ubiquitination of a target protein by bringing the E3 ubiquitin ligase complex protein and the target protein into close proximity using a chimeric construct (e.g., PROTAC) described herein. which binds the E3 ubiquitin ligase complex protein (eg, VHL and cereblon) and a target protein, such as tau protein. Accordingly, the present description provides compounds, compositions containing these compounds, and associated methods of use for promoting ubiquitination and degradation of a selected target protein.

[42] The following terms are used to describe the present invention. Where a term is not specifically defined herein, such term has the meaning generally recognized by those of ordinary skill in the art when used in the context of its use in describing the present invention.

[43] Where a range of values is presented, each intermediate value is understood to be to the nearest tenth of a unit lower limit, unless the context clearly requires otherwise (as, for example, in the case of a group containing a specified number of carbon atoms, in which case the number of each carbon atom that falls within the range), between the upper and lower limits of that range, and any other specified or intermediate value within that specified range are covered by the present invention. The upper and lower limits of such smaller ranges, which may be independently included in the smaller ranges, are also are covered by the present invention, subject to any specifically excluded limit within the specified range. If the specified range includes one or both limits, ranges excluding both of these included limits are also included in the present invention.

[44] The singular forms used herein and in the accompanying claims are used herein to refer to one or more than one (i.e., at least one) grammatical entities of that singular form unless the context clearly indicates other. By way of example, "element" means one element or more than one element.

[45] The phrase “and/or” as used herein in the description and claims should be understood to mean “one or both” of the elements so combined, i.e. elements that in some cases are present together, and in other cases present separately. Multiple elements listed using “and/or” must be interpreted in the same way, i.e. "one or more" of the elements so combined. Other elements other than those specifically identified by the expression “and/or” may optionally be present, whether related or unrelated to the elements specifically identified. Thus, by way of non-limiting example, reference to “A and/or B,” when used in conjunction with open-ended language such as “comprising,” may refer in one embodiment to A only (not necessarily including elements other than B); in another embodiment, only to B (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements), etc.

[46] As used herein in the description and claims, the term “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating objects in a list, “or” or “and/or” should be understood as inclusive, i.e. including at least one, but also including more than one, of a number or list of items and optionally additional non-listed items. Only terms clearly indicating the contrary, such as “only one of” or “exactly one of,” or, if used in the claims, “consisting of,” will refer to the inclusion of exactly one element from a number or list of elements. In general, the term “or” as used herein should be understood only to indicate exclusive alternatives (i.e., “one or the other, but not both”) when preceded by exclusivity terms such as “either,” “ one of", "only one of" or "exactly one of".

[47] In the claims, as well as in the above description, all transitional phrases such as “comprising”, “comprising”, “carrying”, “having”, “accommodating”, “providing”, “holding”, “consisting of” etc. should be understood as open, i.e. meaning inclusive without limitation. Only the transitional phrases “consisting of” and “substantially consisting of” must be closed or semi-closed transitional phrases, respectively, as set forth in section 2111.03 of the United States Patent Office Manual of Patent Examination Procedures.

[48] As used herein in the specification and claims, the phrase “at least one” with respect to a list of one or more elements is to be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of absolutely all of the elements specifically listed in the list of elements, and not excluding any combinations of elements from the list of elements. This definition also allows that elements other than those specifically identified in the list of elements to which the phrase “at least one” refers may optionally be present, whether or not they are related to those specifically identified elements. Thus, by way of 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 in an embodiment, to at least one, optionally including more than one, A, without the presence of B (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, without the presence 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.

[49] 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 acts of the method is not necessarily limited to the order in which the steps or acts of the method are set forth, unless the context indicates otherwise.

[50] The term "compound" as used herein, unless otherwise noted, refers to any specific chemical compound disclosed herein and includes its tautomers, regioisomers, geometric isomers and, where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as its pharmaceutically acceptable salts and derivatives (including prodrug forms) where applicable in the appropriate context. When used in the appropriate context, the term compound generally refers to a single compound, but it 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 disclosed compounds. In the appropriate context, the term also refers to prodrug forms of compounds that have been modified to facilitate administration and delivery of the compounds to the site of activity. It should be noted that in describing the compounds of the present invention, among other things, numerous substituents and variables associated therewith are described. Those of ordinary skill in the art will understand that the molecules that are described herein are stable compounds as generally described herein.

[51] If communication is shown then in the context of the compound shown, both a double bond and a single bond are represented.

[52] The term “patient” or “subject” is used throughout this specification to describe an animal, preferably a human or pet, that is treated, including prophylactic treatment, with the compositions of the present invention. For the treatment of those infections, conditions or disease states that are specific to a particular animal, such as a human patient, the term patient refers to that particular animal, including a domestic animal such as a dog or cat, or a farm animal, such as horse, cow, sheep, etc. In general, as used herein, the term patient refers to a human patient unless otherwise stated or implied by the context of use of the term.

[53] The term “effective” is used to describe the amount of a compound, composition or component that, when used in the context of its intended use, produces the intended result. The term “effective” includes all other terms of effective amount or effective concentration that are otherwise described or used in this application.

[54] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for destruction. For example, cereblon is a protein of the E3 ubiquitin ligase complex that, alone or in combination with an E2 ubiquitin conjugating enzyme, mediates the attachment of ubiquitin to a lysine on a target protein and subsequently targets specific protein substrates for destruction by the proteasome. Thus, E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to target proteins. In general, ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is added to the first, a third is added to the second, and so on. Through polyubiquitination, proteins are marked for destruction by the proteasome. However, there are some ubiquitination phenomena that are limited to monoubiquitination, in which only one ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted by the proteasome for destruction, but instead their cellular location or function can be altered, for example by binding to other proteins that contain domains that can bind ubiquitin. Further complicating the matter is that E3 can target different lysines on ubiquitin to form chains. The most abundant lysine is Lys48 in the ubiquitin chain. This lysine is used to form polyubiquitin, which is recognized by the proteasome.

[55] The term "protein targeting moiety" or PTM is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest and positions/presences the protein or polypeptide in close proximity to a ubiquitin ligase such that that protein or polypeptide destruction can occur through ubiquitin ligase. Non-limiting examples of small molecule fragments that bind a target protein include compounds that target tau protein.

[56] The term “target protein” is used herein to describe a protein or polypeptide that is a target for binding to a compound of the present invention and destruction by a ubiquitin ligase. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of such compositions, as well as other small molecules that can target the protein of interest. Such linking moieties are connected to ULM groups via L linker groups.

[57] The tau protein target can be used in screens to identify fragments of a compound that bind to the protein, and by incorporating the fragment into compounds of the present invention, the level of activity of the protein can be altered to achieve the ultimate therapeutic outcome.

[58] The term "disease or condition" is used to describe any disease or condition in which protein dysregulation occurs (i.e., the amount of protein expressed in the patient is increased) and the tau protein in the patient is destroyed may provide beneficial therapy or symptomatic relief to a patient in need. In certain cases, a disease or condition can be cured.

[59] Disease conditions or conditions that can be treated with the compounds of the present invention include neuronal disease, for example, neurodegeneration, Huntington's disease and muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten disease, spinal cord and brain injuries, seizure disorders, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformation, cerebral aneurysm, dural arteriovenous fistulas, headache, memory disorders, peripheral neuropathy, postherpetic neuralgia, spinal cord tumor, stroke.

[60] The term “neurological disorder” or “neurological disorders” as used herein refers to any disorder, disease and/or syndrome caused by or resulting from a neurological, psychiatric, psychological and/or cerebrovascular symptom or origin. The term “neurological disorder” or “neurological disorders” as used herein also refers to diseases, disorders or conditions of the brain and nervous system or mental disorders or conditions. Neurological disorders include, but are not limited to, absence of septum pellucidum, acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, Eydie-Holmes syndrome, Eydie syndrome, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Ecardi's syndrome, neurological complications of AIDS, Alexander disease, Alpers disease, alternating hemiplegia , Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, ataxia, telangiectasia, forms of ataxia and cerebellar/ spinocerebellar degeneration, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Barth syndrome, Batten disease, Becker myotonia, Behçet disease, Bell's palsy, benign essential blepharospasm, benign focal amyotrophy, benign intracranial hypertension, Bernhardt-Roth syndrome, Binswanger's disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus injury during childbirth, brachial plexus injury, Bradbury-Eggleston syndrome, brain and spinal cord tumors, cerebral aneurysm, brain injury, Brown-Séquard syndrome, bulbospinal muscular atrophy, disease Canavan, carpal tunnel syndrome, causalgia, cavernomas, cavernous angioma, cavernous malformation, central palsy syndrome, pyramidal palsy, central pain syndrome, cephalic disorders, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral take the form -beri, cerebral gigantism, cerebral hypoxia, cerebral palsy, cerebrooculofacioskeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chorea-acanthocytosis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic orthostatic intolerance, chronic pain, Cockayne syndrome type II , Coffin-Lowry syndrome, COFS, colpocephaly, coma and persistent vegetative state, complex regional pain syndrome, congenital facial diplegia, congenital myasthenia gravis, congenital myopathy, congenital cavernous vascular malformations, corticobasal degeneration, temporal arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cu mulative traumatic disorders, Cushing's syndrome, inclusion cytomegaly, cytomegalovirus infection, opso-myoclonal syndrome, Dandy-Walker syndrome, Dawson's disease, de Morsier syndrome, deep brain stimulation in Parkinson's disease, Dejerine-Klumpke palsy, dementia, multi-infarct dementia, semantic dementia, subcortical dementia, dementia with Lewy bodies, progressive cerebellar ataxia, dentorubral atrophy, dermatomyositis, developmental dyspraxia, Devic's syndrome, diabetic neuropathy, diffuse sclerosis, autonomic dystonia, dysgraphia, dyslexia, dysphagia, dyspraxia, cerebellar myoclonic Hunt's dyssynergia, progressive cerebellar eye dyssynergia, forms dystonia, epileptic encephalopathy of early childhood, empty sella syndrome, lethargic encephalitis, cranial hernias, encephalopathy, encephalotrigeminal angiomatosis, epilepsy, Duchenne-Erb and Dejerine-Klumpke palsies, Erb's spinal palsy, Fabry's disease, Fahr syndrome, syncope, familial dysautonomia, familial hemangioma, familial idiopathic calcification of the basal ganglia, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher syndrome, floppy child syndrome, hereditary Friedreich ataxia, frontotemporal dementia, Gaucher disease, Gerstmann syndrome, Gerstmann-Straussler syndrome -Scheinker, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, glossopharyngeal neuralgia, Guillain-Barre syndrome, Hallerwarden-Spatz disease, traumatic brain injury, headache, prolonged hemicrania, hemifacial spasm, alternating hemiplegia, hereditary neuropathies, inheritance natural spastic paraplegia, polyneuritis-like hemeralopic heredoataxia, herpes zoster, ganglion neuralgia, Hirayama syndrome, Eydie-Holmes syndrome, holoprosencephaly, HTLV-1-associated myelopathy, Huntington's disease, hydroanencephaly, hydrocephalus, normal pressure hydrocephalus, hydromyelia, hyperfunction , hypercortisolism, hypersomnia, hypertension, infantile hypotonia, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, pigmentary dermatosis, infantile hypotonia, infantile neuroaxonal dystrophy, infantile phytanic acid storage disease, infantile Refsum's disease, infantile spasms, inflammatory myopathy, inencephaly, intestinal lipodystrophy, intracranial ist, intracranial hypertension, Isaac syndrome, Joubert syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsborne syndrome, Kleine-Levin syndrome, Klippel-Feil syndrome, Klippel-Trenaunay syndrome (KTS), Klüver-Bucy syndrome, Korsakoff amnestic syndrome, Krabbe disease, disease Kugelberg-Welander, kuru, Lambert-Eaton myasthenic syndrome, Landau-Klefner syndrome, neuropathy of the lateral femoral cutaneous nerve, Wallenberg syndrome, learning disabilities, Leigh disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Levine-Critchley syndrome , dementia with Lewy bodies, lipid storage diseases, lissencephaly, locked-in syndrome, Lou Gehrig's disease, neurological complications of lupus, neurological complications of Lyme disease, Machado-Joseph disease, macroencephaly, manic syndrome, macroencephaly, Melkersson-Rosenthal syndrome, meningitis, meningitis and encephalitis, Menkes disease, meralgia paresthetica, metachromatic leukodystrophy, microcephaly, migraine, Miller-Fisher syndrome, microstrokes, mitochondrial myopathies, Mobius syndrome, monomelic amyotrophy, motor neuron diseases, Moya-Moya disease, mucolipidoses, mucopolysaccharidoses, multifocal motor neuropathy, multi-infarct dementia, multiple sclerosis, multiple system atrophy, multiple system atrophy with orthostatic hypotension, muscular dystrophy, congenital myasthenia, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic encephalopathy in infants, myoclonus, myopathy, congenital myopathy, thyrotoxic myopathy , myotonia, congenital myotonia, narcolepsy, neuroacanthocytosis, neurodegeneration with iron accumulation in the brain, neurofibromatosis, neuroleptic malignant syndrome, neurological complications of AIDS, neurological complications of Lyme disease, neurological consequences of cytomegalovirus infection, neurological manifestations of Pompe disease, neurological complications of lupus, neuromyelitis optica, neuromyotonia, neuronal ceroid lipofuscinosis, disorders neuronal migrations, hereditary neuropathy, neurosarcoidosis, neurotoxicity, carvenous hemangioma, Niemann-Pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, latent spinal cord dysraphism, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus, orthostatic hypotension, O'Sullivan-MacLeod syndrome , overload syndrome, chronic pain, pain, pantothenate kinase-associated neurodegeneration, paraneoplastic syndromes, paresthesia, Parkinson's disease, paroxysmal choreoathetosis, paroxysmal hemicrania, Paris-Romberg syndrome, Pelizaeus-Merzbacher disease, Pena-Choqueir II syndrome, perineural cysts, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent vegetative state, pervasive developmental disorders, phytanic acid storage disease, Pick's disease, pinched nerve, piriformis syndrome, pituitary tumors, polymyositis, Pompe disease, porencephaly, postherpetic neuralgia, postinfectious encephalomyelitis, postpolio syndrome, postural hypotension , postural orthostatic tachycardia syndrome, postural tachycardia syndrome, progressive cerebellar dyssynergia, primary lateral sclerosis, primary progressive aphasia, prion diseases, progressive hemifacial atrophy, progressive motor ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing polydystrophy, progressive supranuclear palsy , prosopagnosia, benign intracranial hypertension , Ramsay-Hunt syndrome I (formerly known as), Ramsay-Hunt syndrome II (formerly known as), Rasmussen's encephalitis, sympathetic reflex dystrophy, Refsum's disease, infantile form of Refsum's disease, repetitive motion disorder, carpal tunnel syndrome, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye syndrome, Riley-Day syndrome, perihilar cysts of the sacral nerve, St. Vitus's dance, salivary gland disease, Sandhoff disease, Schilder disease, schizencephaly, Seitelberger disease, seizure disorder, semantic dementia , septo-optic dysplasia, shaken baby syndrome, herpes zoster, Shy-Drager syndrome, Sjogren's syndrome, sleep apnea, sleeping sickness, Sotos syndrome, spasticity, spina bifida, spinal cord infarction, spinal cord injury, spinal cord tumors, spinal cord muscle atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Steele-Richardson-Olszewski syndrome, muscle stiffness syndrome, striatonigral degeneration, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, short-term attacks of unilateral neuralgic headache with conjunctiva ral injection and lacrimation, disturbances swallowing function, Sydenham's chorea, syncope, syphilitic spinal sclerosis, syringohydromyelia, syringomyelia, systemic erythematous lupus, tabes spinal cord, tardive dyskinesia, Tarlov cysts, Tay-Sachs disease, temporal arteritis, tethered spinal cord syndrome, Thomsen's myotonia, scalene syndrome, thyrotoxic myopathy, trigeminal neuralgia, Todd's palsy, Tourette's syndrome, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, tuberous sclerosis, cavernous angioma, vasculitis, including temporal arteritis , Economo disease, Hippel-Lindau disease (VHL), Recklinghausen disease, Wallenberg syndrome, Werdnig-Hoffmann disease, Wernicke-Korsakoff syndrome, West syndrome, whiplash injury, Whipple disease, Williams syndrome, Wilson disease, X-linked spino- bulbar muscular atrophy or Zellweger syndrome.

[61] The term "biologically active agent" is used to describe an agent, other than a compound of the present invention, that is used in combination with the compounds of the present invention as an agent with biological activity to assist in the intended therapy, inhibition and/or prevention /prophylaxis for which the compounds of the present invention are used.

[62] The term "pharmaceutically acceptable salt" is used throughout the specification to describe, as applicable, a salt form of one or more of the compounds described herein that is present to increase the solubility of the compound in the gastric juices of the gastrointestinal tract of a patient to promote dissolution and bioavailability of compounds. Pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids, as appropriate. Suitable salts include salts derived from alkali metals, such as potassium and sodium salts, alkaline earth metals, such as calcium, magnesium and ammonium salts, among a number of other acids and bases well known in the pharmaceutical field. Sodium and potassium salts are particularly preferred as phosphate neutralizing salts in accordance with the present invention.

[63] The term "pharmaceutically acceptable derivative" is used throughout the specification to describe any pharmaceutically acceptable form of prodrug (such as an ester, amide, other prodrug group) that, when administered to a patient, provides directly or indirectly a compound of the present invention or an active metabolite of a compound of the present invention. the present invention.

[64] The term “independently” is used herein to indicate that a variable that is applied independently varies from application to application.

[65] By "hydrocarbon radical" is meant a compound which contains carbon and hydrogen atoms and which may be fully saturated, partially unsaturated or aromatic, and includes aryl groups, alkyl groups, alkenyl groups and alkynyl groups.

[66] The term "alkyl" in its appropriate context is to be understood as 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 an alkyl group which may be optionally substituted. Examples of alkyl groups include, among others, 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.

[67] The term "lower alkyl" means alkyl groups containing no more than six carbon atoms.

[68] The term “unsubstituted” should be understood to mean substituted only by hydrogen atoms. The range of carbon atoms that includes C ₀ means that carbon is missing and is replaced by H. Thus, the range of carbon atoms that is C ₀ -C ₆ includes 1, 2, 3, 4, 5 and 6 carbon atoms, and in the case of C ₀ , instead of carbon there is H. The term “substituted” or “optionally substituted” should be understood independently (i.e., if more than one substituent occurs, each substituent is independent of the other substituent) one or more substituents (independently no more than five substituents, preferably no more than three substituents, often 1 or 2 substituents on a moiety in a compound of the present invention, and may include substituents which themselves may be further substituted) at a carbon (or nitrogen) position anywhere in the molecule in appropriate context, and substituents include hydroxyl, thiol, carboxyl, cyano (C=N), nitro (NO ₂ ), halogen (preferably 1, 2 or 3 halogen, especially on an alkyl, especially a methyl group, such as trifluoromethyl ), alkyl group (preferably C ₁ -C ₁₀ , more preferably C ₁ -C ₆ ), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy group a (preferably C ₁ -C ₆ alkyl or aryl , including phenyl and substituted phenyl), thioether (C ₁ -C ₆ alkyl or aryl), acyl (preferably C ₁ -C ₆ acyl), ester or thioester (preferably C ₁ -C ₆ alkyl or aryl) , including an alkylene ester (so that the attachment occurs at the alkylene group rather than at the ester functionality, which is preferably a substituted C ₁ -C ₆ alkyl or aryl group), preferably a C ₁ -C ₆ alkyl or aryl, halogen (preferably F or Cl), amine (including a five- or six-membered cyclic alkylene amine, including additionally a C ₁ -C ₆ alkylamine or a C ₁ -C ₆ dialkylamine, wherein the alkyl groups may be replaced by one or two hydroxyl groups ) or an optionally substituted group -N(C ₀ -C ₆ alkyl)C(O)(O-C ₁ -C ₆ alkyl) (which may be optionally substituted by a polyethylene glycol chain to which is additionally attached an alkyl group containing one halogen atom, preferably a substituent representing a chlorine atom), hydrazine, amido, preferably substituted with one or two C ₁ -C ₆ alkyl groups (including a carboxamide which is optionally substituted with one or two C ₁ -C ₆ alkyl groups), alkanol (preferably C ₁ -C ₆ alkyl or aryl) or alkanoic acid (preferably C ₁ -C ₆ alkyl or aryl). Substituents in accordance with the present invention may include, for example, -SiR ₁ R ₂ R ₃ groups, wherein each of R ₁ and R ₂ is described later herein, and R ₃ represents H or a C ₁ -C ₆ alkyl group, preferably R ₁ , R ₂ , R ₃ in this context represent a C ₁ -C ₃ alkyl group (including isopropyl or tert-butyl group). Each of the above groups can be directly connected to the substituted moiety, or, alternatively, the substituent can be connected to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via an optionally substituted (CH ₂ ) _m - group or, alternatively, optionally substituted groups -(OSH ₂ ) _m -, -(OSH ₂ CH ₂ ) _m - or -(CH ₂ CH ₂ O) _m -, which may be substituted by any one or more of the above-described substituents. Alkylene groups -(CH ₂ ) _m -, or -(CH ₂ ) _n - groups, or other chains, such as ethylene glycol chains, as defined above, may be substituted anywhere on the chain. Preferred substituents on alkylene groups include halogen or C ₁ -C ₆ alkyl groups (preferably C ₁ -C ₃ ), which may be optionally substituted with one or two hydroxyl groups, one or two ether groups (OC ₁ -C ₆ groups), no more than three groups representing a halogen atom (preferably F), or an amino acid side chain as further described herein, and an optionally substituted amide (preferably a carboxamide substituted as described above) or urethane groups (often with one or two substituents representing C ₀ -C ₆ alkyl, wherein the group(s) may be further substituted(s)). In certain embodiments, the alkylene group (often one methylene group) is substituted with one or two optionally substituted C ₁ -C ₆ alkyl groups, preferably a C ₁ -C ₄ alkyl group, most often a methyl or O-methyl group or an amino acid side chain, as follows described in this document. In the present invention, a moiety in a molecule may optionally be substituted with no more than five substituents, preferably no more than three substituents. Most often in the present invention, moieties that are substituted are substituted with one or two substituents.

[69] The term “substituted” (each substituent is independent of any other substituent) in the context of its use should also be understood as C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, amido, carboxamido, sulfone, including sulfonamide, keto, carboxy, C ₁ -C ₆ ester (hydroxy ester or carbonyl ester), C ₁ -C ₆ keto, urethane -OC(O)-NR ₁ R ₂ or -N(R ₁ )-C( O)-OR ₁ , nitro, cyano and amine (including, in particular, C ₁ -C ₆ alkylene-NR ₁ R ₂ , mono or disubstituted C ₁ -C ₆ alkyl amines, which may be optionally substituted by one or two hydroxyl groups). Each of these groups contains, unless otherwise indicated in the appropriate context, from 1 to 6 carbon atoms. In certain embodiments, preferred substituents will include, for example, -NH-, -NHC(O)-, -O-, =O, -( _CH2 ) _m- (in this context, m and n 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)-Rs (Rs represents a C ₁ -C ₆ alkyl or a -(CH ₂ ) _{m -} group NR ₁ R ₂ ), NO ₂ , CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context of use of the substituent. Each of R ₁ and R ₂ in the appropriate context represents an H or a C ₁ -C ₆ alkyl group (which may optionally be substituted by one or two hydroxyl groups or by up to three groups representing a halogen atom, preferably a fluorine atom). In the chemical context of the particular compound and the substituent used, the term “substituted” also includes an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group, as described later herein. Alkylene groups may also be substituted, as further disclosed herein, preferably with optionally substituted C ₁ -C ₆ alkyl groups (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, thereby providing a chiral center), a group representing a side chain an amino acid as further described herein, an amido group as described above herein, or a urethane group, an O-C(O)-NR ₁ R ₂ group, wherein R ₁ and R ₂ are as described later herein , although numerous other groups can also be used as substituents. The 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 cases where a substitution is required in a compound at a particular position of the molecule (mainly due to valence), but the substitution is not specified, then the substituent is interpreted or understood as H, unless the context of the substitution suggests otherwise.

[70] The term "aryl" or "aromatic" in the appropriate context refers to a substituted (as further described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl , anthracenyl, phenanthrenyl, etc.), and may be linked to a compound of the present invention at any available stable position on the ring(s), or otherwise as indicated by the chemical structure provided. Other examples of aryl groups in the appropriate context may include, among others, 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., which may be optionally substituted as described above. Heteroaryl groups that may be mentioned include, but are not limited to, nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolysine, azaindolysine , purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolysine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carba zol, carbazoline, perimidine, phenanthroline, phenacene , oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles containing 2 or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, all of which may be optionally substituted.

[71] The term "heterocycle" refers to a cyclic group that contains at least one heteroatom, i.e. O, N or S, and may be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties are included in the definition of heterocycle, depending on the context of their use. Exemplary heteroaryl groups are described above herein. Exemplary non-aromatic heterocyclic groups for use in the present invention include, for example, but are not limited to, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl, pyridone, 2-pyrrolidone, ethylene urea , 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, phthalimide and succinimide, as described herein.

[72] By the term “co-administration” or “combination therapy” it is meant that at least two compounds or compositions are administered to a patient at the same time such that effective amounts or concentrations of each of the two or more compounds can be detected in patient at a given point in time. Although the compounds of the present invention can be co-administered to a patient at the same time, the term covers the administration of two or more agents either at the same time or at different times, provided that the effective concentrations of all co-administered compounds or compositions are detected in the subject at a given point in time. In certain preferred aspects of the present invention, one or more of the compounds of the present invention described above are co-administered in combination with at least one additional biologically active agent, including, in particular, an anticancer agent. In specific aspects of the present invention, coadministration of the compounds results in a synergistic therapeutic effect, including anticancer therapy.

[73] The present invention describes bifunctional compounds whose function is to recruit endogenous proteins to E3 ubiquitin ligase for destruction, and methods for their use. In particular, the present invention provides bifunctional or chimeric proteolytic targeting compounds (PROTACs) that find use as modulators of targeted ubiquitination of tau proteins. The advantage of the compounds presented herein is that a wide range of pharmacological activities are possible, consistent with the destruction/inhibition of tau protein.

[74] Thus, the present invention provides such compounds and compositions comprising an E3 ubiquitin ligase targeting moiety ("ULM") linked to a tau protein target binding moiety ("TBM"), resulting in to ubiquitination of tau protein, which leads to the destruction (and/or inhibition) of tau protein. The present invention also provides a composition library and its use.

[75] Provided herein are compounds that contain a ligand, for example, a low molecular weight ligand (ie, having a molecular weight of less than 2000, 1000, 500 or 200 daltons) that is capable of binding to a ubiquitin ligase such as VHL or Cereblon. The compounds also contain a moiety that is capable of binding to a target protein such that the target protein is placed in close proximity to the ubiquitin ligase to cause degradation (and/or inhibition) of the protein. Low molecular weight may mean, in addition to the above, that the molecule is not a peptidyl, i.e. not usually considered a peptide, e.g. contains less than 4, 3 or 2 amino acids. In accordance with the present description, the PTM, ULM or PROTAC molecule may be low molecular weight.

[76] In one embodiment, the description provides a composition useful for regulating the activity of a protein. The composition contains a ubiquitin pathway protein-binding moiety (preferably VHL or Cereblon), according to a specific chemical structure, and a tau protein-targeting moiety, which are linked together, preferably by a linker, wherein the ubiquitin pathway protein-binding moiety recognizes a ubiquitin pathway protein and wherein the targeting moiety recognizes the target tau protein, and wherein the ubiquitin pathway protein-binding moiety is associated with the tau protein-targeting moiety.

[77] In another embodiment, the present invention provides a library of compounds. The library contains more than one compound, where each composition contains a ubiquitin pathway protein binding moiety (preferably VHL or Cereblon) and a tau binding moiety, where ULM is linked (preferably via a linker moiety) to tau protein, and wherein the tau binding moiety ubiquitin pathway protein, recognizes ubiquitin pathway protein, specifically E3 ubiquitin ligase.

[78] In another embodiment, the present invention provides a method for causing ubiquitination/degradation of a target protein (eg, tau protein) in a cell. The method involves administering a bifunctional composition comprising a ubiquitin pathway protein-binding moiety and a targeting moiety, preferably linked via a linker moiety as further described herein, wherein the ubiquitin pathway protein-binding moiety is linked to the targeting moiety, and wherein the protein-binding moiety ubiquitin pathway, recognizes a ubiquitin pathway protein (eg, VHL, cereblon), and the targeting moiety recognizes the target protein (eg, tau protein) such that when the target protein is placed in close proximity to the ubiquitin ligase, degradation of the target protein will occur, thus , results in reduction/inhibition of the effects of the target protein and control of protein levels. The control of protein levels provided by the present invention provides treatment for a disease state or condition modulated by a target protein by reducing the level of that protein in the patient's cells.

[79] In yet another embodiment, the present invention is directed to a method of treating a patient in need of modulation of a disease state or condition by a protein (eg, tau protein), wherein disruption of the protein will have a therapeutic effect in the patient, the method comprising administering to a patient in need an effective amount of a compound according to the present invention, optionally in combination with another biologically active agent. The disease state or condition may be a disease caused by a microbial organism or other exogenous organism, such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a disease condition that is caused by overexpression of a protein, i.e. accumulation or aggregation of tau protein, resulting in a disease state and/or condition.

[80] In one aspect, the present invention provides compounds useful for regulating protein activity. The composition contains a ubiquitin pathway protein binding moiety, an E3 ubiquitin ligase, and a protein targeting moiety that are joined or linked together, preferably by a linker, wherein the ubiquitin pathway protein binding moiety recognizes the ubiquitin pathway protein, and the targeting moiety recognizes the target protein ( e.g. tau protein). Such compounds may be referred to herein as PROTAC or PROTAC compounds with the following general chemical structure:

ULM-L-RTM,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,

wherein ULM is a small molecule E3 ubiquitin ligase binding fragment that binds E3 ubiquitin ligase;

PTM is a small molecule comprising a tau targeting moiety that causes tau protein to be destroyed; And

L represents the bond or chemical linker moiety connecting the ULM and PTM.

[81] In certain embodiments, the E3 ubiquitin ligase binding moiety targets a member of the group consisting of Hippel-Lindau protein (VLM), cereblon (CLM), mouse double minute homologue 2 (MLM), and IAP (ILM).

[82] In one aspect, the disclosure provides tau protein binding moieties (TBMs). In certain embodiments, the PTM is represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI:

, Where

A, B, C, D, E and F are independently selected from optionally substituted 5- or 6-membered aryl or heteroaryl ring, optionally substituted 4-7 membered cycloalkyl or heterocycloalkyl, wherein contact between the rings indicates ring condensation; And

L _PTM is selected from a bond, alkyl, alkenyl or alkynyl, optionally interrupted by one or more rings (i.e. cycloalkyl, heterocycloalkyl, aryl or heteroaryl) or one or more functional groups selected from the groups -O-, -S-, - NR ¹ _PTM - (where R ¹ _PTM is selected from H or alkyl), -N=N-, -S(O)-, -SO ₂ -, -C(O)-, -NHC(O)-, -C (O)NH-, -NHSO ₂ -, -NHC(O)NH-, -NHC(O)O- or -OC(O)NH-, wherein said functional group is optionally located at either end of the linker.

[83] In certain embodiments, the aryl and heteroaryl rings A, B, C, D, E and F in PTM are optionally substituted with 1-3 substituents, each independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy , amino, alkylamino, dialkylamino, acylamino, trifluoromethyl and cyano, wherein said alkyl and alkenyl groups are further optionally substituted.

[84] In certain embodiments, the rings of at least one of A, B, C, F, or combinations thereof are selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings.

[85] In certain embodiments, PTM has a chemical structure of Formula I, wherein

rings A, B and C are independently 5- or 6-membered fused aryl or heteroaryl rings;

L _PTM is selected from a bond or alkyl, and

D is selected from 6-membered aryl, heteroaryl or heterocycloalkyl,

wherein A, B, C and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino or cyano.

[86] In certain further embodiments, PTM has a chemical structure of Formula I, wherein

A and C represent a phenyl or 6-membered heteroaryl ring;

B is a 5-membered heteroaryl ring;

L _PTM represents the link; And

D represents a 6-membered heteroaryl or 6-membered heterocycloalkyl ring;

wherein each of A, B, C and D is optionally independently substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino or cyano, and wherein a nitrogen atom in any of rings A, B, C and D is not directly connected to a heteroatom or with a carbon atom to which another heteroatom is directly attached.

[87] In other embodiments, PTM has a chemical structure of formula III or IV, wherein A, B, and C are 5- or 6-membered fused aryl or heteroaryl rings, L _PTM is selected from a bond or alkyl, and D and E are 5- or 6-membered fused aryl or heteroaryl rings, wherein A, B, C, D and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino or cyano.

[88] In certain embodiments, PTM is represented by the following chemical structure:

Where

R ¹ , R ² and R ³ are independently selected from H, methyl, ethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl;

R ⁴ and R ⁵ are independently selected from H, methyl, ethyl and halogen; And

R ⁶ represents 1-2 substituents independently selected from H, methyl, ethyl and halogen,

where RTM is connected to ULM via L.

[89] In any of the aspects or embodiments described herein, the PTM is covalently linked to one or more ULM groups (VLM or CLM) or a linker to which one or more ULM groups (VLM or CLM) is attached, as described in this document.

[90] In certain embodiments, PTM is represented by the chemical structure:

Where

R ¹ , R ² and R ³ are independently selected from H, optionally substituted alkyl, methyl, ethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl; And

R ⁷ , R ⁸ , R ⁹ and R ¹⁰ represent 1-8 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino, trifluoromethyl or cyano, and wherein PTM is bonded to ULM (VLM or CLM) via L.

[91] In certain additional embodiments, PTM is represented by the chemical structure:

[92] In certain embodiments, the point of attachment of the linker to the PTM is indicated by a dotted line:

Illustrative VLMs

[93] In one aspect, ULM is VHL.

[94] In certain embodiments of the compounds described herein, the ULM is a VLM and has a chemical structure selected from the group ULM-a:

Where

wherein the dotted line indicates the attachment of at least one PTM, another ULM or VLM or CLM (i.e., ULM' or VLM' or CLM'), or a chemical linker moiety linking at least one PTM, ULM' or VLM' or CLM' with the other end of the linker;

each of X ¹ , X ² is independently selected from the group consisting of bond, O, NR ^Y3 , CR ^Y3 R ^Y4 , C=O, OS, SO and SO ₂ ;

each of R ^Y3 , R ^Y4 is independently selected from the group consisting of H, straight or branched C _1-6 alkyl, optionally substituted with 1 or more halogen atoms, C _1-6 alkoxy);

R ^P represents 1, 2 or 3 groups, each independently selected from the group consisting of H, halogen, -OH, C _1-3 alkyl;

W ³ is selected from the group consisting of optionally substituted -TN(R ^1a R ^1b ), optionally substituted -TN(R ^1a R ^1b )X ³ , -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;

X ³ represents C=O, R ¹ , R ^1a , R ^1b ;

each of R ¹ , R ^1a , R ^1b is independently selected from the group consisting of an H, straight or branched C ₁ -C ₆ alkyl group, optionally substituted with 1 or more halogen atoms or -OH groups, R ^Y3 C=O, R ^Y3 C=S, R ^Y3 SO, R ^Y3 SO ₂ , N(R ^Y3 R ^Y4 )C=O, N(R ^Y3 R ^Y4 )C=S, N(R ^Y3 R ^Y4 )SO and N(R ^Y3 R ^Y4 )SO ₂ ;

where T is covalently bonded to X1;

W ⁴ is an optionally substituted -NR1-T-aryl, an optionally substituted -NR1-T-heteroaryl group or an optionally substituted -NR1-T heterocycle, where -NR1 is covalently linked to X2 and R1 is H or CH3, preferably H .

[95] In any of the embodiments described herein, T is selected from the group consisting of an optionally substituted alkyl group -(CH ₂ ) _n -, wherein each of the methylene groups is optionally substituted with one or two substituents selected from the group, consisting of a halogen, methyl, linear or branched C ₁ -C ₆ alkyl group, optionally substituted with 1 or more halogen atoms or -OH groups, or an optionally substituted amino acid side chain; And

n is 0-6, often 0, 1, 2 or 3, preferably 0 or 1.

[96] In certain embodiments, W4 is

wherein each of R _14a , R _14b is independently selected from the group consisting of H, haloalkyl or optionally substituted alkyl.

[97] In any of the aspects or embodiments described herein, W ⁵ is selected from the group consisting of phenyl or 5-10 membered heteroaryl,

R ₁₅ is selected from the group consisting of H, halogen, CN, OH, NO ₂ , NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a COR _14b , SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl or cycloheteroalkyl.

[98] In additional embodiments, W ⁴ substituents for use in the present invention also specifically include (and without limitation to the specific compound disclosed) W ⁴ substituents that are found in certain compounds disclosed herein. Each of these W ⁴ substituents may be used in conjunction with any number of W ³ substituents also disclosed herein.

[99] In certain additional embodiments, ULM-a is optionally substituted with 1-3 ^RP groups on the pyrrolidine moiety. Each R ^P is independently H, halogen, -OH, C1-3 alkyl.

[100] In any of the embodiments described herein, W ³ , W ⁴ can be independently covalently linked to a linker to which one or more PTM groups are attached.

and wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to the ULM.

[101] In certain embodiments, the ULM is a VHL and is represented by the structure:

Where

W ³ is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, or

R ₉ and R ₁₀ independently represent hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, 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 selected from the group consisting of optionally substituted heterocyclic group, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

R ₁₂ is selected from the group consisting of H or optionally substituted alkyl;

R ₁₃ is selected from the group consisting of 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;

each of R _14a , R _14b is independently selected from the group consisting of H, haloalkyl or optionally substituted alkyl;

W ⁵ is selected from the group consisting of phenyl or 5-10 membered heteroaryl,

R ₁₅ is selected from the group consisting of H, halogen, CN, OH, NO ₂ , NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a COR _14b , SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl or cycloheteroalkyl (each independently optionally substituted);

R ₁₆ is independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy or optionally substituted haloalkoxy;

o equals 0, 1, 2, 3 or 4;

R ₁₈ is independently selected from the group consisting of halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker; And

p is 0, 1, 2, 3 or 4, and where the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety binding at least one PTM or ULM', or both of them, to ULM.

[102] In certain embodiments, R ₁₅ is where R ₁₇ represents H, halogen, optionally substituted C _3-6 cycloalkyl, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkenyl and C _1-6 haloalkyl; and Xa represents S or O.

[103] In certain embodiments, R ₁₇ is selected from the group consisting of methyl, ethyl, isopropyl and cyclopropyl.

[104] In certain additional embodiments, R ₁₅ is selected from the group consisting of

[105] In certain embodiments, R ₁₁ is selected from the group consisting of

[106] In certain embodiments, the ULM has a chemical structure selected from the group consisting of

Where

R ₁ is H, ethyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl;

R _14a represents H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

R15 is selected from the group consisting of H, halogen, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl or cycloheteroalkyl;

X represents C, CH ₂ or C=O;

R ₃ represents a bond or an optionally substituted 5- or 6-membered heteroaryl; And

wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to a ULM (ULM-a).

[107] In certain embodiments, the ULM provides a group according to the chemical structure:

Where

R _14a represents H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

R ₉ represents H;

R ₁₀ is H, ethyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R11 represents

or optionally substituted heteroaryl;

p equals 0, 1, 2, 3 or 4;

each R ₁₈ independently represents halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker;

R12 represents H, C=O;

R13 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,

R ₁₅ is selected from the group consisting of H, halogen, Cl, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl;

wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to the ULM.

[108] In certain embodiments, the ULM is selected from the following structures:

where n is 0 or 1.

[109] In certain embodiments, the ULM is selected from the following structures:

wherein the phenyl ring in ULM-a1-ULM-a15, ULM-b1-ULM-b12, ULM-c1-ULM-c15 and ULM-d1-ULM-d9 is optionally substituted with fluorine, lower alkyl and alkoxy groups, and wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM-a.

[110] In one embodiment, the phenyl ring in ULM-a1-ULM-a15, ULM-b1-ULM-b12, ULM-c1-ULM-c15 and ULM-d1-ULM-d9 can be functionalized as an ester to make part of the prodrug.

[111] In certain embodiments, the hydroxyl group on the pyrrolidine ring in ULM-a1-ULM-a15, ULM-b1-ULM-b12, ULM-c1-ULM-c15, and ULM-d1-ULM-d9, respectively, contains an ester-linked moiety prodrugs.

[112] In any of the aspects or embodiments described herein, each of ULM and ULM', when present, independently represents a group according to the chemical structure:

Where

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

each of R ₁ and R ₂ in ULM-g independently represents an H or a C ₁ -C ₆ alkyl group, which may be optionally substituted by one or two hydroxyl groups or no more than three groups representing a halogen atom (preferably fluorine);

_RS in ULM-g represents a C ₁ -C ₆ alkyl group, optionally substituted by an aryl, heteroaryl or heterocyclic group or a -(CH ₂ ) _m NR ₁ R ₂ group;

each of X and X' in ULM-g independently represents C=O, C=S, -S(O), S(O) ₂ (preferably both X and X' represent C=O);

R ^2' in ULM-g represents an optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w alkyl group, an optionally substituted -(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 -aryl, optionally substituted -( CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -(CH ₂ ) _n -(C=O) _v NR ₁ (SO ₂ ) _w -heterocycle, optional substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -NR ₁ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optional substituted -NR ¹ -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -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 -X ^R2' -alkyl group; an optionally substituted -X ^R2' -aryl group; an optionally substituted -X ^R2' -heteroaryl group; an optionally substituted -X ^R2' -heterocyclic group; optionally substituted;

R ^3' in ULM-g is optionally substituted alkyl, optionally substituted -(CH ₂ ) _n -(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -(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 -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -(CH ₂ ) _n - C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycle, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -NR ¹ -(CH ₂ )nC(O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycle, optionally substituted -O-(CH ₂ )n-(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -O-(CH ₂ )n-(C= O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -O-(CH ₂ )n-(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C (O)R _1N , optionally substituted -O-(CH ₂ )n-(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -O-(CH ₂ ) _n -(C= O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl or optionally substituted -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 -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -( V) _n' -aryl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -heteroaryl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -heterocyclic group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -alkyl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -aryl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C= O) _m' -(V) _n' -heteroaryl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -heterocyclic group, optionally substituted -X ^R3' is an alkyl group; an optionally substituted -X ^R3' -aryl group; an optionally substituted -X ^R3' -heteroaryl group; an optionally substituted -X ^R3' heterocyclic group; optionally substituted;

each of R _1N and R _2N in ULM-g independently represents H, C ₁ -C ₆ alkyl, which is optionally substituted by one or two hydroxyl groups and no more than three groups representing a halogen atom, or optionally substituted -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -heteroaryl or -(CH ₂ ) _n -heterocyclic group;

V in ULM-g is O, S or NR ₁ ;

R ₁ in ULM-g is the same as above;

each of R ¹ and R _1' in ULM-g independently represents an H or a C ₁ -C ₃ alkyl group;

each of X ^R2' and X ^R3' in ULM-g is 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 represents H, halogen or C ₁ -C ₃ alkyl group, which optionally substituted;

each m in ULM-g is independently equal to 0, 1, 2, 3, 4, 5, 6;

each m' in ULM-g is independently 0 or 1;

each n in ULM-g is independently equal to 0, 1, 2, 3, 4, 5, 6;

each n' in ULM-g is independently 0 or 1;

each u in ULM-g is independently 0 or 1;

each v in ULM-g is independently 0 or 1;

each w in ULM-g is independently 0 or 1; And

any one or more of R ^1' , R ^2' , R ³ ', X and X' in ULM-g are optionally modified to be covalently linked to a PTM group via a linker group if the PTM is not ULM', or if the PTM is ULM', then any one or more of R ^1' , R ^2' , R ^3' , X and X' in each of ULM and ULM' are optionally modified to be covalently linked to each other directly or via a linker group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[113] In any of the aspects or embodiments described herein, each of ULM and ULM', when present, independently represents a group according to the chemical structure:

Where

each of R ^1' , R ² and R ^3' in ULM-h is the same as above, and X represents a C=O, C=S, -S(O) group or an S(O) ₂ group. more preferably the C=O group, and

any one or more of R ^1' , R ^2' and R ^3' in ULM-h are optionally modified to bind to a linker group to which a PTM group is further covalently linked, if PTM is not ULM', or if PTM is is ULM', then any one or more of R ^1' , R ^2' , R ^3' in each of ULM and ULM' are optionally modified to be covalently linked to each other directly or via a linker group, or

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

[114] In any of the aspects or embodiments described herein, each of ULM and ULM', when present, independently corresponds to the chemical structure:

Where

any one or more of R ^1' , R ^2' and R ^3' in ULM-I are optionally modified to bind to a linker group to which a PTM group is further covalently linked if PTM is not ULM', or if PTM is is ULM', then any one or more of R ^1' , R ^2' , R ^3' in each of ULM and ULM' are optionally modified to be covalently linked to each other directly or via a linker group, or

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

[115] In further preferred aspects of the present invention, R ^1' in ULM-g - ULM-i preferably represents a hydroxyl group or a group that can be metabolized to a hydroxyl or carboxyl group, whereby the compound is a prodrug form of the active compound. Exemplary 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 -(CH ₂ ) _n OC(O)-(C ₁ -C ₆ alkyl) or optionally substituted -(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 amino group, then the hydroxyl group, carboxylic acid group, or amino group (each of which may be optionally substituted) may be further chemically modified to provide a covalent bond with a linker group to which the PTM group (including the ULM' group) is linked;

[116] X and X', when present in ULM-g and ULM-h, are preferably a C=O, C=S, -S(O) group or an S(O) ₂ group, more preferably a C=O group ;

[117] R ^2' in ULM-g - ULM-i is preferably an optionally substituted -NR ¹ -T-aryl group, an optionally substituted -NR ¹ -T-heteroaryl group or an optionally substituted -NR ¹ -T-heterocycle, wherein R ¹ represents H or CH ₃ , preferably H, and T represents an optionally substituted -(CH ₂ ) _n group, wherein each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, a side chain of an amino acid, as follows described herein, or a C ₁ -C ₃ alkyl group, preferably one or two methyl groups, which may be optionally substituted; and n is 0-6, often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T may also be a -(CH ₂ O) _n - group, -(OCH ₂ ) _n - group, -(CH ₂ CH ₂ O) _n -, group (OCH ₂ CH ₂ O) _n -, all groups of which are optionally substituted.

[118] Preferred aryl groups for R ^2' in ULM-g to ULM-i include optionally substituted phenyl or naphthyl groups, preferably phenyl groups wherein the phenyl or naphthyl group is optionally connected to a PTM group (including a ULM' group) via a linker group, 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 a 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 as such is optionally connected to a PTM group (including a ULM group ') via a linker group) and/or at least one of F, Cl, OH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN group (in ortho-, meta- and/or para- positions of the phenyl ring, preferably para-), a naphthyl group, which may be optionally substituted, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including a methyl substituted isoxazole, an optionally substituted oxazole, including a methyl substituted oxazole, an 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 a pure diazole group, in including a methyldiazole group, an optionally substituted triazole group, including a methyl-substituted triazole group, an optionally substituted pyridine group, including a halo- (preferably F) or methyl-substituted pyridine group or an oxapyridine group (wherein the pyridine group is connected to the phenyl group by an oxygen atom ), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3 or 4-azaindolizine), optionally substituted quinoline, optionally substituted group according to the chemical structure:

Where

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, 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 no more than three halogen-containing groups (for example, CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or at most three groups, representing a halogen atom), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or optionally substituted -C(O)(C ₁ - C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each group of which optionally substituted with one or two hydroxyl groups or at most three groups representing a halogen atom, preferably a fluorine atom, or an optionally substituted phenyl group, an optionally substituted heteroaryl or an optionally substituted heterocycle, preferably, for example, piperidine, morpholine, pyrrolidine, tetrahydrofuran);

R ^PRO in ULM-g - ULM-i is H, optionally substituted 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, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a group representing a halogen atom, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

each of R ^PRO1 and R ^{PRO2 in ULM-g - ULM-i} independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group; And

each n in ULM-g - ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), or is an optionally substituted heterocycle, preferably tetrahydrofuran, tetrahydrothiene, piperidine, piperazine or morpholine ( each group of which, if substituted, is preferably substituted with methyl or halogen (F, Br, Cl)), each group of which may optionally be connected to a PTM group (including a ULM' group) via a linker group.

[119] In certain preferred aspects in ULM-g - ULM-i represents a group

where R ^PRO and n in ULM-g - ULM-i are the same as above.

[120] Preferred heteroaryl groups for R ² in ULM-g - ULM-i include optionally substituted quinoline (which can be attached to a pharmacophore or substituted at any carbon atom on 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, an optionally substituted diazole, an optionally substituted triazole, a tetrazole, an optionally substituted oximidazole, or a group according to the chemical structure:

Where

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, 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 no more than three halogen-containing groups (eg CF ₃ )), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or an optionally substituted acetylene group -C≡CR _a , where R _a in ULM-g - ULM-i represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or at most three groups, representing a halogen atom), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or optionally substituted -C(O)(C ₁ - C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or C(O)(C ₁ -C ₆ alkyl), each group of which is optional substituted with one or two hydroxyl groups or at most three groups representing a halogen atom, preferably a fluorine atom, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

Y ^C in ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or at most three halogen-containing groups (for example, CF ₃ )), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or at most three groups representing a halogen atom ) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl), each group of which may optionally be connected to a PTM group (including including the ULM' group) via a linker group.

[121] Preferred heterocyclic groups for R ^2' in ULM-g - ULM-i include tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane or thiane, each group of which may be optionally substituted, or a group according to with chemical structure:

preferably a group

Where

R ^PRO in ULM-g - ULM-i represents H, an optionally substituted C ₁ -C ₆ alkyl or an optionally substituted aryl, heteroaryl or heterocyclic group;

each of R ^PRO1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group; And

each n in ULM-g - ULM-i is independently equal to 0, 1, 2, 3, 4, 5 or 6 (often 0 or 1), each group of which may optionally be connected to a PTM group (including a ULM' group ) via a linker group.

[122] Preferred R ^2' substituents in ULM-g - ULM-i also specifically include (and without limitation to the specific compound disclosed) R ^2' substituents that are found in certain compounds disclosed herein (which include specific compounds that are disclosed in this description and the accompanying graphic materials). Each of these R ^2' substituents may be used in conjunction with any number of R ^3' substituents also disclosed herein.

[123] R ³ in ULM-g - ULM-i is 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 represents H or a C ₁ -C ₃ alkyl group, preferably H or CH ₃ , T represents an optionally substituted -(CH ₂ ) _n group wherein each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, a C ₁ -C ₃ alkyl group or an amino acid side chain as further described herein, preferably methyl, which may be optionally substituted; and n is 0-6, often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T may also be a -(CH ₂ O) _n - group, a -(OCH ₂ ) _n group, a - group (CH ₂ CH ₂ O) _n -, group -(OCH ₂ CH ₂ ) _n , each group of which is optionally substituted.

[124] Preferred aryl groups for R ³ in ULM-g to ULM-i include optionally substituted phenyl or naphthyl groups, preferably phenyl groups wherein the phenyl or naphthyl group is optionally connected to a PTM group (including a ULM' group) via a linker group and/or a halogen (preferably F or Cl), an amine, a monoalkyl or dialkylamine (preferably a dimethylamine), an amido group (preferably a (CH ₂ ) _m -NR ₁ C(O)R ₂ group, where m, R ₁ and R ₂ are same as above), halogen (often F or Cl), OH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ , CN or _S (O) ₂ RS group ( _RS is C ₁ - a C ₆ alkyl group, an optionally substituted aryl, 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 phenyl substituent group is an optionally substituted phenyl group (i.e., the phenyl substituent itself is preferably substituted by 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 a ULM' group), where the substitution occurs at the ortho, meta and/or para positions of the phenyl ring, preferably para), a naphthyl group which may be optionally substituted, including as described above, 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, benzylimidazole or methoxybenzylimidazole, oxymidazole or methyloximidazole, optionally substituted diazole group, including methyldiazole group, optionally substituted triazole group, including methyl-substituted triazole group, pyridine group, in including a halogen (preferably F) or methyl substituted pyridine group or oxapyridine group (where the pyridine group is connected to the phenyl group by an oxygen atom), or an optionally substituted heterocycle (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane or tian). Each of the aryl, heteroaryl or heterocyclic groups may optionally be connected to a PTM group (including a ULM' group) via a linker group.

[125] Preferred heteroaryl groups for R ³ in ULM-g - ULM-i include optionally substituted quinoline (which may be attached to a pharmacophore or substituted at any carbon atom on the quinoline ring), optionally substituted indole (including dihydroindole), optionally Subscribed indolizin, not necessarily replaced by azaldolysis (2, 3 or 4 azindolisine), optionally substituted gasymidazole, benzodiazole, benzofuran, optionally substituted imidazole, optionally substituted Isoxazole, optionally replaced oxazole (preferably methyl-membrane), not mandatory diaazole, not necessarily noticeable triasol, teterazol. , 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 a methyl group, triisopropylsilyl group, optionally substituted -(CH ₂ ) _m -OC ₁ -C ₆ alkyl group or optionally substituted -(CH ₂ ) _m -C(O)-O-C ₁ -C ₆ alkyl group), optionally substituted pyridine (2-, 3 or 4-pyridine) or group according to chemical structure:

Where

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, 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 no more than three halogen-containing groups (for example, CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or at most three groups, representing a halogen atom), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or optionally substituted -C(O)(C ₁ - C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each group of which optionally substituted with one or two hydroxyl groups or with at most three groups representing a halogen atom, preferably a fluorine atom, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, And

Y ^C in ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or at most three halogen-containing groups (for example CF ₃ )), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or at most three groups representing a halogen atom) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably a C ₁ -C ₃ alkyl). Each of these heteroaryl groups may optionally be connected to a PTM group (including a ULM' group) via a linker group.

[126] Preferred heterocyclic groups for R ³ in ULM-g - ULM-i include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane and thiane, each group of which may be optionally substituted, or a group according to chemical structure:

preferably a group

Where

R ^PRO in ULM-g - ULM-i is H, optionally substituted 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, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a group representing a halogen atom, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

each of R ^PRO1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group, and

each n in ULM-g - ULM-i is 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), where each of said heterocyclic groups may optionally be connected to a PTM group (including a ULM group ') via a linker group.

[127] Preferred R ^3' substituents in ULM-g - ULM-i also specifically include (and without limitation to the specific compound disclosed) R ^3' substituents that are found in certain compounds disclosed herein (which include specific compounds that are disclosed in this description and the accompanying graphic materials). Each of these R ^3' substituents may be used in conjunction with any number of R ^2' substituents also disclosed herein.

[128] In certain alternative preferred embodiments, R ^2' in ULM-g - ULM-i 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-NO or optionally substituted -NR ₁ -X ^R2' -NO-aryl,

Where

R ₁ in ULM-g - ULM-i represents H or a C ₁ -C ₃ alkyl group (preferably H);

X ^R2' in ULM-g - ULM-i 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; And

X _v in ULM-g - ULM-i represents H, halogen or a C ₁ -C ₃ alkyl group, which is optionally substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom;

alkyl in ULM-g - ULM-i is an optionally substituted C1- _C10 alkyl (preferably _C1 - _C6 alkyl) group (in certain preferred embodiments, the alkyl group is terminated by a group representing a halogen atom, often Cl or Br );

the aryl in ULM-g - ULM-i is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); And

NO in ULM-g - ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine , benzofuran, indole, indolizine, azaindolizine, quinoline (wherein, if substituted, each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a group representing a halogen atom, preferably F or Cl) or a group according to the chemical structure:

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, 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 no more than three halogen-containing groups (for example, CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or at most three groups, representing a halogen atom), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or optionally substituted -C(O)(C ₁ - C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each group of which optionally substituted with one or two hydroxyl groups or at most three groups representing a halogen atom, preferably a fluorine atom, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C in ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or no more than three halogen-containing groups (e.g. CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted by one or two hydroxyl groups or no more than three groups representing a halogen atom) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably a C ₁ -C ₃ alkyl);

R ^PRO in ULM-g - ULM-i is H, optionally substituted 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, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a group representing a halogen atom, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

each of R ^PRO1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group, and

each n in ULM-g - ULM-i is independently equal to 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1).

[129] Each of these groups may optionally be connected to a PTM group (including a ULM' group) via a linker group.

[130] In certain alternative preferred embodiments of the present invention, R ^3' in ULM-g - ULM-i is an optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n group _' -R ^S3' , an optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -R ^S3' group, an optionally substituted -X ^R3' -alkyl group, an optionally substituted -X ^R3' -aryl group; an optionally substituted -X ^R3' -NO group, an optionally substituted -X ^R3' -aryl-NO group or an optionally substituted -X ^R3' -NO-aryl group,

Where

R ^S3' represents an optionally substituted alkyl group (C ₁ -C ₁₀ , preferably C ₁ -C ₆ alkyl), an optionally substituted aryl group or a NO group;

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

V represents O, S or NR ₁ ;

X ^R3' represents -(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 of which are optionally substituted;

X _v represents H, halogen or a C ₁ -C ₃ alkyl group, which is optionally substituted with one or two hydroxyl groups or at most three groups representing a halogen atom;

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 by a group representing a halogen atom, often Cl or Br);

aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); And

NO represents an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine , quinoline (if substituted, each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a group representing a halogen atom, preferably F or Cl) or a group according to the chemical structure:

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, 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 no more than three halogen-containing groups (for example, CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or at most three groups, representing a halogen atom), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or optionally substituted -C(O)(C ₁ - C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₀ -C ₆ alkyl), each group of which optionally substituted with one or two hydroxyl groups or at most three groups representing a halogen atom, preferably a fluorine atom, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C in ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or no more than three halogen-containing groups (e.g. CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted by one or two hydroxyl groups or no more than three groups representing a halogen atom) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably a C ₁ -C ₃ alkyl);

R ^PRO in ULM-g - ULM-i is H, optionally substituted 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, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a group representing a halogen atom, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

each of R ^PRO1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group;

each n in ULM-g - ULM-i is independently equal to 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1);

every m' in ULM-g - ULM-i is 0 or 1; And

every n' in ULM-g - ULM-i is 0 or 1;

wherein each of these compounds, preferably with alkyl, aryl or Het groups, is optionally connected to a PTM group (including a ULM' group) via a linker group.

[131] In alternative embodiments, R ³ ' in ULM-g - ULM-i is -(CH ₂ ) _n -aryl, (CH ₂ CH ₂ O) _n -aryl, -(CH ₂ ) _n -NO, or - (CH ₂ CH ₂ O) _n - NO,

Where

said aryl in ULM-g - ULM-i is phenyl which is optionally substituted with one or two substituents, where said substituent(s) are preferably selected from -(CH ₂ ) _n OH, C ₁ -C ₆ alkyl, which itself is optionally further substituted with CN, halogen (not more than three groups representing a halogen atom), OH, -(CH ₂ ) _n O(C ₁ -C ₆ )alkyl, amine, mono- or a di-(C ₁ -C ₆ alkyl)amine, wherein the alkyl group on the amine is optionally replaced by 1 or 2 hydroxyl groups or by no more than three groups representing a halogen atom (preferably F, Cl), or

the specified aryl group in ULM-g - ULM-i is replaced by -(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 replaced by 1 or 2 hydroxyl groups or not more than three groups representing a halogen atom (preferably F, Cl), CN, NO ₂ , optionally substituted -(CH ₂ ) _n -(V) _m' -CH ₂ ) _n -(V) _m' - (C ₁ -C ₆ )alkyl group, group -(V) _m' -(CH ₂ CH ₂ O) _n -R ^PEG , where V represents O, S or NR _1' , R _1' represents H or C _{a 1} -C ₃ alkyl group (preferably H), and R ^PEG is an H or a C ₁ -C ₆ alkyl group that is optionally substituted (including optionally substituted with a carboxyl group), or

said aryl group in ULM-g - ULM-i is optionally substituted with a heterocycle, including a heteroaryl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolysine, azaindolysine (wherein, if substituted, each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a group representing an atom halogen, preferably F or Cl) or group according to the chemical structure:

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, 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 no more than three halogen-containing groups (for example, CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or at most three groups, representing a halogen atom), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or optionally substituted -C(O)(C ₁ - C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or C(O)(C ₀ -C ₆ alkyl), each group of which is optional substituted with one or two hydroxyl groups or at most three groups representing a halogen atom, preferably a fluorine atom, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C in ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or no more than three halogen-containing groups (e.g. CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted by one or two hydroxyl groups or no more than three groups representing a halogen atom) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably a C ₁ -C ₃ alkyl);

R ^PRO in ULM-g - ULM-i is H, optionally substituted 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, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a group representing a halogen atom, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

each of R ^PRO1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group;

NO in ULM-g - ULM-i is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a group representing a halogen atom, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine or group according to the chemical structure:

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, 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 no more than three halogen-containing groups (for example, CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or at most three groups, representing a halogen atom), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom) or optionally substituted -C(O)(C ₁ - C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three groups representing a halogen atom);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or C(O)(C ₀ -C ₆ alkyl), each group of which is optional substituted with one or two hydroxyl groups or at most three groups representing a halogen atom, preferably a fluorine atom, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C in ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or no more than three halogen-containing groups (e.g. CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted by one or two hydroxyl groups or no more than three groups representing a halogen atom) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably a C ₁ -C ₃ alkyl);

R ^PRO in ULM-g - ULM-i represents H, an optionally substituted C ₁ -C ₆ alkyl or an optionally substituted aryl, heteroaryl or heterocyclic group;

each of R ^PRO1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group;

each m' in ULM-g - ULM-i is independently 0 or 1; And

each n in ULM-g - ULM-i is independently equal to 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1),

wherein each of said compounds, preferably with said aryl or NET groups, is optionally connected to a PTM group (including a ULM' group) via a linker group.

[132] In yet further embodiments, preferred compounds include compounds according to chemical structure:

Where

R ^1' in ULM-i represents OH or a group that is metabolized in the patient or subject to OH;

R ^2' in ULM-i is -NH-CH ₂ -aryl-NET (preferably phenyl coupled directly to a methyl-substituted thiazole);

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

R ^CR3' in ULM-i represents a C ₁ -C ₄ alkyl group, preferably methyl, isopropyl or tert-butyl;

R ^3P1 in ULM-i is a C ₁ -C ₃ alkyl (preferably methyl), an optionally substituted oxetane group (preferably a methyl substituted -(CH ₂ ) _n OCH ₃ group, where n is 1 or 2 (preferably 2), or a (the ethyl ether group is preferably substituted on the phenyl moiety in the meta position), a morpholine group (connected to a carbonyl at the 2 or 3 position;

R ^3P2 in ULM-i represents the group

aryl in ULM-i is phenyl;

NO in ULM-i is an optionally substituted thiazole or isothiazole; And

R ^HET in ULM-i is H or a halogen group (preferably H);

or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, wherein each of these compounds is optionally connected to a PTM group (including a ULM' group) via a linker group.

[133] In certain aspects, bifunctional compounds contain an E3 ubiquitin ligase binding moiety (ULM), where ULM is a group according to the chemical structure:

Where

each of R ₅ and R ₆ in ULM-j independently represents 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 in ULM-j represents H or optionally substituted alkyl;

E in ULM-j represents a bond, C=O or C=S;

G in ULM-j represents a bond, optionally substituted alkyl, -COOH or C=J;

J in ULM-j represents O or NR ₈ ;

R ₈ in ULM-j is H, CN, optionally substituted alkyl or optionally substituted alkoxy;

M in ULM-j represents an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclic group, or

R ₉ and R ₁₀ in ULM-j are each independently H; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide-linked ULM, 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 in ULM-j is an optionally substituted heterocyclic group, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

R ₁₂ in ULM-j represents H or optionally substituted alkyl;

R ₁₃ in ULM-j 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 in ULM-j independently represents H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl;

R ₁₅ in ULM-j is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl;

each R ₁₆ in ULM-j independently represents halogen, optionally substituted alkyl, optionally substituted haloalkyl, CN or optionally substituted haloalkoxy;

each R ₂₅ in ULM-j independently represents H or optionally substituted alkyl; or both R ₂₅ groups can be taken together to form an oxo or optionally substituted cycloalkyl group;

R ₂₃ in ULM-j is H or OH;

Z ₁ , Z ₂ , Z ₃ and Z ₄ in ULM-j are independently C or N; And

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

[134] In certain embodiments, where G in ULM-j is C=J, J is O, _R7 is H, each _R14 is H, and o is 0.

[135] In certain embodiments, wherein G in ULM-j is C=J, J is O, R ₇ is H, each R ₁₄ is H, R ₁₅ is optionally substituted heteroaryl, and O is 0 In other cases, E represents C=O, and M represents

[136] In certain embodiments, where E in ULM-j is C=O, R ₁₁ is an optionally substituted heterocyclic group, or and M represents

[137] In certain embodiments, where E in ULM-j is C=O, M is and R ₁₁ represents each R ₁₈ independently represents halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl or haloalkoxy; and p equals 0, 1, 2, 3 or 4.

[138] In certain embodiments, each of ULM and ULM', when present, independently represents a group according to chemical structure:

Where

G in ULM-k represents C=J, J represents O;

R ₇ in ULM-k is H;

each R ₁₄ in ULM-k represents H;

o in ULM-k is 0;

R ₁₅ in ULM-k represents And

R ₁₇ in ULM-k is H, halogen, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl and haloalkyl.

[139] In other cases, R ₁₇ in ULM-k is alkyl (eg, methyl) or cycloalkyl (eg, cyclopropyl).

[140] In other embodiments, each of ULM and ULM', when present, independently represents a group according to the chemical structure:

Where

G in ULM-k represents C=J, J represents O;

R ₇ in ULM-k is H;

each R ₁₄ in ULM-k represents H;

o in ULM-k is 0; And

R ₁₅ in ULM-k is selected from the group consisting of:

where R ₃₀ in ULM-k represents H or optionally substituted alkyl.

[141] In other embodiments, each of ULM and ULM', when present, independently represents a group according to the chemical structure:

Where

E in ULM-k is C=O;

M in ULM-k represents And

R ₁₁ in ULM-k is selected from the group consisting of:

[142] In yet other embodiments, the compound has the chemical structure:

Where

E in ULM-k represents C=O;

R ₁₁ in ULM-k represents And

The M in ULM-k represents ;

q in ULM-k is 1 or 2;

R ₂₀ in ULM-k is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or

R ₂₁ in ULM-k represents H or optionally substituted alkyl; And

R ₂₂ in ULM-k is H, optionally substituted alkyl, optionally substituted alkoxy or haloalkyl.

[143] In any embodiment described herein, R ₁₁ in ULM-j or ULM-k is selected from the group consisting of:

[144] In certain embodiments, R ₁₁ in ULM-j or ULM-k is selected from the group consisting of:

[145] In certain embodiments, the ULM (or ULM' when present) is a group according to the chemical structure:

Where

X in ULM-1 represents O or S;

Y in ULM-1 is H, methyl or ethyl;

R ₁₇ in ULM-1 is H, methyl, ethyl, hydroxymethyl or cyclopropyl;

M in ULM-1 is optionally substituted aryl, optionally substituted heteroaryl, or

R _{9 in ULM-1} is H;

R ₁₀ in ULM-1 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl;

R11 in ULM-1 is an optionally substituted heteroaromatic group, an optionally substituted heterocyclic group, an optionally substituted aryl group, or

R ₁₂ in ULM-1 represents H or optionally substituted alkyl; And

R ₁₃ in ULM-1 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.

[146] In some embodiments, each of ULM and ULM', when present, independently represents a group according to chemical structure:

Where

Y in ULM-m is H, methyl or ethyl;

R ₉ in ULM-m is H;

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

R ₁₁ in ULM-m represents an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isooxazole, an optionally substituted heterocycle.

[147] In other preferred embodiments of the present invention, each of ULM and ULM', when present, independently represents a group according to the chemical structure:

Where

R ₁₇ in ULM-n is methyl, ethyl or cyclopropyl; And

R ₉ , R ₁₀ and R ₁₁ in ULM-n are defined above. In other cases, R ₉ represents H; And

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

[148] In any of the aspects or embodiments described herein, ULM (or ULM' when present) as described herein may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. Additionally, in any of the aspects or embodiments described herein, the ULM (or ULM' when present) as described herein may be linked to the PTM directly via a bond or chemical linker.

[149] In certain aspects of the present invention, the ULM fragment is selected from the group consisting of:

wherein the VLM may be linked to the PTM by a linker as described herein at any suitable position, including, for example, an aryl, heteroaryl, phenyl, or phenyl indole group, optionally by any suitable functional group, such as an amine, a complex ether, ether, alkyl or alkoxy.

Illustrative CLMs

[150] In any aspect or embodiment described herein, compounds useful for binding and/or inhibiting cereblon are disclosed (e.g., ULM is CLM, PTM is CLM, or both ULM and PTM are CLM ).

[151] In some embodiments, the ULM is a CLM that is tapidomide, lenapidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.

Neoimide compounds

[152] In certain embodiments, the CLM is selected from the group consisting of chemical structures:

Where

W is selected from the group consisting of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

each X is independently selected from the group consisting of O, S and H ₂ ;

Y is selected from the group consisting of CH ₂ , -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Z is selected from the group consisting of O, S and H ₂ ;

G and G' are independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted with R'), OH, R'OCOOR, R'OCONRR'', CH ₂ -heterocyclyl, optionally substituted with R', and benzyl, optionally substituted R';

Q ₁ , Q ₂ , Q ₃ and Q ₄ represent a C carbon atom substituted by a group independently selected from R', N or N-oxide;

A is independently selected from the group consisting of H, alkyl, cycloalkyl, Cl and F;

R provides without limitation -CONR'R'', -OR', -NR'R'', -SR', -SO ₂ R', -SO ₂ NR'R'', -CR'R''-, - CR'NR'R''-, -aryl, -heteroaryl, -alkyl (linear, branched, optionally substituted), -cycloalkyl, -heterocyclyl, P(O)(OR')R'', -P(O)R 'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF ₃ , -CN, -NR 'SO ₂ NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR 'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO ₂ )NR'R'', -SO ₂ NR'COR'', -NO ₂ , - CO ₂ R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF ₅ or -OCF ₃ ;

R' and R'' are independently selected from the group consisting of a bond, H, N, N-oxide, alkyl (straight, branched), cycloalkyl, aryl, heteroaryl, heterocyclic group, -C(=O)R or heterocyclyl, each of which is optionally substituted;

is a bond that may or may not provide a stereospecific configuration ((R) or (S)); And

_Rn provides a functional group or atom,

where n is an integer from 1 to 4, and where

if n is 1, then R _n is modified to covalently bind to the linker group (L), and

if n is 2, 3 or 4, then one R _n is modified to covalently bind to a linker group (L), and any other R _n is optionally modified to covalently bind to a PTM, a CLM, a second CLM having the same chemical a structure such as CLM, CLM', a second linker, or any plurality or combination thereof.

Illustrative CLMs

[153] In any of the compounds described herein, the CLM provides a chemical structure selected from the group

Where

W is independently selected from the group consisting of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

X is independently selected from the group; consisting of O, S and H ₂ ;

Y is independently selected from the group consisting of CH ₂ , -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Z is independently selected from the group consisting of O and S or H ₂ except that both X and Z may not be H 2 ;

G and G' are independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted with R'), OH, R'OCOOR, R'OCONRR'', CH ₂ -heterocyclyl, optionally substituted with R', and benzyl, optionally substituted R';

Q1 to Q4 represent a C carbon atom substituted by a group independently selected from R', N or N-oxide;

A is independently selected from the group consisting of H, alkyl, cycloalkyl, C1 and F;

R provides without limitation -CONR'R'', -OR', -NR'R'', -SR', -SO ₂ R', -SO ₂ NR'R'', -CR'R''-, - CR'NR'R''-, -aryl, -heteroaryl, -alkyl (linear, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -P(O)(OR')R'', -P(O) R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF3, -CN, -NR 'SO2NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R '', -NR'C(=N-CN)R'', -NR'C(=C-NO ₂ )NR'R'', -SO ₂ NR'COR'', -NO ₂ , -CO ₂ R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF ₅ or -OCF ₃ ;

R' and R'' are independently selected from the group consisting of a bond, H, N, N-oxide, alkyl (straight, branched), cycloalkyl, aryl, heteroaryl, heterocyclic group, -C(=O)R or heterocyclyl, each of which is optionally substituted;

n is an integer from 1 to 4;

is a bond that may or may not provide a stereospecific configuration ((R) or (S)); And

Rn contains 1-4 independent functional groups or atoms, and optionally one of them is modified so as to covalently bind to ABM, a chemical linker group (L), ULM, CLM (or CLM'), or the combination.

[154] In certain embodiments described herein, the CLM or ULM provides a chemical structure selected from the group:

Where

W is independently selected from the group consisting of CH ₂ , C=O, NH and N-alkyl;

R is independently selected from H, methyl, alkyl;

is a bond that may or may not provide a stereospecific configuration ((R) or (S)); And

Rn contains 1-4 independently selected functional groups or atoms, and optionally one of them is modified to covalently bind to a PTM, a chemical linker group (L), a CLM (or CLM'), or a combination thereof .

[155] In some embodiments, the CLM is represented by the following structures, with dotted lines indicating linker attachment points:

[156] More specifically, non-limiting examples of CLMs include the CLMs shown below, as well as “hybrid” CLM molecules that are formed by the combination of 1 or more different features shown in the molecules below.

[157] In any of the compounds described herein, the CLM provides a chemical structure selected from the group:

Where

W in formulas (h)-(ab) is independently selected from CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ in formulas (h)-(ab) independently represent a C carbon atom substituted by a group independently selected from R', N or N-oxide;

R ¹ in formulas (h)-(ab) is selected from H, CN, C1-C3-alkyl;

R ² in formulas (h)-(ab) is selected from the group consisting of H, CN, C1-C3 alkyl, CHF ₂ , CF ₃ , CHO;

R ³ in formulas (h)-(ab) is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R ⁴ in formulas (h)-(ab) is selected from H, alkyl, substituted alkyl;

R ⁵ in formulas (h)-(ab) represents H or lower alkyl;

X in formulas (h)-(ab) represents C, CH or N;

R' in formulas (h)-(ab) is selected from H, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R in formulas (h)-(ab) represents H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy or halogenated lower alkyl;

in formulas (h)-(ab) represents a single or double bond; And

CLM is covalently linked to a PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[158] In any aspect or embodiment described herein, CLM or CLM' is covalently linked to a PTM, a chemical linker group (L), ULM, CLM, CLM', or a combination thereof via an R group (such as R, R ¹ , R ² , R ³ , R ⁴ or R'), W, X or Q groups (such as Q ₁ , Q ₂ , Q ₃ , Q ₄ or Q ₅ ) from formulas (h)-(ab).

[159] In any of the embodiments described herein, CLM or CLM' is covalently linked to a PTM, a chemical linker group (L), ULM, CLM, CLM', or a combination thereof via W, X, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R', Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ from formulas (h)-(ab).

[160] In any of the embodiments described herein, W, X, R ¹ , R ² , R ³ , R ⁴ , R', Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ of formulas ( h)-(ab) may be independently covalently linked to a linker and/or a linker to which one or more PTM, ULM, ULM', CLM or CLM' groups are attached.

[161] More specifically, non-limiting examples of CLMs include the CLMs shown below, as well as “hybrid” molecules or compounds that are formed by the combination of 1 or more features of the following compounds:

Where

W in formulas (ac)-(an) is independently selected from the group consisting of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

R ¹ in formulas (ac)-(an) is selected from the group consisting of H, CN, C1-C3 alkyl;

R ³ in formulas (ac)-(an) is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R in formulas (ac)-(an) represents H;

represents a single or double bond; And

Rn in formulas (ac)-(an) provides a functional group or atom.

[162] In any of the embodiments described herein, W, R ¹ , R ² , Q ₁ , Q ₂ , Q ₃ , Q ₄ and Rn in formulas (ac)-(an) can be independently covalently linked to a linker and/or a linker to which one or more PTM, ULM, ULM', CLM or CLM' groups are attached.

[163] In any of the embodiments described herein, R ¹ , R ² , Q ₁ , Q ₂ , Q ₃ , Q ₄ and Rn in formulas (ac)-(an) may be independently covalently linked to the linker and /or a linker to which one or more PTM, ULM, ULM', CLM or CLM' groups are attached.

[164] In any of the embodiments described herein, Q ₁ , Q ₂ , Q ₃ , Q ₄ and Rn in formulas (ac)-(an) can be independently covalently linked to a linker and/or a linker to which one or more PTM, ULM, ULM', CLM or CLM' groups are attached.

[165] In any aspect or embodiment described herein, R _n in formulas (ac)-(an) is modified to covalently bind to a linker group (L), PTM, ULM, a second CLM having the same chemical a structure such as CLM, CLM', a second linker, or any plurality or combination thereof.

[166] In any aspect or embodiment described herein, the CLM is selected from:

where R' represents halogen, and R ¹ is described above in relation to formulas (h)-(ab) or (ac)-(an).

[167] In certain cases, CLM may be imides that bind to the cereblon of the E3 ligase complex. Such imides and the point of attachment of the linker can be represented, without limitation, by the following structures:

where R' represents halogen.

Illustrative Linkers

[168] In any of the aspects or embodiments providing the ULM-L-PTM structure, the linker (L) provides a chemical entity represented by the formula:

Where

A represents a group that is connected to a ULM or PTM moiety; And

q represents an integer that is greater than or equal to 1,

where A is selected from the group consisting of communication, 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≡С, 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 groups ^RL1 and/or ^RL2 , C _3-11 heterocyclyl, optionally substituted with 0-6 groups ^RL1 and/or ^RL2 , aryl, optionally substituted with 0-6 groups ^RL1 and/or ^RL2 , heteroaryl, optionally substituted with 0-6 groups ^RL1 and/or ^RL2 , where each of ^RL1 or ^RL2 is independently optionally combined with other groups to form a cycloalkyl and /or a heterocyclyl fragment, optionally substituted with 0-4 R ^L5 groups;

R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are each independently H, halogen, 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 , NHSO ₂ NH(C _1-8 alkyl), NHSO ₂ N(C _1-8 alkyl) ₂ , NHSO ₂ NH ₂ .

[169] In any aspect or embodiment described herein, the linker (L) provides the following chemical structure:

Where

W ^L1 and W ^L2 are each independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with RQ, wherein each RQ is independently H, halogen, OH, CN, CF3, C1-C6 alkyl (linear , branched, optionally substituted), C1-C6 alkoxy (linear, branched, optionally substituted), or 2 RQ groups, taken together with the atom to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms ;

each Y ^L1 independently represents a bond, C1-C6 alkyl (linear, branched, optionally substituted), and optionally one or more C atoms are replaced by O; or C1-C6 alkoxy (linear, branched, optionally substituted); And

the dotted line indicates the point of attachment to the PTM or ULM fragments.

[170] In any aspect or embodiment described herein, the linker (L) provides the following chemical structure:

or

Where

each of W ^L1 and W ^L2 is independently aryl, heteroaryl, cyclic group, heterocyclic group, C _1-6 alkyl, bicyclic group, biaryl, biheteroaryl or biheterocyclic group, each optionally substituted with R ^Q , with each R ^Q independently represents H, halogen, OH, CN, CF ₃ , hydroxyl, nitro, C≡CH, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ -C ₆ alkyl (linear, branched, optionally substituted), C ₁ -C ₆ alkoxy (linear, branched, optionally substituted), OC _1-3 alkyl (optionally substituted with 1 or more -F), OH, NH ₂ , NR ^Y1 R ^Y2 , CN, or 2 R ^Q groups taken together with an atom , to which they are attached, form a 4-8-membered ring system containing 0-4 heteroatoms;

each Y ^L1 independently represents a bond, NR ^YL1 , O, S, NR ^YL2 , CR ^YL1 R ^YL2 , C=O, C=S, SO, SO ₂ , C ₁ -C ₆ alkyl (linear, branched, optionally substituted) , and optionally one or more C atoms are replaced by O; C ₁ -C ₆ alkoxy (linear, branched, optionally substituted);

^QL is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 ^RQ , wherein each ^RQ is independently H, _C1-6 alkyl (linear, branched, optionally substituted with 1 or more halogen atoms, C _1-6 alkoxyl), or 2 R ^Q groups, taken together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms);

each of R ^YL1 , R ^YL2 independently represents H, OH, C _1-6 alkyl (linear, branched, optionally substituted with 1 or more halogen atoms, C _1-6 alkoxyl), or R ¹ , R ² together with an atom, k to which they are attached form a 3-8-membered ring system containing 0-2 heteroatoms);

n equals 0-10; And

the dotted line indicates the point of attachment to the PTM or ULM fragments.

[171] In some embodiments, the linker (L) includes a group represented by a general structure selected from the group consisting of:

-N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-,

-O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-,

-O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-;

where m, n, o, p, q and r are each independently equal to 0, 1, 2, 3, 4, 5, 6, provided that if the number is zero, then there is no NO or O-O bond; R is selected from the group consisting of H, methyl or ethyl, and X is selected from the group consisting of H or F;

[172] In some further embodiments, the linker (L) is selected from the group consisting of:

[173] In some preferred embodiments, the linker (L) is selected from the group consisting of:

, where each of n and m is independently equal to 0, 1, 2, 3, 4, 5 or 6.

[174] In some embodiments, L is an optionally substituted polyethyleneoxy group containing from 1 to 10 units.

[175] In some further embodiments, L is a polyethylene group, optionally substituted with aryl or phenyl, containing from 1 to 10 ethylene glycol units.

[176] In any embodiment, the compound contains multiple ULMs, multiple PTMs, multiple linkers, or any combination thereof.

Exemplary PROTAC Compounds Targeting Tau Protein

[177] As described above, in certain aspects, provided herein are bifunctional PROTAC compounds containing at least one PTM group, a linker, and at least one ULM group (VLM or CLM) described herein.

[178] In certain embodiments, the compound is selected from the group consisting of compounds 1-330 (eg, selected from Table 1 or 2) and salts and polymorphs thereof.

[179] In certain embodiments, the compound is selected from Table 1 or 2 (ie, the compound is selected from compounds 1-330) and salts and polymorphs thereof.

[180] In any aspect or embodiment described herein, the compound is selected from the formulas CI-CV:

or

Where

R ¹⁰¹ represents 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;

R ¹⁰² is selected from H, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl;

R ¹⁰³ represents 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;

R ¹⁰⁴ represents 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;

R ¹⁰⁵ represents 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;

each of R ¹⁰⁶ , R ^{107 ,} R ¹⁰⁹ , R ¹¹⁰ , R ¹¹¹ , R 112, R ¹¹³ , R ¹¹⁴ , R ¹¹⁶ , R ¹¹⁷ , R ¹²⁰ , R ¹²¹ , R ¹²⁶ , R ¹²⁷ , R ¹²² and R ¹²³ independently selected from H, alkyl, halogen or haloalkyl;

R ¹⁰⁸ represents 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl, cyano or methoxy;

R ¹¹⁵ is selected from H, alkyl and haloalkyl;

R ¹¹⁸ and R ¹¹⁹ are independently selected from H, alkyl, halogen or haloalkyl, or R ¹¹⁸ and R ¹¹⁹ , taken together with the carbon atom to which they are attached, represent a 3-6 membered cycloalkyl or heterocycloalkyl ring such as cyclopropane or oxetane;

R ¹²⁴ and R ¹²⁵ are independently selected from H, alkyl, halogen or haloalkyl, or R ¹²⁴ and R ¹²⁵ , taken together with the carbon atom to which they are attached, represent a 3-6 membered cycloalkyl or heterocycloalkyl ring such as cyclopropane or oxetane;

G represents a phenyl or a 5- or 6-membered heteroaryl ring; And

Z represents CH ₂ or C=O.

[181] Any aspect or embodiment described herein does at least one of:

R ¹⁰¹ represents H, F or Cl;

R ¹⁰² represents H, CH ₃ or CF ₂ H;

R ¹⁰³ represents H or F;

R ¹⁰⁴ represents H, CH ₃ , F or CN;

R ¹⁰⁵ is H, CN, CH ₃ or CF ₃ ;

R ¹⁰⁶ and R ¹⁰⁷ are each independently H, F or CH ₃ ;

R ¹⁰⁸ represents H, F or CH ₃ O;

R ¹⁰⁹ and R ¹¹⁰ are each independently H or CH ₃ ;

R ¹¹¹ and R ¹¹² are each independently H, F or CH ₃ ;

R ¹¹³ and R ¹¹⁴ are each independently H or CH ₃ ;

R ¹¹⁵ represents H or CH ₃ ;

R ¹¹⁶ and R ¹¹⁷ are each independently H or CH ₃ ;

each of R ¹¹⁸ and R ¹¹⁹ independently represents H, CH ₃ , F, or R ¹¹⁸ and R ¹¹⁹ taken together with the carbon atom to which they are attached represent a cyclopropane or oxetane ring;

R ¹²⁰ and R ¹²¹ are each independently H or CH ₃ ;

R ¹²² and R ¹²³ are each independently H or CH ₃ ;

each of R ¹²⁴ and R ¹²⁵ independently represents H, CH ₃ , F, or R ¹²⁴ and R ¹²⁵ taken together with the carbon atom to which they are attached represent a cyclopropane or oxetane ring;

R ¹²⁶ and R ¹²⁷ are each independently H or CH ₃ ;

A is pyridine or pyrimidine;

Z represents CH ₂ or C=O; or

their combination.

[182] In any aspect or embodiment described herein, the compound is selected from the group consisting of: (2S,4R)-1-((S)-14-(5-(5H-pyrido[4,3- b]indol-7-yl)pyridin-2-yloxy)-2-tert-butyl-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-N-(-(4-( 4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (1); 4-(2-(2-(2-(2-(5-(5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yloxy)ethoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (2); 4-(2-(2- (2-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (3); 4-(14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12- tetraoxatetradecylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4); (2S,4R)-1-((S)-2-(2-(2-(2 -(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (5); (2S,4R)-1-((S)-17-(5-(5H-pyrido[4,3-b]indole -7-yl)pyridin-2-yloxy)-2-tert-butyl-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecane)-4-hydroxy-N-(4-(4-methylthiazole -5-yl)benzyl)pyrrolidine-2-carboxamide (6); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide (7); (2S,4R)-1-((S)-2-tert-butyl-15-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12-trioxa -3-azapentadecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (8); (2S,4R)-1-((S)-2-tert-butyl-18-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15 -tetraoxa-3-azaoctadecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (9); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (10 ); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidin-2-carboxamide (11); (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidin-2-carboxamide (12 ); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidin-2-carboxamide (13 ); (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidin-2-carboxamide (14); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide (15); (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl) ethyl)pyrrolidine-2-carboxamide (16); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl) ethyl)pyrrolidine-2-carboxamide (17); (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl) phenyl)ethyl)pyrrolidine-2-carboxamide (18); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide (19); (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl) ethyl)pyrrolidine-2-carboxamide (20); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl) ethyl)pyrrolidine-2-carboxamide (21); (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl) phenyl)ethyl)pyrrolidine-2-carboxamide (22); (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide (23 ); (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert -butyl)-4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (24); 4-((2-(2-(2-(2-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethoxy )ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (25); 4-((14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-3,6,9,12-tetraoxatetradecyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (26); (2S,4R)-1-((S)-2-(2-(2-(2-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)ethoxy)ethoxy)acetamido)-3, 3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (27); (2S,4R)-1-((S)-2-(2-(2-(2-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)ethoxy)ethoxy)acetamido)-3, 3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (28); (2S,4R)-1-((S)-2-tert-butyl-14-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12-trioxa -3-azatetradecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (29); (2S,4R)-1-((S)-2-tert-butyl-14-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12-trioxa -3-azatetradecane)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (30); (2S,4R)-1-((S)-2-tert-butyl-17-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15 -tetraoxa-3-azaheptadecane)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (31); (2S,4R)-1-((S)-2-tert-butyl-17-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15 -tetraoxa-3-azaheptadecane)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (32); (2S,4R)-1-((S)-2-(2-(4-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)butoxy)acetamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (33); (2S,4R)-1-((S)-2-(2-(4-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)butoxy)acetamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (34); (2S,4R)-1-((S)-2-(2-(3-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)propoxy)propoxy)acetamido)-3, 3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (35); (2S,4R)-1-((S)-2-(2-(3-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)propoxy)propoxy)acetamido)-3, 3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (36); (2S,4R)-1-((S)-2-(2-(5-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)pentyloxy)acetamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (37); (2S,4R)-1-((S)-2-(2-(5-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)pentyloxy)acetamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (38); (2S,4R)-1-((S)-2-tert-butyl-18-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15 -tetraoxa-3-azaoctadecane)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (39); 4-(15-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-3,6,9,12-tetraoxapentadecylamino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione (40); 4-((2-(2-(2-(2-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-oxoethoxy) ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (41); 4-((14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl )amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (42); (2S,4R)-1-((2S)-2-tert-butyl-15-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-14-hydroxy-4-oxo-6,9 ,12-trioxa-3-azapentadecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (43); 4-(2-(2-(2-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)propoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3 -yl)isoindoline-1,3-dione (44); 4-(15-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-14-hydroxy-3,6,9,12-tetraoxapentadecylamino)-2-(2,6-dioxopiperidin-3-yl )isoindoline-1,3-dione (45); (2S,4R)-1-((28)-2-tert-butyl-18-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-17-hydroxy-4-oxo-6,9 ,12,15-tetraoxa-3-azaoctadecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (46); 4-(2-(2-(2-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-2-hydroxypropoxy)ethoxy)ethoxy)ethylamino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (47); 2-(2,6-dioxopiperidin-3-yl)-4-(14-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)- 3,6,9,12-tetraoxatetradecylamino)isoindoline-1,3-dione (48); 3-(4-(14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12-tetraoxatetradecylamino)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (49); 3-(4-(14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12-tetraoxatetradecyloxy)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (50); 5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2 -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (51); 5-((5-(4-(2-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propoxy)ethyl)piperazin-1-yl )pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (52); 5-(4-(3-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl) piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (53); 5-((5-(4-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (54); 5-(3-(6-(4-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pyridin- 3-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (55); 5-((5-(4-(2-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)ethyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (56); 5-((14-(4-(5H-pyrido[4,3-b]indol-7-yl)piperidin-1-yl)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (57); 5-((5-(2-(4-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)ethoxy )pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (58); 5-((5-(4-(2-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)ethyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (59); 5-(4-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl) piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (60); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3- b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindoline-1,3-dione (61); 3-(5-((5-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazine-1 -yl)pentyl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (62); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl) -3-(trifluoromethyl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindoline-1,3-dione (63); 5-(4-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy )pyridin-2-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (64); 5-((5-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidine -1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (65); 5-(4-(2-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy )piperidin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (66); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl )pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (67); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)piperazin-1-yl)isoindoline-1,3-dione (68); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-4-(trifluoromethyl )pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (69); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (70); 2-(2,6-dioxopiperidin-3-yl)-5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) -3,6,9,12-tetraoxapentadec-14-yn-1-yl)oxy)isoindoline-1,3-dione (71); 5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2 -(2,6-dioxopiperidin-3-yl)-4,6,7-trifluoroisoindoline-1,3-dione (72); [5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy) pyridin-2-yl)prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione] (73); 2-(2,6-dioxopiperidin-3-yl)-5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) -3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione (74); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)pentyl)oxy)pentyl)piperidin-1-yl)isoindoline-1,3-dione (75); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)pyridin-2-yl)prop-2-yn-1-yl)piperazin-1-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione (76); 5-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin- 2-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (77); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)piperazin-1-yl)isoindoline-1,3-dione (78); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)oxy)azetidin-1-yl)isoindoline-1,3-dione (79); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)azetidin-3-yl)oxy)isoindoline-1,3-dione (80); 5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2 -(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (81); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)isoindoline-1,3-dione (82); 5-((5-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridine -2-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (83); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenoxy)hexyl)oxy)isoindoline-1,3-dione (84); 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-((5-((5-((5-(5-methyl-5H-pyrido[4,3- b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)oxy)cyclobutoxy)isoindoline-1,3-dione (85); 4-((14-(4-(5H-pyrido[4,3-b]indol-7-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidine -3-yl)isoindoline-1,3-dione (86); 6-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2 -(2,6-dioxopiperidin-3-yl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (87); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (88); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3,3,3-trifluoro-2-(2-((5-((5-(5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)ethoxy)propyl)piperidin-1-yl)isoindolin-1,3-dione (89); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-((4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)but-2-yn-1-yl)oxy)butoxy)butoxy)isoindoline-1,3-dione (90); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(8-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)octyl)piperazin-1-yl)isoindoline-1,3-dione (91); 5-((14-((3-chloro-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9, 12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (92); 5-((6-((5-(2,2-difluoro-2-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)ethoxy )pentyl)oxy)hexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (93); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-yl)oxy)isoindoline-1,3-dione (94); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pentyl)oxy)isoindoline-1,3-dione (95); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)-3-(trifluoromethyl)piperazin-1-yl)isoindolin-1,3-dione (96); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione (97); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)hexyl)oxy)isoindoline-1,3-dione (98); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)isoindoline-1,3-dione (99); 2-(2,6-dioxopiperidin-3-yl)-5-(6-(4-(4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl) pyridin-2-yl)oxy)butoxy)butoxy)-2-azaspiro[3.3]heptan-2-yl)isoindoline-1,3-dione (100); 5-((1-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin- 2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (101); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione (102); 5-((14-((5-(8,9-difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12- tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (103); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione (104); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)isoindoline-1,3-dione (105); 2-(2,6-dioxopiperidin-3-yl)-5-((5-((5-(3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)pyridin-2-yl)oxy)azetidin-1-yl)pentyl)oxy)pentyl)oxy)isoindoline-1,3-dione (106); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(6-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl) pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)butoxy)butoxy)isoindoline-1,3-dione (107); 2-(2,6-dioxopiperidin-3-yl)-5-((6-((6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3- b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)oxy)hexyl)oxy)isoindoline-1,3-dione (108); 2-(2,6-dioxopiperidin-3-yl)-5-((6-((4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3- b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)oxy)hexyl)oxy)isoindoline-1,3-dione (109); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hexyl)oxy)isoindoline-1,3-dione (110); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)azetidin-1-yl)isoindolin-1,3- dione (111); 5-((14-((5-(8,9-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6, 9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (112); 5-((14-((4-chloro-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9, 12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (113); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)pentyl)oxy)isoindoline-1,3-dione (114); 2-(2,6-dioxopiperidin-3-yl)-5-((5-((5-((1-(5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)pyridin-2-yl)azetidin-3-yl)oxy)pentyl)oxy)pentyl)oxy)isoindoline-1,3-dione (115); 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)butoxy)butyl)-2-azaspiro[3.3]heptan-6-yl)oxy)isoindoline-1,3-dione (116); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione (117); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)azetidin-1-yl) isoindoline-1,3-dione (118); (2S,4R)-1-((S)-17-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy) -2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5 -yl)phenyl)ethyl)pyrrolidine-2-carboxamide (119); (2S,4R)-1-((S)-2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (120); (2S,4R)-1-((S)-20-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-(tert- butyl)-4-oxo-6,9,12,15,18-pentaoxa-3-azaicosanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl )ethyl)pyrrolidine-2-carboxamide (121); (2S,4R)-1-((S)-23-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-(tert- butyl)-4-oxo-6,9,12,15,18,21-hexaoxa-3-azatricosanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl )phenyl)ethyl)pyrrolidine-2-carboxamide (122); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)isoindoline-1,3-dione (123); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenyl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione (124); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)isoindolin-1,3-dione (125); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)pentyl)oxy)isoindoline-1,3-dione (126); 3-(5-(4-((1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (127); 3-(5-(4-(2-(1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl) ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (128); 2-(2,6-dioxopiperidin-3-yl)-5-((1,1,1-trifluoro-6-(2-(2-(2-((5-(5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)hexan-2-yl)oxy)isoindoline-1,3-dione (129); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-(4-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)propoxy)propoxy)azetidin-1-yl)isoindolin-1,3-dione (130); 2-(2,6-dioxopiperidin-3-yl)-5-((17-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)-3,6,9,12,15-pentaoxaheptadecyl)oxy)isoindoline-1,3-dione (131); 2-(2,6-dioxopiperidin-3-yl)-5-((20-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)-3,6,9,12,15,18-hexaoxaicosyl)oxy)isoindoline-1,3-dione (132); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(6-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)pentyl)oxy)hexyl)azetidin-1-yl)isoindoline-1,3-dione (133); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione (134); 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3- b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione (135); 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutan-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione (136); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)-5-oxopentyl)oxy)isoindoline-1,3-dione (137 ); 5-((14-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12- tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (138); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((3-fluoro-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (139); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((3-methyl-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (140); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrimidin-2-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione (141); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)azetidin-3-yl)oxy) isoindoline-1,3-dione (142); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-6-(trifluoromethyl )pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (143); 2-(2,6-dioxopiperidin-3-yl)-5-(6-(6-((1s,3s)-3-(5-(5-methyl-5H-pyrido[4,3-b]indole -7-yl)pyridin-2-yloxy)cyclobutoxy)pyridin-3-yl)hex-5-ynyloxy)isoindoline-1,3-dione (144); 2-(2,6-dioxopiperidin-3-yl)-5-(6-(6-((1s,3s)-3-(5-(5-methyl-5H-pyrido[4,3-b]indole -7-yl)pyridin-2-yloxy)cyclobutoxy)pyridin-3-yl)hexyloxy)isoindoline-1,3-dione (145); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)propoxy)pyridin-3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione (146); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenyl)hexyl)oxy)isoindoline-1,3-dione (147); 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2 -yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (148); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)hexyl)oxy)isoindoline-1,3-dione (149); 5-(6-(2,2-difluoro-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin- 2-yl)oxy)cyclobutoxy)pentyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (150); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrimidin-2-yl)hexyl)oxy)isoindoline-1,3-dione (151); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)azetidin-3-yl)oxy)isoindolin-1,3- dione (152); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3,3,3-trifluoro-2-((5-((1r,3r)-3-((5-(5- methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)oxy)propyl)azetidin-1-yl)isoindolin-1,3-dione (153) ; 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2,2,2-trifluoro-1-((6-((1r,3r)-3-((5-(5- methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)oxy)ethyl)azetidin-1-yl)isoindolin-1,3-dione (154) ; 2-(2,6-dioxopiperidin-3-yl)-5-(3-((5-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)pyridin-2-yl)oxy)azetidin-1-yl)isoindolin-1,3-dione (155); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindolin-1,3-dione (156); 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutan-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione (157); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridazin-4-yl)oxy)ethoxy)isoindoline-1,3-dione (158); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)azetidin-1-yl)isoindolin-1,3- dione (159); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindolin-1,3-dione (160); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)azetidin-1-yl)isoindolin-1,3-dione (161); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)butoxy)azetidin-1-yl)isoindoline-1,3-dione (162); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)azetidin-1-yl)isoindolin-1,3-dione (163); 5-(6-(4-((1r,3r)-3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)cyclobutoxy)piperidin-1-yl )-6-oxohexyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (164); 5-((5-((1-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutan- 1-carbonyl)piperidin-4-yl)oxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (165); 5-((5-((1((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutan-1 -carbonyl)piperidin-4-yl)oxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (166); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol- 7-yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindolin-1,3-dione (167); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-(3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione (168); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4 ,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)oxetan-3-yl)methoxy)propoxy)azetidin-1-yl)isoindolin-1,3-dione (169); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione (170); 5-((4,4-difluoro-5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (171); 5-((6-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridine -2-yl)hex-5-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (172); 5-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (173); 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3- b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)butoxy)isoindoline-1,3-dione (174); 2-(2,6-dioxopiperidin-3-yl)-5-((5-((3-(3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)pyridin-2-yl)oxy)azetidin-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pentyl)oxy)isoindoline-1,3-dione (175); 5-(3-(3-(3-((1r,3r)-3-((5-(8,9-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (176); 3-(5-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin- 2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (177); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(((6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3- b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)oxy)methyl)azetidin-1-yl)isoindoline-1,3-dione (178); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione (179) ; 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (180); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)oxy)ethyl)azetidin-1-yl)isoindoline-1,3-dione (181); 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy )propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (182); 5-((3-(5-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridine -2-yl)prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (183); 2-(2,6-dioxopiperidin-3-yl)-5-((7-(3-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)azetidin-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)heptyl)oxy)isoindoline-1,3-dione (184); (2S,4R)-N-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)-4-(4 -methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (185); (2S,4R)-N-(2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy) -4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidin-2-carboxamide (186 ); (2S,4R)-N-(2-(2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy )ethoxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidin- 2-carboxamide (187); 5-(2-((3-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)phenyl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (188); 5-((3-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenyl )prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (189); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethyl)azetidin-1-yl)isoindolin-1,3-dione (190); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)propoxy)methyl)azetidin-1-yl)isoindolin-1,3-dione (191); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)methyl)azetidin-1-yl)isoindolin-1,3-dione (192); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(2-(6-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-2-oxoethoxy)propoxy)azetidin-1-yl)isoindolin-1,3-dione (193); 5-(3-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (194) ; 5-((14-((5-(4-chloro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9, 12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (195); (2S,4R)-N-(2-(2-(2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)ethoxy)ethoxy)ethoxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl )butanoyl)pyrrolidine-2-carboxamide (196); 5-(6-((2,2-difluoro-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)pentyl)oxy)-2-azaspiro[3.3]heptan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (197) ; 2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione (198) ; 3-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butoxy)methyl)-N-methyl-N-((1r,3r )-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)bicyclo[1.1.1]pentane-1-carboxamide (199); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((7-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)heptyl)oxy)azetidin-1-yl)isoindoline-1,3-dione (200); (2S,4R)-N-(2-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9 ,12-tetraoxatetradecyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl) pyrrolidine-2-carboxamide (201); 2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methoxy)-N-methyl-N-(3-( (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)acetamide (202); 2-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-5- (5-methyl-5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile (203); 5-((3-(5-((1r,3r)-3-((5-(8,9-difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (204); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)propoxy)isoindoline-1,3-dione (205); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)methyl)azetidin-1-yl)isoindolin-1,3-dione (206); 5-((14-((5-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl) oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (207); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((1-(5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)azetidin-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (208); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4 ,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)ethoxy)ethoxy)isoindoline-1,3-dione (209 ); 2-(2,6-dioxopiperidin-3-yl)-5-((15-(4-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperazin-1-yl) -3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione (210); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(2-(6-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)ethoxy)propoxy)azetidin-1-yl)isoindolin-1,3-dione (211); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)but-2-yn-1-yl)oxy)ethoxy)azetidin-1-yl)isoindolin-1,3-dione (212) ; 2-(2,6-dioxopiperidin-3-yl)-5-(6-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)-2-azaspiro[3.3]heptan-2-yl)isoindolin-1,3-dione (213); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)piperazin-1-yl)isoindoline-1,3-dione (214); 2-(2,6-dioxopiperidin-3-yl)-5-((1R,3r)-3-(isopropyl(2-(3-((1r,3R)-3-((5-(5-methyl -5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)ethyl)amino)cyclobutoxy)isoindoline-1,3-dione (215); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)ethoxy)piperidin-1-yl)isoindoline-1,3-dione (216); 2-(2,6-dioxopiperidin-3-yl)-5-((1R,3r)-3-((2-(3-((1r,3R)-3-((5-(5-methyl- 5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)ethyl)amino)cyclobutoxy)isoindoline-1,3-dione (217); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(4-fluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (218); 3-(5-((3-(5-((1r,3r)-3-((5-(8,9-difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin- 2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (219); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (220); 3-(5-(3-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (221); 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)pyrimidin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (222); 3-(5-((3-(6-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)pyridin-3-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (223); 3-(5-(3-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)cyclobutoxy)pyridin-2-yl)propoxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (224); 3-(5-(3-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)propyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (225); 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-4,6-difluoro-1-oxoisoindolin-2-yl)piperidin-2,6-dione (226); 3-(5-((1R,3r)-3-((3-(5-((1r,3R)-3-((5-(5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)cyclobutoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (227) ; 3-(5-(4-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (228); 2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridine -2-yl)prop-2-in-1-yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-methylacetamide (229) ; 3-(5-((1R,3r)-3-((3-(5-((1r,3R)-3-((5-(5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)cyclobutyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (230) ; 3-(5-((3-(6-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)pyridazin-3-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (231); 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)pyrazin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (232); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (233); 3-(5-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2- yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (234); 2-((1r,3r)-3-((6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy )prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile (235); 5-(2-((3-(5-((1r,3r)-3-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin- 2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione ( 236); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((3-methyl-5-(5-methyl-5H- pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3- dione (237); 2-((1r,3r)-3-((6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)prop -1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile (238); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (239) ; 3-(5-(2-((3-(5-((1r,3r)-3-((3-methyl-5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 240); 3-(5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (241); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridin-2-yl)prop-2-in-1-yl)oxy)isoindolin-1,3- dione (242); 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridin-2-yl)prop-2-in-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 243); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-2-yl)prop-2-in-1-yl)oxy)isoindolin-1,3- dione (244); 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-2-yl)prop-2-in-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 245); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)prop-2-in-1-yl)oxy)isoindolin-1,3- dione (246); 3-(5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)prop-2-in-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 247); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)propoxy)ethoxy)isoindoline-1,3-dione (248); 3-(5-(2-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin- 2-yl)oxy)cyclobutoxy)piperidin-1-yl)propoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (249); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)hex-2-yn-1-yl)oxy)isoindoline-1,3-dione (250); 3-(5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2- yl)oxy)cyclobutoxy)piperidin-1-yl)hex-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (251); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-(3-((5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)oxy)azetidin-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (252); N-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)ethyl)-N-methyl-4 -((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butanamide (253); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-2-oxoethyl)azetidin-3-yl)oxy)isoindoline-1,3-dione (254); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-2-oxoethoxy)azetidin-1-yl)isoindolin-1,3-dione (255); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenoxy)azetidin-1-yl)isoindolin-1,3-dione (256); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-(((1s,3s)-1-hydroxy-3-((5-(5-methyl-5H- pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methoxy)propoxy)propoxy)azetidin-1-yl)isoindolin-1,3-dione (257); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(9-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy)isoindoline-1,3-dione ( 258); 2-(2,6-dioxopiperidin-3-yl)-5-((4-(9-(((1s,3s)-1-hydroxy-3-((5-(5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)but-2-in-1 -yl)oxy)isoindoline-1,3-dione (259); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-(((1s,3s)-1-hydroxy-3-((5-(5-methyl-5H -pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)piperazin-1-yl)phenyl)prop-2-in-1-yl)oxy)isoindoline-1 ,3-dione (260); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4 ,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)piperazin-1-yl)phenyl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione (261); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(3-(((1s,3s)-1-hydroxy-3-((5-(5-methyl-5H- pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methoxy)propoxy)propoxy)ethoxy)isoindoline-1,3-dione (262); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(3-((3-hydroxy-1-(5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)azetidin-3-yl)methoxy)propoxy)propoxy)ethoxy)isoindoline-1,3-dione (263); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-((5'-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )-3'H-spiro[cyclobutan-1,2'-furo[2,3-b]pyridin]-3-yl)oxy)propoxy)propoxy)azetidin-1-yl)isoindolin-1,3-dione ( 264); 5-((14-((5-(6,8-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6, 9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (265); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((1-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperidin-4-yl )oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (266); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((1R,3r)-3-(2-((1r,3R)-3-((5-(5- methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)cyclobutyl)ethoxy)azetidin-1-yl)isoindolin-1,3-dione (267) ; 2-(2,6-dioxopiperidin-3-yl)-5-(3-((1S,2R)-2-((4-((1r,3R)-3-((5-(5-methyl- 5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)methyl)cyclopropyl)azetidin-1-yl)isoindolin-1,3-dione (268); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((1R,2R)-2-((1r,3R)-3-((5-(5-methyl- 5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)cyclopropyl)methoxy)butoxy)azetidin-1-yl)isoindolin-1,3-dione (269); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-(((1R,2R)-2-((1r,3R)-3-((5-(5 -methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)cyclobutyl)cyclopropyl)methoxy)ethoxy)ethoxy)azetidin-1-yl)isoindolin-1,3 -dione (270); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((1R,3r)-3-(((1r,3R)-3-((5-(5-methyl- 5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)cyclobutoxy)ethoxy)azetidin-1-yl)isoindolin-1,3-dione (271); 5-(3-(3-(2,2-difluoro-3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (272); 5-(3-(2,2-difluoro-3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (273); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)propoxy)isoindoline-1,3-dione (274) ; 2-(2,6-dioxopiperidin-3-yl)-5-(2-((4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-2-yl)oxy)ethoxy)isoindoline-1,3-dione (275) ; 5-(2-((1,1-difluoro-3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1, 3-dione (276); 3-(5-((4-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)pyridin-2-yl)but-3-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (277); 3-(5-(((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy )cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (278); 3-(5-(3-((4-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-1-yl)oxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (279); 5-(3-((4-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)pyridin-2-yl)but-3-in-1-yl)oxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (280) ; 5-(3-((5-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)pyridin-2-yl)pent-4-in-1-yl)oxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (281) ; 3-(5-(3-((5-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-yl)oxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (282); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-in-1-yl)azetidin-3-yl)oxy)isoindolin-1,3- dione (283); 3-(5-((1-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-in-1-yl)azetidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 284); 5-(2-(2,2-difluoro-3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)propoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (285); 2-((1r,3r)-3-((6-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)prop-1-in- 1-yl)pyridin-3-yl)oxy)ciutobutoxy)-5-(5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile (286); 3-(5-((3-(5-((1r,3r)-3-((3-methyl-5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2- yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (287); 3-(5-((3-(5-((1r,3r)-3-((5-(4-chloro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2- yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (288); 3-(5-((3-(5-((1r,3r)-3-((5-(4-fluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2- yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (289); 3-(5-((3-(5-((1r,3r)-3-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin- 2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (290); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(3-((((1r,3r)-3-((5-(5-methyl-5H-pyrido[4 ,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)prop-2-in-1-yl)oxy)ethoxy)isoindoline -1,3-dione (291); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-((1R,3r)-3-(((1r,3R)-3-((5-(5-methyl -5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)cyclobutyl)prop-2-in-1-yl)oxy)ethoxy)isoindoline-1,3 -dione (292); 3-(5-(4-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (293); 6-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)-1H-pyrrolo[3,4-c]pyridin-1 ,3(2H)-dione (294); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4 ,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)ethoxy)azetidin-1-yl)isoindolin-1,3 -dione (295); 2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)prop-1-in-1-yl)-5 -((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)isonicotinonitrile (296); 2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)prop-1-in-1-yl)-5-( (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)isonicotinonitrile (297); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(4-methyl-5-((1r,3r)-3-((5-(5-methyl-5H- pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3- dione (298); 3-(5-(2-((3-(4-methyl-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 299); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)-4-(trifluoromethyl)pyridin-2-yl)prop-2-in-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidin-2,6- dione (300); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)-4-(trifluoromethyl)pyridin-2-yl)prop-2-in-1-yl)oxy)ethoxy)isoindoline-1, 3-dione (301); 6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)prop-1-in-1-yl)-3 -((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)picolinonitrile (302); 6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)prop-1-in-1-yl)-3-( (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)picolinonitrile (303); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(6-methyl-5-((1r,3r)-3-((5-(5-methyl-5H- pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3- dione (304); 3-(5-(2-((3-(6-methyl-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 305); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)-6-(trifluoromethyl)pyridin-2-yl)prop-2-in-1-yl)oxy)ethoxy)isoindoline-1, 3-dione (306); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)-6-(trifluoromethyl)pyridin-2-yl)prop-2-in-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidin-2,6- dione (307); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((2-methyl-4-(5-((1r,3r)-3-((5-(5-methyl-5H- pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-2-yl)oxy)ethoxy)isoindoline-1,3- dione (308); 3-(5-(2-((2-methyl-4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-2-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 309); 3-(5-(2-(1-((5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)pyridin-2-yl)ethynyl)cyclopropoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (310); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(1-((5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)ethynyl)cyclopropoxy)ethoxy)isoindoline-1,3-dione (311); 4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)prop-1-in-1-yl)-2-(4-( (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)benzonitrile (312); 4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)prop-1-in-1-yl)-2-(4-((1r ,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)benzonitrile (313 ); 3-(5-((3-(4-methyl-3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 314); 3-(5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)piperidin-1-yl)-4-(trifluoromethyl)phenyl)prop-2-in-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6- dione (315); 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)piperidin-1-yl)-5-(trifluoromethyl)pyridin-2-yl)prop-2-in-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin- 2,6-dione (316); 6-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)prop-1-in-1-yl)-4-(4-((1r ,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)nicotinonitrile (317 ); 3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)prop-1-yn-1-yl)-5-(4-( (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)benzonitrile (318); 3-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)prop-1-in-1-yl)-5-(4-((1r ,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)benzonitrile (319 ); 3-(5-((3-(3-methyl-5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 320); 3-(5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)prop-2-in-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6- dione (321); 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)piperidin-1-yl)-6-(trifluoromethyl)pyridin-2-yl)prop-2-in-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin- 2,6-dione (322); 3-(5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)piperidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)prop-2-in-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin- 2,6-dione (323); 2-(2,6-dioxopiperidin-3-yl)-5-((2-methyl-4-(3-(4-((1r,3r)-3-((5-(5-methyl-5H- pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)but-3-in-2-yl)oxy)isoindolin-1,3- dione (324); 3-(5-((2-methyl-4-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)but-3-yn-2-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( 325); 3-(5-((2-methyl-4-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridin-2-yl)but-3-in-2-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2, 6-dione (326); 3-(5-((1,1-difluoro-3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole -7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridin-2-yl)prop-2-in-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin- 2,6-dione (327); 3-(5-((2-methyl-4-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-2-yl)but-3-in-2-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2, 6-dione (328); 6-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-3-methylbut-1-in-1-yl)-4-(4- ((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl) nicotinonitrile (329); 2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)-3-methylbut-1-in-1-yl)- 5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)isonicotinonitrile (330) .

[183] Included herein as applicable are compositions containing pharmaceutically acceptable salts, particularly acid or base addition salts, of the compounds of the present invention.

[184] The term "pharmaceutically acceptable salt" is used throughout the specification to describe, as applicable, a salt form of one or more of the compounds described herein that is present to increase the solubility of the compound in the gastric juices of the gastrointestinal tract of a patient to promote dissolution and bioavailability of compounds. Pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids, as appropriate. Suitable salts include salts derived from alkali metals, such as potassium and sodium salts, alkaline earth metals, such as calcium, magnesium and ammonium salts, among a number of other acids and bases well known in the pharmaceutical field. Sodium and potassium salts are particularly preferred as phosphate neutralizing salts in accordance with the present invention.

[185] Acids that are used to prepare pharmaceutically acceptable acid addition salts of the above basic compounds useful in the present invention are acids that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as, among others, 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'-methylene-bis-(2-hydroxy-3 naphthoate)] salt.

[186] Pharmaceutically acceptable base addition salts can also be used to prepare pharmaceutically acceptable salt forms of the compounds or derivatives of the present invention. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the compounds of the present invention that are acidic in nature are bases 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 cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium, zinc and magnesium), ammonium or water-soluble addition salts amine, such as N-methylglucamine (meglumine) and lower alkanolammonium, as well as other basic salts of pharmaceutically acceptable organic amines.

Compositions

[187] In another aspect, the description provides compositions containing the compounds described herein, including salts thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the compositions are therapeutic or pharmaceutical compositions containing an effective amount of a compound described herein and a pharmaceutically acceptable carrier.

[188] The amount of a compound in the pharmaceutical composition of the present invention that can be combined with carrier materials to form a single dosage form will vary depending on the organism and disease being treated and the particular route of administration. In general, the active ingredients are administered in amounts ranging from 0.1 mg/kg to 1000 mg/kg body weight/day depending on the effectiveness of the agent. The toxicity and therapeutic efficacy of such compounds can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the LD50 (dose lethal in 50% of the population) and ED50 (dose therapeutically effective in 50% of the population). The ratio of the toxic dose to the therapeutic dose is the therapeutic index and can be expressed as the LD50/ED50 ratio. Compounds having high therapeutic index values are preferred. Although compounds with toxic side effects may be used, care should be taken to develop a delivery system that directs such compounds to the site of diseased tissue to minimize potential damage to unaffected cells and thereby reduce side effects. Data obtained from cell culture assays and animal studies can be used to develop dosage ranges for use in humans. The dose of such compounds is preferably within a circulating concentration range that includes the ED50 with little or no toxicity. The dose may vary within this range depending on the dosage form used and the route of administration. For any compound used in the method of the present invention, a therapeutically effective dose can initially be estimated based on the results of cell culture assays. In animal models, the dose can be determined to achieve a range of circulating plasma concentrations that includes the IC50 (ie, the concentration of the test compound at which half-maximal symptom suppression is achieved) determined in cell culture. Such information can be used to more accurately determine doses applicable to humans. Plasma levels can be measured, for example, using high performance liquid chromatography.

[189] The compositions of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and can also be administered as controlled release formulations. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures partial glycerides 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, block copolymers of polyethylene and polyoxypropylene, polyethylene glycol and lanolin.

[190] In any of the aspects or embodiments described herein, the PTM, ULM, or both have an affinity (IC ₅₀ ) for their respective target protein of less than about 500 μM, 450 μM, 400 μM, 350 μM, 300 µM, 250 µM, 200 µM, 150 µM, 100 µM, 50 µM, 10 µM, 0.10 µM, 0.01 µM, 0.001 µM, 0.1 nM, 0.01 nM, 0.001 nM or less. Determination of IC ₅₀ can be carried out using methods well known to those skilled in the art in light of the present invention.

[191] In any aspect or embodiment, the compounds described herein provide ubiquitination of a target protein at levels or in amounts sufficient to promote or induce destruction of the target protein.

[192] The active compound is included 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 receiving treatment. The preferred dose of the active compound for all conditions listed herein is in the range from about 10 ng/kg to 300 mg/kg, preferably from 0.1 to 100 mg/kg per day, in general from 0.5 to about 25 mg per day. kilogram of recipient/patient body weight per day. A typical dose for topical application will be in the range of 0.01 to 5% w/w in a suitable vehicle.

[193] The compound is conveniently administered in any suitable unit dosage form, including, but not limited to, a dosage form containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dose of approximately 25-250 mg is often appropriate.

[194] The active ingredient is preferably administered to achieve maximum 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 formulation of the active ingredient, optionally in saline or aqueous media, or by administering the active ingredient as a bolus. Oral administration is also suitable to achieve effective plasma concentrations of the active agent.

[195] The concentration of the active compound in the drug formulation will depend on the rates of absorption, distribution, inactivation and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage levels will also vary depending on the severity of the condition being alleviated. It should also be understood that for any particular subject, specific dosage regimens should be adjusted over time in accordance with individual need and the professional judgment of the specialist administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are illustrative only and are not intended to limitations on the scope or practical application of the claimed composition. The active ingredient may be administered at one time or may be divided into several smaller doses to be administered at various time intervals.

[196] When administered intravenously, the preferred vehicles are physiological saline or phosphate-buffered saline (PBS).

[197] In one embodiment, the active compounds are formulated with carriers that will protect the compound from rapid elimination from the body, such as a controlled release formulation, 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 will be apparent to those skilled in the art.

[198] Liposomal suspensions may also be pharmaceutically acceptable carriers. They can be prepared in accordance with methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations can be prepared by dissolving a suitable lipid(s) (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine and cholesterol) in an inorganic solvent, which is then evaporated, leaving a thin film of dried lipid on the surface of the container. The aqueous solution of the active compound is then added to the container. The container is then manually rotated to separate the lipid material from the walls of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

Methods of administration

[199] In any of the aspects or embodiments described herein, therapeutic compositions containing the compounds described herein may be in any suitable dosage form capable of delivery by any suitable route. For example, the compounds can be administered by any suitable route, for example, orally, parenterally, intravenously, intradermally, subcutaneously or topically, including transdermally, in liquid, cream, gel or solid form, rectally, nasally, buccally, vaginally, or via implanted reservoir, or in aerosol form.

[200] The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. The compositions are preferably administered orally, intraperitoneally or intravenously.

[201] The compounds described herein can be administered in a single dose or in divided doses by oral, parenteral or topical routes. Administration of the active compound may range from continuous (intravenous infusion) to multiple oral administrations per day (e.g., Q.I.D.) and may include, among other routes of administration, oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancer ), buccal, sublingual and suppository administration. Enteric-coated oral tablets can also be used to increase the bioavailability of compounds via the oral route. The most effective dosage form will depend on the pharmacokinetic characteristics of the particular agent chosen, as well as the severity of the patient's disease.

[202] Administration of compounds in the form of sprays, mists or aerosols for intranasal, intratracheal or inhalation administration may also be used. The compounds described herein can be administered in immediate release, timed release, or sustained or controlled release forms. Sustained or controlled release forms are preferably administered orally, but also in suppository and transdermal or other topical forms. Intramuscular injections in liposomal form can also be used to control or slow the release of the compound at the injection site.

[203] Sterile injectable forms of the compositions described herein can be an aqueous or oleaginous suspension. These suspensions can be formulated according to techniques 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 diluent or solvent suitable for parenteral administration, for example, a solution in 1,3-butanediol. Acceptable carrier media and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are traditionally used as a solvent or suspending medium. For this purpose, any light, fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and their glyceride derivatives are useful for the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain a diluent or dispersant which is a long chain alcohol such as that specified in the Swiss Pharmacopoeia or a similar alcohol.

[204] The pharmaceutical compositions described herein can be administered orally in any dosage form acceptable for oral administration, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For oral tablets, conventional carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. Certain sweeteners, flavorings, or colors may also be added if desired. Compositions for oral administration will generally include an inert diluent or edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or a prodrug derivative thereof can be combined with excipients and administered in the form of tablets, lozenges or capsules. Pharmaceutically compatible binders and/or auxiliary materials are included as part of the composition.

[205] Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of similar origin: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient 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 silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint flavor, methyl salicylate, or orange flavor. If the unit dosage form is a capsule, it may contain, in addition to the above type of material, a liquid carrier such as a fatty oil. In addition, unit dosage forms may contain various other materials that alter the physical form of the dosage form, such as coatings of sugar, shellac, or enteric agents.

[206] The active compound or a pharmaceutically acceptable salt thereof may be administered as a component of a tincture, suspension, syrup, cachet, chewing gum, or the like. The syrup may contain, in addition to the active compounds, sucrose as a sweetener and certain preservatives, dyes and coloring agents, and flavoring agents.

[207] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration. These 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 will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[208] The pharmaceutical compositions of the present invention can also be administered topically. Suitable topical formulations are readily available for each of these areas or organs. Topical application to the lower intestine can be achieved using a rectal suppository formulation (see above) or a suitable douche formulation. Transdermal patches that are acceptable for topical use may also be used. For topical applications, the pharmaceutical compositions can be formulated in the form of a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, a propylene glycol compound, polyoxyethylene, polyoxypropylene, emulsified wax and water. In certain preferred aspects of the present invention, the compounds can be coated on a stent that is surgically implanted in a patient to prevent or reduce the likelihood of occlusion of the stent in the patient.

[209] Alternatively, the pharmaceutical compositions can be formulated in the form of a suitable lotion or cream containing the active ingredients 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.

[210] For ophthalmic use, the pharmaceutical compositions can be formulated as fine suspensions in isotonic, sterile, pH-adjusted saline, or preferably as solutions in isotonic, sterile, pH-adjusted saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic applications, the pharmaceutical compositions can be formulated in ointment form, such as with Vaseline.

[211] The pharmaceutical compositions of the present invention can also be administered by nasal aerosol or by inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents. .

[212] Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical use 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 methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents to regulate tonicity such as sodium chloride or dextrose. The drug for parenteral administration may be contained in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[213] It should also be understood that the specific dosage regimen and treatment regimen for any particular patient will depend on a number of factors, including the potency of the particular compound administered, age, body weight, general health, sex, diet, time of administration, rate excretion, drug combinations and the judgment of the treating physician, as well as the severity of the particular disease or condition being treated.

[214] A patient or subject in need of therapy with the compounds described herein can be treated by administering to the patient (subject) an effective amount of a compound, including pharmaceutically acceptable salts, solvates or polymorphs thereof, optionally in a pharmaceutically acceptable carrier or diluent, either alone or in combination with other known agents.

Joint introduction

[215] Disease conditions that can be treated with the compounds or compositions herein include, but are not limited to, cancer (eg, prostate cancer) and Kennedy's disease. In certain embodiments, the therapeutic or pharmaceutical compositions contain an effective amount of an additional biological or biologically active agent, for example, an agent effective for treating cancer, which is co-administered.

[216] By "co-administration" or "combination therapy" it is meant that at least two compounds or compositions are administered to a patient at the same time such that effective amounts or concentrations of each of the two or more compounds can be detected in patient at a given point in time. Although the compounds of the present invention can be co-administered to a patient at the same time, the term covers the administration of two or more agents either at the same time or at different times, provided that the effective concentrations of all co-administered compounds or compositions are detected in the subject at a given point in time. In certain preferred aspects of the present invention, one or more of the compounds of the present invention described above are co-administered in combination with at least one additional biologically active agent, including, in particular, an anticancer agent. In particularly preferred aspects of the present invention, coadministration of the compounds results in a synergistic therapeutic effect, including anticancer therapy.

[217] In another aspect, the description provides a composition containing an effective amount of two or more PROTAC compounds described herein and a pharmaceutically acceptable carrier. In certain embodiments, the composition further comprises an effective or synergistic amount of another biologically active agent that is not a PROTAC compound.

[218] Pharmaceutical compositions containing combinations of an effective amount of at least one bifunctional compound according to the present invention, and one or more of the compounds described later herein, all in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive, or excipients constitute a further aspect of the present invention.

[219] The term "biologically active agent" is used to describe an agent, other than the PROTAC compounds described herein, that is used in combination with the compounds of the present invention as an agent with biological activity to facilitate the intended therapy, inhibition and/or prevention /prophylaxis for which the compounds of the present invention are used. Preferred biologically active agents for use herein include those that promote the intended therapy, for example, P-gp inhibitors or agents that have pharmacological activity similar to that for which the compounds of the present invention are used or administered, and include, for example , anti-neurodegenerative agents.

[220] The term "P-gp" is used to describe "penetration-influencing glycoprotein" or P-glycoprotein (ABCB1), which was discovered in 1976 in rodent cells. The presence of “endogenous or physiological” P-gp poses a potential challenge to achieving targeted effects with therapeutic agents. P-gp is expressed in barrier tissues at sites inaccessible to drugs (eg, blood-brain barrier) and in secretory/absorbent tissues (eg, gastrointestinal tract) (Cordon-Cardo et al., 1989, 1990). The protein functions as a cell protector and influences the overall pharmacokinetic profile of numerous drugs by actively pumping them out of the intracellular environment (efflux), thereby reducing drug penetration into barrier tissues. In particular, the efflux mediated by P-gp reduces drug permeation of gastrointestinal membranes and may result in reduced systemic drug exposure. The efflux mediated by P-gp also reduces drug access into the blood-brain barrier. P-gp inhibitors may indirectly contribute to efficacy by increasing PROTAC exposure, particularly CNS exposure

[221] The term “additional anti-neurodegenerative agent” is used to describe an anti-neurodegenerative agent that can be combined with PROTAC compounds as described herein for the treatment of neurodegenerative diseases.

[222] In certain embodiments, PROTACs are used in conjunction with P-gp inhibitors.

[223] In certain additional embodiments, the P-gp inhibitors are selected from the group consisting of, but not limited to, amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tariquidar, elacridar, and verapamil.

Treatment options

[224] In another aspect, the present invention provides methods for modulating ubiquitination and protein degradation in a subject, such as a cell, tissue, mammal, or human patient, the method comprising administering an effective amount of a PROTAC compound described herein or a composition, containing an effective amount of the compound, to a subject, wherein the compound or composition containing the compound is effective in modulating protein ubiquitination and protein degradation in the subject. In certain embodiments, the protein is tau protein.

[225] In certain embodiments, the disclosure provides a method of regulating the activity of a tau protein by disrupting tau protein aggregates in a patient in need, comprising administering to the patient an amount of a compound described herein to the patient.

[226] In still further embodiments, the disclosure provides a method of treating a disease state or condition in a patient wherein dysregulated protein activity (tau protein aggregation and accumulation) is responsible for said disease state or condition, wherein said method comprises administering to said to a patient, an effective amount of a compound described herein to said patient to provide regulation of the activity of said protein in said patient. In certain embodiments, the protein is tau protein.

[227] The terms “treat,” “treat,” and “treat,” etc., as used herein, refer to any action that provides benefit to a patient to whom the compounds of the present invention may be administered, including treatment of any a disease state or condition modulated by a protein to which the compounds of the present invention bind. Disease conditions or conditions, including neurological and neurodegenerative diseases, that can be treated with the compounds of the present invention are set forth above herein.

[228] In another aspect, the present invention provides methods for modulating the ubiquitination and degradation of tau protein in a subject, such as a cell, tissue, mammal, or human patient, the method comprising administering an effective amount of a compound described herein or composition containing an effective amount of a compound described herein to a subject, wherein the compound or composition containing the compound is effective in modulating the ubiquitination and degradation of tau protein in the subject.

[229] In another aspect, the present invention provides methods for treating or alleviating a disease symptom associated with the accumulation or aggregation of tau protein in a subject, such as a cell, tissue, mammal or human patient, the method comprising administering an effective amount of the compound described herein, or a composition containing an effective amount of the compound, to a subject in need thereof, wherein the compound or composition containing the compound is effective in treating or alleviating a symptom of a tau protein aggregation disease in the subject.

[230] In certain embodiments, the disease or disorder is a neurological disorder, including, without limitation, absence of septum pellucidum, acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, Eydie-Holmes syndrome, Eydie syndrome, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Ecardi syndrome, neurological complications of AIDS, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformation , Asperger's syndrome, ataxia, ataxia, telangiectasia, forms of ataxia and cerebellar/spinocerebellar degeneration, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Barth syndrome, Batten disease, Becker myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal amyotrophy, benign intracranial hypertension, Bernhardt-Roth syndrome, Binswanger disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus injury during childbirth, brachial plexus injury, Bradbury-Eggleston syndrome, brain and spinal cord tumors, cerebral aneurysm , brain damage, Brown-Séquard syndrome, bulbospinal muscular atrophy, Canavan disease, carpal tunnel syndrome, causalgia, cavernomas, cavernous angioma, cavernous malformation, central palsy syndrome, pyramidal palsy, central pain syndrome, cephalic disorders, cerebellar degeneration, cerebellar hypoplasia , cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral form of beriberi, cerebral gigantism, cerebral hypoxia, cerebral palsy, cerebrooculofacioskeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chorea-acanthocytosis, chronic inflammatory demy Elinating polyneuropathy (CIDP), chronic orthostatic intolerance, chronic pain, Cockayne syndrome type II, Coffin-Lowry syndrome, COFS, colpocephaly, coma and persistent vegetative state, complex regional pain syndrome, congenital facial diplegia, congenital myasthenia, congenital myopathy, congenital carvenous vascular malformations , corticobasal degeneration, temporal arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative traumatic disorders, Cushing's syndrome, inclusion cytomegaly, cytomegalovirus infection, opso-myoclonal syndrome, Dandy-Walker syndrome, Dawson's disease, de Morsier syndrome, deep brain stimulation for disease Parkinson's, Dejerine-Klumpke's palsy, dementia, multi-infarct dementia, semantic dementia, subcortical dementia, dementia with Lewy bodies, progressive cerebellar ataxia, dentorubral atrophy, dermatomyositis, developmental dyspraxia, Devic's syndrome, diabetic neuropathy, diffuse sclerosis, autonomic dystonia, dysgraphia, dyslexia this , dysphagia, dyspraxia, cerebellar myoclonic dyssynergia of Hunt, progressive cerebellar dyssynergia, forms of dystonia, epileptic encephalopathy of early childhood, empty sella syndrome, lethargic encephalitis, cranial hernia, encephalopathy, encephalotrigeminal angiomatosis, epilepsy, paralysis and Duchenne-Herb and Dejerine- Klumpke, Erb's spinal palsy, Fabry's disease, Fahr's syndrome, syncope, familial dysautonomia, familial hemangioma, familial idiopathic calcification of the basal ganglia, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher's syndrome, floppy child syndrome, Friedreich's hereditary ataxia, frontotemporal dementia, Gaucher disease, Gerstmann syndrome, Gerstmann-Straussler-Scheinker syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, glossopharyngeal neuralgia, Guillain-Barre syndrome, Hallervorden-Spatz disease, traumatic brain injury, headache , prolonged hemicrania, hemifacial spasm, alternating hemiplegia, hereditary neuropathies, hereditary paraplegia, polyneuritis-like hemeralopic heredoataxia, herpes zoster, ganglion neuralgia, Hirayama syndrome, Eydie-Holmes syndrome, holoprosencephaly, HTLV-1-associated myelopathy yu, Huntington's disease, hydroanencephaly, hydrocephalus , normal pressure hydrocephalus, hydromyelia, hyperfunction, hypercortisolism, hypersomnia, hypertension, infantile hypotension, hypoxia, immune-mediated encephalomyelitis, myositis with inclusion bodies, pigmentary dermatosis, infantile hypotonia, infantile neuroaxonal dystrophy, infantile form of phytanic acid storage disease, infantile form of Refsum's disease, infant spasms, inflammatory myopathy, inencephaly, intestinal lipodystrophy, intracranial cysts, intracranial hypertension, Isaac's syndrome, Joubert syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Kleine-Levin syndrome, Klippel-Feil syndrome, Klippel-Trenaunay syndrome (KTS) , Klüver-Bucy syndrome, Korsakoff amnestic syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lambert-Eaton myasthenic syndrome, Landau-Klefner syndrome, neuropathy of the lateral cutaneous nerve of the thigh, Wallenberg syndrome, learning disabilities, Leigh disease, Lennox syndrome -Gastaut, Lesch-Nyhan syndrome, leukodystrophy, Levine-Critchley syndrome, dementia with Lewy bodies, lipid storage diseases, lissencephaly, locked-in syndrome, Lou Gehrig's disease, neurological complications of lupus, neurological complications of Lyme disease, Machado-Joseph disease, macroencephaly, manic syndrome, macroencephaly, Melkersson-Rosenthal syndrome, meningitis, meningitis and encephalitis, Menkes disease, meralgia paresthetica, metachromatic leukodystrophy, microcephaly, migraine, Miller-Fisher syndrome, microstroke, mitochondrial myopathies, Mobius syndrome, monomelic amyotroph Iu, motor neuron diseases , Moya-Moya disease, mucolipidoses, mucopolysaccharidoses, multifocal motor neuropathy, multi-infarct dementia, multiple sclerosis, multiple system atrophy, multiple system atrophy with orthostatic hypotension, muscular dystrophy, congenital myasthenia, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonus encephalopathy in infants, myoclonus, myopathy, congenital myopathy, thyrotoxic myopathy, myotonia, myotonia congenita, narcolepsy, neuroacanthocytosis, neurodegeneration with iron accumulation in the brain, neurofibromatosis, neuroleptic malignant syndrome, neurological complications of AIDS, neurological complications of Lyme disease, neurological consequences of cytomegalovirus infection, neurological manifestations of Pompe disease, neurological complication of lupus, neuromyelitis optica, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorders, hereditary neuropathy, neurosarcoidosis, neurotoxicity, carvenous angioma, Niemann-Pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, latent spinal cord dysraphism, Otachar syndrome s , olivopontocerebellar atrophy, opsoclonus-myoclonus, orthostatic hypotension, O'Sullivan-MacLeod syndrome, overload syndrome, chronic pain, pain, pantothenate kinase-associated neurodegeneration, paraneoplastic syndromes, paresthesia, Parkinson's disease, paroxysmal choreoathetosis, paroxysmal hemicrania, Paris-Romberg syndrome, Pelizaeus-Merzbacher disease, Pen-Choqueir II syndrome, perineural cysts, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent vegetative state, pervasive developmental disorders, phytanic acid storage disease, Pick's disease, pinched nerve, piriformis syndrome, pituitary tumors, polymyositis , Pompe disease, porencephaly, postherpetic neuralgia, post-infectious encephalomyelitis, post-polio syndrome, postural hypotension, postural orthostatic tachycardia syndrome, postural tachycardia syndrome, progressive cerebellar dyssynergia, primary lateral sclerosis, primary progressive aphasia, prion diseases, progressive hemifacial atrophy iu, progressive motor ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing polydystrophy, progressive supranuclear palsy, prosopagnosia, benign intracranial hypertension, Ramsay-Hunt syndrome I (formerly known as), Ramsay-Hunt syndrome II (formerly known as), Rasmussen's encephalitis, sympathetic reflex dystrophy, Refsum's disease, infantile Refsum's disease, repetitive motion disorder, tunnel syndrome, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye syndrome, Riley-Day syndrome, perihilar cysts of the sacral nerve, St. Vitus's dance, salivary gland disease , Sandhoff's disease, Schilder's disease, schizencephaly, Seitelberger's disease, seizure disorder, semantic dementia, septo-optic dysplasia, shaken baby syndrome, herpes zoster, Shy-Drager syndrome, Sjögren's syndrome, sleep apnea, sleeping sickness, Sotos syndrome, spasticity, spina bifida, spinal cord infarction, spinal cord injury, spinal cord tumors, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Steele-Richardson-Olszewski syndrome, muscle stiffness syndrome, striatonigral degeneration, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, short-term attacks of unilateral neuralgic headache with conjunctival injection and lacrimation, swallowing dysfunction, Sydenham's chorea, syncope, syphilitic spinal sclerosis, syringohydromyelia, syringomyelia, systemic erythematous lupus, tabes spinal cord, tardive disk inesia, Tarlov cysts, Tay's disease Sachs, temporal arteritis, tethered spinal cord syndrome, Thomsen's myotonia, scalene muscle syndrome, thyrotoxic myopathy, trigeminal neuralgia, Todd's palsy, Tourette's syndrome, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, tuberous sclerosis, cavernous angioma, vasculitis, including temporal arteritis, Economo disease, Hippel-Lindau disease (VHL), Recklinghausen disease, Wallenberg syndrome, Werdnig-Hoffmann disease, Wernicke-Korsakoff syndrome, West syndrome, whiplash injury , Whipple's disease, Williams' syndrome, Wilson's disease, X-linked spinobulbar muscular atrophy or Zellweger's syndrome.

[231] In certain embodiments, the disease or disorder is at least one of Huntington's disease, muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten disease, spinal cord and brain injury, seizure disorder, epilepsy, brain tumor, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformation, cerebral aneurysm, dural arteriovenous fistula, headache, memory disorders, peripheral neuropathy, postherpetic neuralgia, spinal cord tumor and stroke.

[232] In certain embodiments, the disease or disorder is Alzheimer's disease.

[233] In another aspect, the present invention provides methods for treating or alleviating a disease symptom associated with the accumulation or aggregation of tau protein. in a subject, for example, in a cell, tissue, mammal or human patient, wherein the method comprises administering an effective amount of a compound described herein, or a composition containing an effective amount of the compound, and an effective amount or amount providing a synergistic effect, another biologically active agent to a subject in need thereof, wherein the composition containing the compound is effective in treating or alleviating a symptom of a disease associated with the accumulation or aggregation of tau protein in the subject by destroying/inhibiting tau protein.

[234] In certain embodiments, the disease being treated is a neurological disorder. In a preferred embodiment, the subject is a human.

[235] In certain additional embodiments, the additional biologically active agent is an anti-neurodegenerative agent.

[236] In alternative aspects, the present invention provides a method of treating a disease state by disrupting a protein or polypeptide by which the disease state or condition is modulated, comprising administering to said patient or subject an effective amount of at least one compound described herein above, optionally in combination with an additional biologically active agent. The method in accordance with the present invention can be used to treat a wide variety of neurological disease states or conditions by administering an effective amount of at least one compound described herein.

[237] In another aspect, the present invention provides methods for identifying the effects of degradation of proteins of interest in a biological system using compounds of the present invention.

Sets

[238] In another aspect, the description provides kits containing the compounds or compositions described herein. The kit may be advertised, distributed, or sold as an article for implementing the methods of the present invention. In addition, kits of the present invention may preferably contain instructions that describe suitable use. Such kits can be conveniently used, for example, in a clinical setting to treat patients with neurological disorders.

Examples

[239] The PROTAC compounds of the present invention are effective in degrading tau protein. Exemplary compounds are presented in Tables 1 and 2 through in vitro data of some selected compounds in Tables 2 and 3 showing tau protein degradation. In vivo studies demonstrating tau protein degradation are illustrated in Figure 1.

General methods of chemical synthesis

[240] The synthesis of the claimed chimeric compounds can be carried out in accordance with general synthesis procedures known from the literature. The synthetic routes shown in the schemes in the present invention are described as one of the methods that can be used to obtain the desired compounds. Other methods known to those skilled in the art of synthesis may also be used. The ULMs and PTMs described in the diagrams represent only one of many ULMs and PTMs described in this application.

LC-MS method for purity analysis (quality control)

[241] LCMS method

Equipment: Agilent infinity 1260 LC; Agilent 6230 TOF mass spectrometer

The analysis was carried out on a Poroshell 120 EC C18 column (50 mm × 3.0 mm (inner diameter), packing diameter 2.7 μm) at 45°C.

The solvents used are:

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

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

The gradient used is as follows.

UV detection is an averaged signal from 210 nm to 350 nm, and mass spectra were recorded on a mass spectrometer using electrospray ionization in positive ionization mode.

[242] Abbreviations

ACN: Acetonitrile

Boc ₂ O: di-tert-butyl dicarbonate

DCM: dichloromethane

DIPEA: N,N-diisopropylethylamine

DMA: N,N-dimethylacetamide

DMF: N,N-dimethylformamide

EA: ethyl acetate

HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

HPLC: High Performance Liquid Chromatography

LC-MS: liquid chromatography with mass spectrometry

min: minutes

MTBE: methyl tert-butyl ether

PE: petroleum ether

K.t.: room temperature

SPB: sodium perborate

tBu: tert-butyl

TBACl: Tetrabutylammonium chloride

TFA: trifluoroacetic acid

THF: tetrahydrofuran

TLC: thin layer chromatography

TMS: trimethylsilyl

t _R : retention time

TsCl: p-toluenesulfonyl chloride

[243] E3 ubiquitin ligase targeting moiety (ULM) and protein targeting moiety (PTM) intermediates

[244] Intermediate 1. (2S,4R)-1-[(2S)-2-Amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (ULM-1)

Step 1. Preparation of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile

[245] To a stirred solution of 4-bromobenzonitrile (20 g, 109.88 mmol) in DMA (250 ml) under a nitrogen atmosphere was added 4-methyl-1,3-thiazole (21.88 g, 220.67 mmol), acetate palladium(II) (743 mg, 3.31 mmol) and potassium acetate (21.66 g, 220.71 mmol) at room temperature. The resulting mixture was heated to 150°C and stirred at this temperature for 5 hours, after which completion of the reaction was indicated by LC-MS. The mixture was cooled to room temperature, diluted with 1 L of water and extracted with ethyl acetate (300 ml x 3). The organic layers were combined, washed with brine (200 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel flash column chromatography (eluent: ethyl acetate/petroleum ether, v:v . = 1:5) to obtain the title compound (yield: 91%) as a white solid.

Step 2. Preparation of [4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine

[246] To a stirred solution of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile (35 g, 174.77 mmol) in tetrahydrofuran (1000 ml) was added LiAlH ₄ (20 g, 526.32 mmol) at 0°C for 10 minutes in a nitrogen atmosphere. The resulting mixture was then stirred at 60°C for 3 hours, after which completion of the reaction was indicated by LC-MS. The mixture was cooled to 0°C, then quenched by adding water (20 ml, added slowly), aq. NaOH solution (15%, 20 ml) and water (60 ml). The resulting mixture was then extracted with ethyl acetate (300 ml x 2). The organic layers were combined, washed with brine (100 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel flash column chromatography (eluent: dichloromethane/methanol (v:v). =10:1)) to obtain the title compound (yield: 56%) as a yellow oil.

Step 3. Preparation of tert-butyl-(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidine-1- carboxylate

[247] Into a stirred solution of (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (2.7 g, 11.68 mmol) in N,N-dimethylformamide (20 ml) DIPEA (2.52 g, 19.50 mmol), HATU (4.47 g, 11.76 mmol) and [4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine were added (2 g, 9.79 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight, after which completion of the reaction was indicated by LC-MS. The reaction mixture was diluted with 20 ml of water and extracted with ethyl acetate (50 ml x 3). The organic layers were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel flash column chromatography (eluent: dichloromethane/methanol (v:v). = 20:1)) to obtain the title compound (yield: 56%) as a yellow solid.

Step 4. Preparation of (2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride

[248] Into a 1 L round bottom flask containing tert-butyl-(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl ]carbamoyl)pyrrolidine-1-carboxylate (45 g, 107.78 mmol) in dioxane, add hydrogen chloride in dioxane (4 N, 300 ml). The resulting solution was stirred for 2 hours at room temperature. The solids were collected by filtration to obtain the title product (yield: 98%) as a yellow solid.

Step 5. Preparation of tert-butyl-N-[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl) phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate

[249] Into a stirred solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoic acid (15.7 g, 68.0 mmol) in N,N-dimethylformamide (500 ml ) DIPEA (29.2 g, 225.9 mmol), HATU (25.9 g, 68.1 mmol) and (2S,4R)-4-hydroxy-N-{[4-(4-methyl-1 ,3-thiazol-5-yl)-phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride (20.0 g, 56.5 mmol) at room temperature.

[250] The resulting solution was stirred at room temperature for 16 hours and LC-MS showed the formation of the desired product. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml x 3). The organic layers were combined, washed with saturated aqueous sodium chloride (50 ml x 2), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a crude residue, which was purified by flash chromatography on silica gel (eluent: ethyl acetate/petroleum ether). v:v = 2:1)) to give the title compound (yield: 51%) as a yellow solid.

Step 6. Synthesis of (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5 -yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (ULM-1)

[251] Into a stirred solution of tert-butyl-N-[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (12 g, 22.61 mmol) in dioxane (20 ml) add a solution of hydrogen chloride in dioxane (4 N, 80 ml) at room temperature. The resulting solution was stirred at room temperature for 2 hours, after which completion of the reaction was indicated by LC-MS. The precipitated solids were collected by filtration to obtain the title product (yield: 48%) as a yellow solid.

[252] d: 48%) as a yellow solid.

^1H NMR (400 MHz, CD ₃ OD): δ 9.84-9.82 (s, 1H), 7.58-7.54 (m, 4H), 4.71 4.41 (m, 4H) , 4.13-4.08 (m, 1H), 3.86-3.71 (m, 2H), 3.36 (s, 1H), 2.60-2.58 (s, 3H), 2 .35-2.07 (m, 2H), 1.19-1.12 (m, 9H). LC-MS (ES ⁺ ): mass/charge 431.11 [MH ⁺ ], t _R =0.73 min.

Intermediate 2. (2S,4R)-1-[(S)-2-Amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(S)-1-(4-(4-methylthiazol-5 -yl)phenyl)ethyl]pyrrolidine-2-carboxamide hydrochloride (ULM-2)

Step 1. Preparation of (S)-tert-butyl-1-(4-bromophenyl)-ethylcarbamate

[253] In a mixture of (S)-1-(4-bromophenyl)ethanamine (3.98 g, 19.9 mmol) and NaHCO ₃ (1.24 g, 14.8 mmol) in H ₂ O (10 ml) and ethyl acetate (10 ml) was added (Boc) _2O (5.20 g, 23.8 mmol) at 5°C. The reaction was continued for 2 hours. TLC indicated completion of the reaction. The reaction mixture was filtered. The solid was collected and suspended in a mixture of hexane (10 ml) and H ₂ O (10 ml) for 0.5 hour. The mixture was filtered and the solid was collected and dried in an oven at 50°C to obtain the title compound as a white solid (5.9 g, 98.7%).

^1H NMR (400 MHz, DMSO-d ₆ ): δ 1.28 (d, J=7.2 Hz, 3H), 1.36 (s, 9H), 4.55-4.60 (m, 1H ), 7.25 (d, J=8.4 Hz, 2H), 7.39 (br, 1H), 7.49 (d, J=8.4 Hz, 2H).

Step 2. Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride

[254] Mixture of (S)-tert-butyl-1-(4-bromophenyl)ethylcarbamate (4.0 g, 13.3 mmol), 4-methylthiazole (2.64 g, 26.6 mmol), palladium acetate ( II) (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in DMF (10 ml) were stirred at 90° C. under N ₂ atmosphere for 18 hours. After cooling to ambient temperature, the reaction mixture was filtered. H ₂ O (50 ml) was added to the filtrate and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered. The solid was collected by filtration and dried in an oven at 50°C to give (S)-tert-butyl-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3% ) as a gray solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.33 (d, J=7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4. 64-1.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J=8 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+1] ⁺ : 319.5

[255] This solid (1.9 g, 6.0 mmol) was dissolved in 4 N. hydrochloride in methanol (5 ml, 20 mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3 hours, then concentrated and triturated with ether. The mixture was filtered and the solid was collected and dried in an oven at 60°C to give (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (1.3 g, 85%) as light -green solid.

^1H NMR (400 MHz, DMSO-d6): δ 1.56 (d, J=6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H) , 7.57 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+1] ⁺ : 219.2

Step 3. Preparation of (2S,4R)-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylic acid

[256] Add HATU (2.15 g, 5.7 mmol) to a solution of (S)-2-(tert-butoxycarbonyl)amino-3,3-dimethylbutanoic acid (1.25 g, 5.4 mol), ( 2S,4R)-methyl-4-hydroxypyrrolidine-2-carboxylate hydrochloride (0.98 g, 5.4 mmol) and DIPEA (2.43 g, 18.9 mmol) in DMF (10 ml) at 0°C in nitrogen atmosphere. The mixture was stirred at ambient temperature for 18 hours. TLC indicated completion of the reaction. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (15 ml X 4). The combined organic layer was washed with 5% citric acid (10 mL x 2), saturated NaHCO ₃ solution (10 mL x 2), brine (10 mL x 2) and dried over Na ₂ SO ₄ . The organic solution was filtered and concentrated to give (2S,4R)-methyl-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylate as pale -yellow oil (1.93 g, 100% yield). This crude product (1.93 g) and lithium hydroxide hydrate (2.2 g, 54 mmol) were taken into THF (20 ml) and H ₂ O (10 ml). The resulting mixture was stirred at ambient temperature for 18 hours. THF was removed by concentration. The residue was diluted with ice water (10 ml) and slowly adjusted to pH 2-3 with 3N. HCI. The resulting suspension was filtered and washed with H ₂ O (6 ml x 2). The solid was collected by filtration and dried in an oven at 50°C to give the title compound as a white solid (1.4 g, 75% in two steps).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 6.50 (d, J=9.6 Hz, 1H), 5.19 (br s, 1H), 4.32 (br s, 1H), 4.25 (t, J=8.4 Hz, 1H), 4.16 (d, J=9.2 Hz, 1H), 3.57-3.66 (m, 2H), 2.08-2 .13 (m, 1H), 1.85-1.91 (m, 1H), 1.38 (s, 9H), 0.94 (s, 9H).

Step 4. Preparation of (2S,4R)-1-[(S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(S)-1-(4-(4-methylthiazol-5 -yl)phenyl)ethyl]pyrrolidine-2-carboxamide hydrochloride (ULM-2)

[257] Add HATU (1.6 g, 4.2 mmol) to the stirred solution containing (2S,4R)-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl }-4-hydroxypyrrolidin-2-carboxylic acid (1.21 g, 3.5 mmol), (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (0.9 g, 3.5 mmol) and DIPEA (1.36 g, 10.5 mmol) in anhydrous THF (15 ml), at 0°C. The resulting mixture was heated to ambient temperature and continued stirring for 2 hours. TLC indicated completion of the reaction. THF was removed by concentration. Water (15 ml) was added to the residue and the resulting mixture was stirred for 4 hours. The resulting mixture was filtered. The solid was collected and dried in an oven at 50°C to obtain a white solid. This solid was taken into methanol (10 ml) and activated carbon (150 mg) was added. The resulting mixture was heated at 80°C and stirred for 1 hour. The mixture was filtered while it was hot. Water (5 ml) was added to the filtrate at 80°C. The resulting mixture was cooled to ambient temperature and continued stirring for 18 hours. The suspension was filtered. The solid was collected and oven dried at 50°C to give tert-butyl-{(S)-1-[(2S,4R)-4-hydroxy]-2-[(S)-1-(4-(4 -methylthiazol-5-yl)phenyl)ethylcarbamoyl]pyrrolidin-1-yl}-3,3-dimethyl-1-oxobutan-2-ylcarbamate (1.41 g, 74.2%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.05 (s, 9H), 1.42 (s, 9H), 1.47 (d, J=7.2 Hz, 3H), 2.04- 2.10 (m, 1H), 2.53 (s, 3H), 2.58-2.64 (m, 1H), 3.23 (s, 1H), 3.58 (dd, J=11, 2 Hz, 3.2 Hz, 1H), 4.11 (d, J=11.6 Hz, 1H), 4.22 (d, J=9.2 Hz, 1H), 4.51 (br, 1H ), 4.79 (t, J=8.0 Hz, 1H), 5.04-5.11 (m, 1H), 5.22 (d, J=8.8 Hz, 1H), 7.36 -7.42 (m, 4H), 7.61 (d, J=7.6 Hz 1H), 8.68 (s, 1H).

[258] This solid (1.04 g, 1.9 mmol) was dissolved in 4 N. hydrogen chloride in methanol (3.0 ml) and the mixture was stirred at ambient temperature for 3 hours. TLC indicated completion of the reaction. The reaction mixture was concentrated to remove all volatiles under reduced pressure to obtain a light yellow solid. The solid was added to TBME (5 ml) and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered and the solid was collected and dried in an oven at 50°C to obtain the title compound (0.92 g, 100%).

^1H NMR (400 MHz, DMSO-d6): δ 1.03 (s, 9H), 1.38 (d, J=7.2 Hz, 3H), 1.72-1.79 (m, 1H) , 2.09-2.14 (m, 1H), 2.49 (s, 3H), 3.48-3.52 (m, 1H), 3.75-3.79 (m, 1H), 3 ,88-3.90 (m, 1H), 4.31 (br, 1H), 4.56 (t, J=8.4 Hz, 1H), 4.89-4.95 (m, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 8.20 (br, 3H), 8.67 (d, J=7 .6 Hz, 1H), 9.22 (s, 1H); ¹³ C NMR (400 MHz, DMSO-d6): δ 170.7, 167.1, 153.0, 146.5, 145.7, 132.5, 129.4, 129.3, 126.9, 69 ,4, 59.3, 58.5, 56.9, 48.3, 38.4, 34.8, 26.6, 23.0, 15.7; LC-MS [M+1] ⁺ : 445.6

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

Step 1. Preparation of 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile

[259] A mixture of 4-bromo-2-hydroxybenzonitrile (15 g, 76 mmol), 4-methylthiazole (14 ml, 152 mmol), KOAc (14.9 g, 152 mmol) and Pd(OAc) ₂ (0. 34 g, 1.52 mmol) in dry NMP (125 ml) at 110°C for 6 hours under nitrogen. TLC indicated completion of the reaction. The mixture was first cooled to room temperature, then partitioned between EtOAc and water. The combined organic fraction was filtered and the filtrate was washed with water, brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was dissolved in toluene (100 ml) and re-evaporated to give the crude product. The crude product was treated with cold MeOH (80 ml). The resulting precipitate was collected by filtration, washed with MeOH (20 mL) and dried under vacuum to give the title compound as a light yellow solid (10.5 g, 64%).

LC/MS: 217.2 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d6): δ 2.49 (s, 3H), 7.07 (dd, J=8.0, 1.6 Hz, 1H), 7.13 (d, J= 1.6 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 9.07 (s, 1H), 11.34 (s, 1H).

Step 2. Preparation of 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol

[260] To a solution of 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile (2.9 g, 13.41 mmol) in dry THF (150 ml) was added LiAlH ₄ (1.5 g, 40 .23 mmol) at 0°C. The resulting mixture was stirred at 50°C for 3 hours under a nitrogen atmosphere. TLC indicated completion of the reaction. The mixture was cooled in an ice water bath, then Na ₂ SO ₄ ^⋅ 10H ₂ O (5 g) was carefully added and stirred at this temperature for 1 hour. The mixture was filtered and the filter cake was washed four times with 10% MeOH in DCM. The combined filtrates were concentrated to give crude 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol as a light yellow solid (2.0 g, 68%). It was used in the next step without further purification.

LCMS: 221.2 [M+H] ⁺ .

^1H NMR (400 MHz, DMSO-d6): δ 2.43 (s, 3H), 3.54 (br, 2H), 6.11 (d, J=7.2 Hz, 1H), 6.40 (d, J=11.6 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 8.81 (s, 1H).

Step 3. Preparation of (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid

[261] Add L-valine (4.37 g, 37.3 mmol) to a solution of phthalic dicarboxaldehyde (5.0 g, 37.3 mmol) in acetonitrile (350 ml). The resulting mixture was heated at reflux for 5 hours. The reaction mixture was filtered while hot and the filtrate was slowly cooled to room temperature. The resulting precipitate was filtered and dried to give (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid as a white solid (6.45 g, 74%).

¹ H NMR (400 MHz, DMSO-d6): δ 0.85 (d, J=6.8 Hz, 3H), 1.0 (d, J=6.8 Hz, 3H), 2.25 2, 34 (m, 1H), 4.51 (d, J=4.4 Hz, 1H), 4.54 (d, J=3.6 Hz, 1H), 4.64 (d, J=18.0 Hz, 1H), 7.48-7.54 (m, 1H), 7.63 (d, J=3.6 Hz, 2H), 7.72 (d, J=7.6 Hz, 1H), 13.01 (br, 1H).

Step 4. Preparation of (2S,4R)-methyl-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylate

[262] In a solution containing 4-hydroxy-L-proline methyl ester hydrochloride (1.0 g, 5.52 mmol), (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butane acid (1.16 g, 4.97 mmol) and DIPEA (2.58 g, 20 mmol) in dry DMF (15 ml), HATU (3.8 g, 10 mmol) was added at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc and water. The organic phase was washed with water, brine and dried over anhydrous Na ₂ SO ₄ . The residue was purified by silica gel chromatography using 30 to 50% EtOAc in hexane as eluant to give the title compound as a light yellow solid (1.21 g, 67.6%).

LCMS: 361.3 [M+1] ⁺ .

Step 5. Preparation of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylic acid

[263] A mixture containing (2S,4R)-methyl-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylate (1, 2 g, 3.33 mmol), LiOH ^⋅ H ₂ O (559 mg, 13.32 mmol) in THF (20 ml) and H ₂ O (10 ml), stirred at room temperature for 2 hours. TLC indicated completion of the reaction. The reaction mixture was acidified with 1 N. HCl to pH 1-2 and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to give the title compound as a light yellow solid (1.05 g, 91% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.91 (d, J=6.4 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H), 2.30 (dd, J=8.4, 2.8 Hz, 2H), 2.44-2.50 (m, 1H), 3.75 (dd, J=11.2, 3.2 Hz, 1H), 4.42 (d, J=17.6 Hz, 1H), 4.50-4.55 (m, 2H), 4.66 (t, J=8.4 Hz, 1H), 4.75 (d, J= 17.6 Hz, 1H), 4.83 (d, J=11.2 Hz, 1H), 7.42-7.45 (m, 2H), 7.51-7.56 (m, 1H), 7.78 (d, J=7.6 Hz, 1H).

Step 6. Preparation of (2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1 -oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide

[264] In a solution containing (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylic acid (1, 0 g, 2.89 mmol), 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol (954 mg, 4.33 mmol) and DIPEA (1.5 g, 11.55 mmol) in DMF (20 ml), HATU (2.2 g, 5.77 mmol) was added at 0°C. The resulting mixture was stirred at room temperature for 1 hour. Completion of the reaction was indicated by TLC. The mixture was partitioned between EtOAc and water. The organic phase was washed with water, brine and dried over anhydrous Na ₂ SO ₄ . The residue was purified by silica gel column chromatography using 2 to 5% MeOH in DCM to give the title compound as a light yellow solid (650 mg, 43% yield).

LCMS: 549.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.80 (d, J=6.8 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H), 1.96-2, 01 (m, 1H), 2.34-2.40 (m, 1H), 2.47-2.53 (m, 4H), 3.61 (dd, J=11.6, 3.6 Hz, 1H), 4.29-4.37 (m, 2H), 4.38 4.41 (m, 1H), 4.47-4.50 (m, 2H), 4.64-4.69 (m , 2H), 4.72 (s, 1H), 6.90 (dd, J=8.0, 2.0 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 7 .14 (d, J=8.0 Hz, 1H), 7.39-7.44 (m, 2H), 7.51-7.54 (m, 1H), 7.76 (d, J=7 .6 Hz, 1H), 8.03 (t, J=6.4 Hz, 1H), 8.66 (s, 1H), 9.27 (br, 1H).

Intermediate 4. (2R,4S)-1-[(S)-2-Amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(S)-1-(4-(4-methylthiazol-5 -yl)phenyl)ethyl]pyrrolidine-2-carboxamide hydrochloride (ULM-4)

[265] This compound was synthesized using the same method as described in the preparation of ULM-2 using (2R,4S)-methyl-4-hydroxypyrrolidine-2-carboxylate hydrochloride. ^1H NMR (400 MHz, CD ₃ OD): δ 1.14 (s, 9H), 1.55 (d, J=6.8 Hz, 3H), 2.00-2.05 (m, 1H) , 2.51-2.58 (m, 1H), 2.65 (s, 3H), 3.77-3.81 (m, 1H), 3.88-3.92 (m, 1H), 4 .06 (br, 1H), 4.41-4.46 (m, 1H), 4.56-4.60 (m, 1H), 5.07-5.12 (m, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 10.02 (s, 1H). LC-MS [M+H] ⁺ : 445.3

Intermediate 5 and Intermediate 6. Tert-butyl-N-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1R)-2-hydroxy-1-[4-( 4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (ULM-5-A) and tert-butyl-N-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-2-hydroxy-1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (ULM-5-B)

Step 1. Synthesis of 2-(4-bromophenyl)oxirane

[266] Heat a mixture of 4-bromobenzaldehyde (2.52 g, 13.6 mmol), trimethylsulfonium iodide (2.87 g, 14.1 mmol), water (0.65 ml, 36.1 mmol) and potassium hydroxide ( 1.56 g, 27.7 mmol) in acetonitrile (20 ml) to 55°C for 4 hours. The resulting solution was partitioned between water and diethyl ether, and the organic layer was washed with water, dilute hydrochloric acid and brine and dried over sodium sulfate. The crude product, 2-(4-bromophenyl)oxirane (2.20 g, 81.8% yield), was obtained by removing the organic solvent under reduced pressure and used for the next reaction without purification.

^1H NMR (400 MHz, CDCl ₃ ) δ 2.74 (1H, q, J=2.8 Hz), 3.14 (1H, dd, J=4.0 Hz, 5.2 Hz), 3, 82 (1H, dd, J=2.4 Hz, 4.0 Hz), 7.15 (2H, d, J=8.4 Hz), 7.47 (2H, d, J=8.8 Hz) .

Step 2. Synthesis of 2-azido-2-(4-bromophenyl)ethanol

[267] Sodium azide (3.28 g, 50.5 mmol) was added to a stirred suspension of 2-(4-bromophenyl)oxirane (5.0 g, 25.3 mmol) in distilled water (70 ml), and the resulting mixture was stirred at 60 °C for 4 hours and monitored by TLC. After completion of the reaction, the mixture was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-azido-2-(4-bromophenyl)ethanol (5.5 g, 90.2%) in as pale yellow oils. The crude product was used directly in the next step.

^1H NMR (400 MHz, CDCl ₃ ) δ 1.94 (1H, s), 3.63-3.66 (2H, m), 4.57 (1H, dd, J=5.2 Hz, 7, 6 Hz), 7.15 (2H, d, J=8.4 Hz), 7.46 (2H, d, J=8.4 Hz).

Step 3. Synthesis of 2-amino-2-(4-bromophenyl)ethanol hydrochloride

[268] To a solution of 2-azido-2-(4-bromophenyl)ethanol (2.0 g, 8.30 mmol) in tetrahydrofuran (20.0 ml) and water (5.00 ml) was added triphenylphosphine (4.35 g, 16.6 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The residue was dissolved in HCl/dioxane (4 M, 10.0 ml) and stirred at room temperature for 1 hour. After concentration, the solid was washed with dichloromethane to obtain 2-amino-2-(4-bromophenyl)ethanol hydrochloride (1.5 g, 72.1% yield) as white solids.

^1H NMR (400 MHz, CDCl ₃ ) δ 3.70 (2H, s), 4.28 (1H, s), 5.55 (1H, s), 7.47 (2H, d, J=8, 4 Hz), 7.63 (2H, d, J=8.4 Hz), 8.61 (3H, s); LC/MS 216.2 [M+H] ⁺ .

Step 4. Synthesis of 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethanamine

[269] To a solution of 2-amino-2-(4-bromophenyl)ethanol hydrochloride (1.80 g, 7.17 mmol) in dichloromethane (50 ml) was added imidazole (1.95 g, 2.87 mmol) and tert. -butyldimethylsilyl chloride (TBSC1) (1.63 g, 10.8 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and then quenched with water. The aqueous phase was extracted with dichloromethane (30 ml x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude compound. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1) to give 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethanamine (1.50 g, 63.6%) as white solids.

LC/MS: 330.1 [M+H] ⁺ ;

Step 5. Synthesis of tert-butyl-1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylcarbamate

[270] To a solution of 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethanamine (1.50 g, 4.56 mmol) in tetrahydrofuran (20 ml) was added triethylamine (0.69 g, 6.84 mmol ) and di-tert-butyl dicarbonate (1.49 g, 6.84 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with water. The aqueous phase was extracted with ethyl acetate (50 ml x 3) and washed with brine. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude compound. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100:1) to give tert-butyl-1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylcarbamate (1.80 g, 92.0 %) in the form of pale yellow oils.

^1H NMR (400 MHz, CDCl ₃ ) δ 0.01 (6H, d, J=9.6 Hz), 0.86 (9H, s), 1.42 (9H, s), 3.65-3 .70 (2H, m), 4.60-4.63 (1H, m), 7.34 (2H, d, J=8.0 Hz), 7.39 (1H, d, J=8.8 Hz), 7.56 (2H, d, J=8.4 Hz).

Step 6. Synthesis of tert-butyl-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate

[271] Dissolved a mixture of tert-butyl-1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylcarbamate (4.0 g, 9.32 mmol), 4-methylthiazole (1.85 g, 18.6 mmol ), potassium acetate (1.82 g, 18.6 mmol), palladium(II) acetate (0.11 g, 0.47 mmol) in dimethylacetamide and stirred under argon. The mixture was heated to 140°C and stirred for 15 hours, then diluted with water. The aqueous phase was extracted with ethyl acetate (50 ml x 3) and washed with brine. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude compound, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100:1) to give tert-butyl-2-hydroxy-1-(4 -(4-methylthiazol-5-yl)phenyl)ethylcarbamate (1.30 g, 41.8%) as pale yellow solids.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.38 (9H, s), 2.46 (3H, s), 3.52 (2H, t, J=6.0 Hz), 4.55-4 .58 (1H, m), 4.84 (1H, t, J=6.0 Hz), 7.30 (1H, d, J=8.0 Hz), 7.38-7.45 (4H, m), 8.99 (1H, s); LC/MS 335.2 [M+H] ⁺ ; Rt=1.859 min.

Step 7. Synthesis of 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride

[272] Dissolve tert-butyl-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (300 mg, 0.536 mmol) in hydrochloric acid/dioxane (5 mL, 4 M). The resulting reaction mixture was stirred at room temperature for 3 hours. The solvent was concentrated in vacuo to give 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride as white solids, which were used in the next step without further purification.

Step 8. Synthesis of tert-butyl-N-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1R)-2-hydroxy-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (ULM-5-A) and tert-butyl- N-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (ULM-5-B)

[273] Stir a solution of 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride (1000 mg, 3.70 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (995 mg, 5.19 mmol), 1-hydroxybenzotriazole (HOBT) (695 mg, 5.19 mmol), (2S,4R)-1-((S)-2-(tert-butoxycarbonylamino)- 3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1273 mg, 3.70 mmol) and triethylamine (747 mg, 7.40 mmol) in N,N-dimethylformamide (50 ml) at room temperature for night under argon atmosphere and then water (80 ml) was added to the mixture. The aqueous layer was extracted with ethyl acetate (50 ml x 5). The combined organic layer was washed with brine (50 ml x 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by preparative TLC (dichloromethyl/methanol = 15:1) to give tert-butyl-(S)-1-((2S,4R)-4-hydroxy-2-((R)-2-hydroxy- l-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (700 mg) as pale yellow oils and tert -butyl-(S)-1-((2S,4R)-4-hydroxy-2-((S)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidine -1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (500 mg) as pale yellow oils.

[274] ULM-5-A: ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (9H, s), 1.39 (9H, s), 1.77-1.83 (1H, m) , 2.01-2.06 (1H, m), 2.46 (3H, s), 3.54-3.60 (4H, m), 4.13-4.19 (1H, m), 4 ,29-4.36 (1H, m), 4.50 (1H, t, J=8.0 Hz), 4.78 (1H, t, J=5.6 Hz), 4.81-4, 88 (1H, m), 5.12-5.16 (1H, m), 6.46 (1H, d, J=9.2 Hz), 7.36-7.46 (4H, m), 8 .41 (1H, d, J=8.0 Hz), 8.99 (1H, s); LC/MS 561.2 [M+H] ⁺ ; Rt=1.897 min.

[275] ULM-5-B: ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.87 (9H, s), 1.38 (9H, s), 1.92 2.06 (2H, m), 2.45 (3H, s), 3.56-3.69 (4H, m), 4.06-4.14 (1H, m), 4.36 (1H, s), 4.56 (1H, t, J=7.6 Hz), 4.76 4.81 (1H, m), 4.87 (1H, t, J=5.6 Hz), 5.146 (1H, d, J=2.8 Hz ), 6.47 (1H, d, J=8.8 Hz), 7.37 (2H, d, J=8.0 Hz), 7.51 (2H, d, J=8.0 Hz), 8.37 (1H, d, J=7.6 Hz), 8.98 (1H, s); LC/MS 561.2 [M+H] ⁺ ; Rt=1.887 min.

Intermediate 7. (2S,4R)-N-[(4-Chloro-2-hydroxyphenyl)methyl]-4-hydroxy-1-[3-methyl-2-(3-methyl-1,2-oxazole-5 -yl)butanoyl]pyrrolidine-2-carboxamide (ULM-6)

[276] This key intermediate was prepared using the above synthetic route. The required 3-methylisoxazole-5-acetic acid was prepared according to the literature (J. Org. Chem. 66, 6595-6603, 2001). Alkylation with 2-iodopropane is described in the literature. The required ULM-6 was prepared using the same synthesis method as described for the preparation of intermediate ULM-3.

[277] ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.33 (s, 0.5H), 9.20 (s, 0.5H), 8.07 (t, J=6.4 Hz, 0.5H), 7.83 (t, J=6.0 Hz, 0.5H), 6.99 (dd, J=2.4, 8.0 Hz, 1H), 6.89-6.90 (m, 1H), 6.76-6.78 (m, 1H), 6.02 (s, 0.5H), 5.99 (s, 0.5H), 5.80-5.83 (m , 0.5H), 4.35 (q, J=6.4 Hz, 1.5), 4.16-4.25 (m, 2H), 3.72-3.76 (m, 0.5H ), 3.61 (d, J=9.2 Hz, 1.0H), 3.51-3.55 (m, 1.5H), 2.30-2.46 (m, 2.5H), 2.26 (s, 1.5H), 2.24 (s, 1.5H), 1.95-2.05 (m, 1H), 1.01 (d, J=6.8 Hz, 1, 5H), 0.82-0.87 (m, 4.5H); LC-MS 436.1 [M+l] ⁺ ; Rt=3.57 min.

PTM synthesis

[278] Preferred embodiments of the PTM of the present invention can be prepared in accordance with the synthetic routes in Schemes 1-3 below. These pathways can be modified and adapted to the synthesis of a particular embodiment of PTM using general methods known to those skilled in the art.

[279]

Synthesis of illustrative PROTACs

[280] Intermediate connection 1

[281] Step 1. 2-(2,6-Dioxopiperidin-3-yl)-5-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)isoindoline-1,3-dione

[282] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (500 mg, 1.82 mmol) in DMF (10 ml) was added K ₂ CO ₃ (756 mg, 5.47 mmol) and 2-(2-(2-hydroxyethoxy)ethoxy)ethyl-4-methylbenzenesulfonate (832 mg, 2.73 mmol) at 25°C. The resulting solution was stirred at 70°C for 5 hours. After cooling to room temperature, the reaction mixture was quenched with H ₂ O (10 ml) and the mixture was extracted with EtOAc (10 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to obtain the desired product (95 mg, 13% yield).

[283] Step 2: 2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)acetaldehyde

[284] In a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (95 mg, 0.23 mmol) in CH ₃ CN (5 ml) was added IBX (130 mg, 0.46 mmol) at 25°C. The reaction mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated to give crude intermediate 1, 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5 -yl)oxy)ethoxy)ethoxy)acetaldehyde (90 mg), which was used without further purification.

[285] Intermediate connection 2

[286] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (10 g, 36.2 mmol) in NMP (70 ml) was added tert-butylpiperazine-1- carboxylate (13.47 g, 72.5 mmol) and DIPEA (18.6 g, 14.5 mmol). The resulting mixture was stirred at 90°C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (100 ml) and the mixture was extracted with ErOAc (300 ml x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA = 100-2/1) to give the desired product, 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindolin-1 ,3-dione (14 g, 31.67 mmol, 87.5% yield) as a light yellow solid.

[287] Scheme for the synthesis of exemplary compound 51

[288] Step 1. 3-(4-Bromophenyl)-4-nitropyridine

[289] Into a stirred solution of 3-bromo-4-nitropyridine (100 g, 492.6 mmol), (4-bromophenyl)boronic acid (98.6 g, 492.6 mmol) and potassium carbonate (203.9 g, 1.47 mol) to a mixture of toluene (1000 ml) - water (100 ml) was added tetrakis(triphenylphosphine) palladium (14.8 g, 12.8 mmol) at room temperature under a nitrogen atmosphere; the mixture was degassed three times with nitrogen. The resulting mixture was stirred at 50°C overnight. TLC indicated completion of the reaction. The solid was removed by filtration and washed with ethyl acetate (100 ml x 3). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (100 ml x 2). The combined organic layers were washed with brine (400 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified with a pad of silica gel (eluting with 10 to 33% ethyl acetate in hexane) to give 3-(4 -bromophenyl)-4-nitropyridine (89 g, 65% yield) as a yellow solid.

[290] Step 2. 7-Bromo-5H-pyrido[4,3-b]indole

[291] Stir a mixture of 3-(4-bromophenyl)-4-nitropyridine (20.0 g, 71.7 mmol) in triethyl phosphate (400 ml) at 110° C. for 2 hours under nitrogen atmosphere. TLC indicated completion of the reaction. The volatiles were evaporated under reduced pressure to leave a residue, which was purified by recrystallization (methanol) to give 7-bromo-5H-pyrido[4,3-b]indole (11.0 g, 62% yield) as a brown solid.

[292] Step 3. 7-(6-Fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole

[293] Heat a mixture of 7-bromo-5H-pyrido[4,3-b]indole (400 mg, 1.63 mmol), (6-fluoropyridin-3-yl)boronic acid (344 mg, 2.44 mmol) , PdCl ₂ (dppf) (120 mg, 0.163 mmol), tBu ₃ PHBF ₄ (95 mg, 0.326 mmol) and Cs ₂ CO ₃ (1.1 g, 3.26 mmol) in dioxane/water (20 ml, 20:1) up to 90°C for 4 hours in an N ₂ atmosphere. The solid was filtered and the filtrate was evaporated. The residue was purified by chromatography (silica gel, 200-300 mesh, CH ₂ Cl ₂ : MeOH = 30:1) to give 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ( 250 mg, yield 59%).

[294] Step 4. 14-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecane-1- ol

[295] To a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (270 mg, 1.13 mmol) in THF (10 ml) was added NaH (45 mg, 60%, 1.13 mmol) at 0°C. After stirring at 20°C for 1 hour, a solution of 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (150 mg, 0.57 mmol) in DMF (2.0 ml). The resulting solution was stirred at 80°C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with EA (30 ml) and the mixture was washed with brine. The organic phase was evaporated under reduced pressure. The residue was purified by silica gel chromatography using a silica gel column (DCM/MeOH = 4/1) to obtain the desired product (200 mg, 72.89% yield) as a colorless oil.

[296] Step 5. tert-Butyl-7-(6-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b] indole-5-carboxylate

[297] Into a solution of 14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol (150 mg, 0.31 mmol) NEt ₃ (94.5 mg, 0.93 mmol) and Boc ₂ O (102.0 mg, 0.47 mmol) were added to DCM (10 ml). The resulting solution was stirred at ambient temperature for 12 hours. The solvent was removed under vacuum. The residue was diluted with EA (30 ml) and the mixture was washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the desired product (120 mg, 66% yield), which was used in the next step without further purification.

[298] Step 6. tert-Butyl-7-(6-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3, 6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate

[299] Into a solution of tert-butyl-7-(6-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole -5-carboxylate (120 mg, 0.31 mmol) and NEt ₃ (93.9 mg, 0.93 mmol) in DCM (10 ml) was added MsCl (38.9 mg, 0.34 mmol) at 0°C . After stirring at 30°C for 1 hour, the solvent was removed. The residue was diluted with EA (30 ml) and washed with brine. The organic phase was concentrated to give the intermediate mesylate.

[300] To a stirred solution of mesylate (100 mg, 0.15 mmol) in dry DMF (10 ml) was added 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (45, 6 mg, 0.17 mmol) and K ₂ CO ₃ (31.4 mg, 0.23 mmol). The resulting mixture was stirred at 68°C for 4 hours. The mixture was diluted with EtOAc (40 ml), washed twice with brine and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH = 20/1) to obtain the desired product as a yellow solid (15 mg, 23.6% yield).

[301] Step 7. 5-((14-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12- tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[302] Into a solution of tert-butyl-7-(6-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6 ,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate (30 mg, 0.036 mmol) in DCM (2 ml) added TFA (5 ml) . The mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC to give the title compound as a white solid (10 mg, 38% yield). ^1H NMR (400 MHz, CDCl ₃ ):δ 12.34-12.48 (m, 1H), 9.19-9.29 (m, 1H), 8.80 (s, 1H), 8.29 -8.42 (m, 1H), 8.02-8.14 (m, 1H), 7.95 (s, 1H), 7.69-7.81 (m, 1H), 7.60 (s , 2H), 7.17 (s, 1H), 7.09 (s, 1H), 6.62 (s, 1H), 4.97 (s, 1H), 4.43 (s, 2H), 4 .14 (s, 2H), 3.88 (d, J=24.1 Hz, 3H), 3.78 (d, J=8.2 Hz, 3H), 3.69 (d, J=10, 0 Hz, 6H), 2.80 (m, 4H), 1.99-2.29 (m, 4H). (M+H) ⁺ 738.3.

[303] Compound 50 was also prepared using procedures similar to those for compound 51.

[304] Scheme for the synthesis of exemplary compound 52

[305] Step 1. tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate

[306] Stir a solution of 2-(piperazin-1-yl)ethanol (5 g, 38.5 mmol) and TEA (12 g, 115 mmol) in DCM at 0°C, add Boc ₂ O, then stir the mixture at 10 °C overnight. Added water. The mixture was then extracted with DCM, dried, and concentrated, and filtered through a pad of silica gel to obtain 8.1 g of product (92% yield).

[307] Step 2. tert-Butyl 4-(2-(prop-2-yn-1-yloxy)ethyl)piperazine-1-carboxylate

[308] Stir a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (3 g, 13 mmol) in THF at 0°C. NaH (624 mg, 15.6 mmol) was added, then the mixture was stirred at room temperature for 1 hour. 3-bromoprop-1-yne (1.85 g, 15.6 mmol) was added and stirring was continued at 70°C overnight. The mixture was then cooled to room temperature. Water was added, then the mixture was extracted with EA, dried with Na ₂ SO ₄ and concentrated. Filter through a pad of silica gel (EA) to obtain 1.5 g of product (43% yield).

[309] Step 3. tert-Butyl 4-(2-((3-(5-bromopyridin-2-yl)prop-2-yn-1-yl)oxy)ethyl)piperazine-1-carboxylate

[310] Stirred tert-butyl 4-(2-(prop-2-yn-1-yloxy)ethyl)piperazine-1-carboxylate (500 mg, 1.86 mmol), 2,5-dibromopyridine (442 mg, 1.86 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (10%), CuI (11%) DIPEA and CH ₃ CN at 5°C overnight and EA was added. The mixture was washed with water and concentrated. Then filtered through silica gel (EA) to obtain 450 mg of product (57% yield).

[311] Step 4. tert-Butyl-4-(2-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propoxy)ethyl)piperazin- 1-carboxylate

[312] 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[4,3-b]indole-5-carboxylate [prepared using the procedure , similar to the procedure in step 1 of illustrative compound 63] (300 mg, 0.76 mmol), Pd(amphos)Cl ₂ (50 mg, 10%) and CsF (450 mg, 2.96 mmol) in CH ₃ CN/H ₂ O (10:1) at 120°C in the microwave for 40 minutes. The mixture was cooled to room temperature and EA was added. The organic layer was washed with water, then filtered through a pad of silica gel (DCM:MeOH = 20:1) to obtain 100 mg of tert-butyl-4-(2-(3-(5-(5H-pyrido[4,3-b]indole -7-yl)pyridin-2-yl)prop-2-ynyloxy)ethyl)piperazine-1-carboxylate. The crude product was dissolved in MeOH, Pd/C was added and the mixture was stirred at 30°C under H ₂ at 2 MPa for 2 hours, filtered and concentrated to give 100 mg of product (26% yield).

[313] Step 5. 7-(6-(3-(2-(Piperazin-1-yl)ethoxy)propyl)pyridin-3-yl)-5H-pyrido[4,3-b]indole

[314] Stir tert-butyl-4-(2-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propoxy)ethyl)piperazine-1- carboxylate (100 mg, 0.2 mmol) in HCl/dioxane solution (2 ml) at 5°C for 1 hour. Concentrated to obtain 100 mg of crude product.

[315] Step 6. 5-((5-(4-(2-(3-(5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propoxy)ethyl )piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[316] Stirred 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)pentanal (86 mg, 0.24 mmol), NaBH ₄ CN (55 mg, 0 .48 mmol) and CH ₃ COOH (cat.) in MeOH at 5°C for 3 hours. DCM was then added. The organic layer was washed with water, concentrated and filtered through a pad of silica gel (DCM:MeOH = 8:1) to obtain 11 mg of product.

[317] ¹ H NMR (400 MHz, MeOD): δ 9.25 (s, 1H), 8.79 (s, 1H), 8.37-8.39 (d, J=8 Hz, 1H), 8.28 8.30 (d, J=8 Hz, 1H), 8.11 8.13 (d, J=8 Hz, 1H), 7.80 (s, 1H), 7.75-7.77 (d, J=8 Hz, 1H), 7.60 (s, 1H), 7.49-7.51 (d, J=8 Hz, 1H), 7.43-7.45 (d, J= 8 Hz, 1H), 7.33 (s, 1H), 5.07-5.09 (m, 1H), 4.06-4.09 (m, 2H), 3.57-3.60 (m , 2H), 3.51-3.54 (m, 2H), 2.93-2.95 (m, 2H), 2.91-2.93 (m, 1H), 2.59-2.75 (m, 12H), 2.37-2.41 (m, 2H), 2.04-2.06 (m, 3H), 1.78-1.80 (m, 2H), 1.46-1 .55 (m, 5H). (M+H) ⁺ 758.3.

[318] Scheme for the synthesis of exemplary compound 53

[319] Step 1. (((1s,3s)-3-(Allyloxy)cyclobutoxy)methyl)benzene

[320] To a solution of (1s,3s)-3-(benzyloxy)cyclobutanol (1.0 g, 5.61 mmol) in DMF (10 ml) was added NaH (60%, 0.336 g, 8.4 mmol) at 0 °C. After stirring for 30 min. 3-bromoprop-1-ene was added dropwise at room temperature. The resulting solution was stirred at room temperature for 3 hours. After quenching the resulting solution with saturated NH ₄ Cl solution (20 ml), the mixture was extracted with EtOAc (20 ml x 2). The combined organic layers were dried with Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by a silica gel column using PE/EA = 10-1 as eluent to give the desired product (1.0 g, 82%) as a colorless oil.

[321] Step 2: 3-((1s,3s)-3-(Benzyloxy)cyclobutoxy)propan-1-ol

[322] To a solution of (((1s,3s)-3-(allyloxy)cyclobutoxy)methyl)benzene (1.0 g, 4.58 mmol) in THF (20 ml) was added dicyclohexylborane in THF (1.0 M, 9.0 ml) at 0°C. After stirring the mixture at room temperature for 4 hours, NaOH (37%, 3.0 ml) and H ₂ O ₂ (30%, 3.0 ml) were added to the mixture at 0°C. The resulting solution was stirred at room temperature overnight. The reaction mixture was quenched with Na ₂ S ₂ O ₃ (20 ml). The mixture was absorbed with DCM. The organic phase was dried with Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by a silica gel column using PE/EA = 2:1 as the eluent to give the desired product (1.0 g, 100%) as a colorless oil.

[323] Step 3. tert-Butyl 4-(3-((1s,3s)-3-(benzyloxy)cyclobutoxy)propyl)piperazine-1-carboxylate

[324] In a solution of 3-((1s,3s)-3-(benzyloxy)cyclobutoxy)propan-1-ol (1.0 g, 4.58 mmol) and TEA (2.0 g, 19.8 mmol) MsCl (0.97 g, 9.2 mmol) was added to DCM (10 ml) at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was quenched with saturated sodium bicarbonate solution (20 ml) and the mixture was extracted with DCM (20 ml x 2). The combined organic layers were dried with Na ₂ SO ₄ and concentrated in vacuo to give the desired product (1.1 g, crude), which was used in the next reaction without further purification.

[325] To a solution of the above intermediate (1.1 g, crude) in DMF (10 ml) was added tert-butylpiperazine-1-carboxylate (1.60 g, 9.2 mmol). The resulting solution was heated to 90°C for 4 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 ml) and the mixture was extracted with EtOAc (20 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by a silica gel column using PE/EA = 2:1 as eluent to give the desired product (980 mg, 58%) as a colorless oil.

[326] Step 4. tert-Butyl 4-(3-((1s,3s)-3-hydroxycyclobutoxy)propyl)piperazine-1-carboxylate

[327] Stir a mixture of tert-butyl 4-(3-((1s,3s)-3-(benzyloxy)cyclobutoxy)propyl)piperazine-1-carboxylate (980 mg, 2.42 mmol) and Pd(OH) ₂ /C (300 mg, 20%) in CH ₃ OH (10 ml) at room temperature overnight in an atmosphere of H ₂ at 1 atm. The mixture was filtered through celite and the filtrate was concentrated to give the desired product (700 mg, crude), which was used in the next reaction without further purification.

[328] Step 5. tert-Butyl-4-(3-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)propyl)piperazine-1-carboxylate

[329] In a solution of tert-butyl 4-(3-((1s,3s)-3-hydroxycyclobutoxy)propyl)piperazine-1-carboxylate (180 mg, 0.57 mmol) and 7-(6-fluoropyridine-3 -yl)-5H-pyrido[4,3-b]indole (100 mg, 0.379 mmol) in NMP (10 ml) was added NaH (60%, 100 mg, 2.5 mmol) at room temperature. The resulting solution was heated to 90°C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NH ₄ Cl solution (20 ml) and the mixture was extracted with EtOAc (20 ml x 3). The combined organic layers were dried with Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC using DCM/CH ₃ OH (15:1) to obtain the desired product (120 mg, 0.21 mmol) as a brown solid.

[330] Step 6. 7-(6-((1s,3s)-3-(3-(Piperazin-1-yl)propoxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b ]indole

[331] Stir the mixture of tert-butyl-4-(3-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)cyclobutoxy)propyl)piperazine-1-carboxylate (120 mg, 0.21 mmol) in CH ₃ OH (2.0 ml) and HCl in 1,4-dioxane (4.0 ml) at room temperature for 2 hours. The solvent was removed in vacuo to obtain the desired product (100 mg, crude), which was used in the next reaction without further purification.

[332] Step 7. 5-(4-(3-((1s,3s)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)cyclobutoxy)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[333] Into a mixture of 7-(6-((1s,3s)-3-(3-(piperazin-1-yl)propoxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b] indole (80 mg, crude) and DIEA (300 mg, 2.36 mmol) in NMP (2.0 ml) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (100 mg, 0.36 mmol). The mixture was heated under microwave radiation at 130°C for 45 minutes. After cooling to room temperature, the reaction mixture was taken up with EtOAc (100 ml). The mixture was washed with brine (20 ml x 3). The organic phase was dried with Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC using DCM/CH ₃ OH/NH ₃ H ₂ O (15:1:0.1) , to obtain the title product (16.0 mg, 13%) as a yellow solid.

[334] ¹ NMR (400 MHz, CDCl ₃ ): δ 9.34 (s, 1H), 8.55 (d, J=5.6 Hz, 1H), 8.44 (m, 2H), 8, 20 (d, J=8.4 Hz, 1H), 7.87-7.92 (m, 3H), 7.68 (d, J=8.4 Hz, 1H), 7.60 (s, 1H ), 7.48-7.50 (m, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.06 (m, 1H), 6.84 (d, J=8, 8 Hz, 2H), 4.93-4.94 (m, 2H), 3.75 (m, 2H), 3.42-3.49 (m, 6H), 2.72-2.98 (m , 5H), 2.61 (s, 4H), 2.53 (t, J=7.2 Hz, 2H), 2.15-2.18 (m, 2H), 1.81 (t, J= 6.8 Hz, 2H). (M+H) ⁺ 714.3

[335] Scheme for the synthesis of exemplary compound 55

[336] Step 1. tert-Butyl 4-(5-(3-methoxy-3-oxoprop-1-en-1-yl)pyridin-2-yl)piperazine-1-carboxylate

[337] In a solution of tert-butyl-4-(5-formylpyridin-2-yl)piperazine-1-carboxylate (1.0 g, 3.44 mmol) and methyl 2-(dimethoxyphosphoryl) acetate (750 mg, 4 .12 mmol) to THF (15 ml) was added DBU (1.57 g, 10.3 mmol). The reaction mixture was stirred at room temperature overnight. After quenching the resulting water, H ₂ O (10 ml), the mixture was extracted with ethyl acetate (50 ml). The organic phase was washed with brine and dried over Na ₂ SO ₄ . The resulting mixture was filtered and concentrated in vacuo. The residue was digested with petroleum ether to give the desired product (800 mg, 2.3 mmol, yield: 66.9%) as a pale solid.

[338] Step 2. tert-Butyl 4-(5-(3-hydroxypropyl)pyridin-2-yl)piperazine-1-carboxylate

[339] Into a solution of tert-butyl 4-(5-(3-methoxy-3-oxoprop-1-en-1-yl)pyridin-2-yl)piperazin-1-carboxylate

[340] (800 mg, 2.3 mmol) NaBH ₄ (874 mg, 23.0 mmol) was added to CH ₃ OH (8 ml) and THF (35 ml). The mixture was heated to 80°C for 3 hours. After cooling to room temperature, the reaction mixture was quenched with 2 N. NH ₄ Cl and the mixture was extracted with EtOAc (80 ml x 3). The combined organic layers were washed with brine and dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by a silica gel column (EA:PE = 1:1) to obtain the desired compound (420 mg, 1.31 mmol, yield: 57.0%) as a yellow oil.

[341] Step 3. tert-Butyl 4-(5-(3-((methylsulfonyl)oxy)propyl)pyridin-2-yl)piperazine-1-carboxylate

[342] In a solution of tert-butyl-4-(5-(3-hydroxypropyl)pyridin-2-yl)piperazine-1-carboxylate (50 mg, 0.16 mmol) and Et ₃ N (48 mg, 0.48 mmol) in DCM (2 ml) was added MsCl (27 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 hour. After quenching the resulting water, H ₂ O (30 ml), the mixture was extracted with DCM (20 ml). The organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude title compound (64 mg) as a yellow oil, which was used in the next reaction without further purification.

[343] Step 4. tert-Butyl-4-(5-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)pyridin- 2-yl)piperazine-1-carboxylate

[344] In a solution of tert-butyl 4-(5-(3-((methylsulfonyl)oxy)propyl)pyridin-2-yl)piperazine-1-carboxylate (64 mg, 0.16 mmol) and 2-(2 ,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (66 mg, 0.24 mmol) in DMF (5 ml) was added K ₂ CO ₃ (55 mg, 0.40 mmol). The reaction mixture was stirred at 90°C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with water (5 ml) and the mixture was extracted with dichloromethane (30 ml). The organic phase was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by a silica gel column (MeOH:DCM = 1:100 to 1:20) to give the title product (30 mg, 0.052 mmol, yield: 32%).

[345] Step 5: 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(6-(piperazin-1-yl)pyridin-3-yl)propoxy)isoindoline-1,3-dione

[346] Into a solution of tert-butyl-4-(5-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)pyridin-2 -yl)piperazine-1-carboxylate (200 mg, 0.39 mmol) in dioxane (10 ml) was added 6 N. HCl in dioxane (2 ml, 12.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to obtain the crude title product (200 mg) as a yellow solid.

[347] Step 6. (6-(3-Hydroxyprop-1-yn-1-yl)pyridin-3-yl)boronic acid

[348] A solution of (b-bromopyridin-3-yl)boronic acid (1.0 g, 4.95 mmol) and prop-2-yn-1-ol (830 mg, 14.8 mmol) in THF (30 ml) PdCl ₂ (PPh ₃ ) ₂ (350 mg, 0.50 mmol), ⁱ Pr ₂ NH (2 g, 19.8 mmol) and CuI (95 mg, 0.5 mmol) were added. The reaction mixture was stirred at room temperature overnight. The mixture was filtered through celite and 1N was added to the filtrate. NaOH (10 ml). The mixture was extracted with DCM. Adjust the pH to approximately 6 with 2N. HCl. The aqueous solution was extracted with ethyl acetate. The combined EtOAc layers were dried over Na ₂ SO ₄ , filtered and evaporated to dryness under reduced pressure to give the title compound (500 mg, 2.82 mmol, 57% yield) as a pale solid.

[349] Step 7. 3-(5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)prop-2-yn-1-ol

[350] In a mixture of 7-bromo-5H-pyrido[4,3-b]indole (50 mg, 0.20 mmol) and (6-(3-hydroxyprop-1-yn-1-yl)pyridin-3- yl)boronic acid (53 mg, 0.30 mmol) in dioxane (10 ml) and water (1.0 ml) was added PdCl ₂ (dppf) (29 mg, 0.04 mmol), Cs ₂ CO ₃ (130 mg , 0.40 mmol) and ^t Bu ₃ PHBF ₄ (23 mg, 0.08 mmol). The mixture was stirred at 100°C for 3 hours under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was quenched with water (3 ml) and the mixture was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by a silica gel column (MeOH:DCM = 1:20 to 1:10) to obtain the desired compound (30 mg, 0.10 mmol, yield: 50.0%) as a yellow solid.

[351] Step 8. 3-(5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propan-1-ol

[352] Into a solution of 3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)prop-2-yn-1-ol (30 mg, 0.10 mmol ) Pd(OH) ₂ /C (20%, 10 mg) and cat. conc. HCl (0.1 ml). The reaction mixture was stirred at room temperature for 2 hours under an H ₂ atmosphere. The mixture was filtered through celite and the filtrate was concentrated to give the crude title compound (30 mg) as a yellow oil.

[353] Step 9. 3-(5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propanal

[354] Mix a solution of 3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propan-1-ol (100 mg, 0.33 mmol) in DMSO ( 4 ml) with IBX (231 mg, 0.82 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with a saturated solution of Na ₂ S ₂ O ₃ (2 ml) and a saturated solution of NaHCO ₃ (2 ml). The mixture was extracted with dichloromethane (30 ml). The organic phase was washed with water and brine. The resultant was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude title product (60 mg) as a yellow oil.

[355] Step 10. 5-(3-(6-(4-(3-(5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin- 1-yl)pyridin-3-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[356] To a solution of 3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propanal (100 mg, crude) in MeOH (10 ml) was added 2-( 2,6-dioxopiperidin-3-yl)-5-(3-(6-(piperazin-1-yl)pyridin-3-yl)propoxy)isoindoline-1,3-dione (100 mg, 0.21 mmol) and NaBH ₃ CN (41 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (6 ml) and extracted with DCM (20 ml x 2). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product (15 mg, 0.02 mmol) as a white solid.

[357] ¹ H NMR (400 MHz, MeOD): δ 9.62 (s, 1H), 9.03 (s, 1H), 8.58 (d, J=6.8 Hz, 1H), 8. 52 (d, J=8.0 Hz, 1H), 8.31 8.40 (m, 1H), 8.08 (s, 1H), 7.87 7.99 (m, 2H), 7.78 -7.87 (m, 3H), 7.68-7.72 (m, 1H), 7.26-7.30 (m, 2H), 7.10-7.14 (m, 1H), 5 .08-5.12 (m, 1H), 4.17 (t, J=6.0 Hz, 2H), 3.81-3.92 (m, 4H), 3.50-3.60 (m , 4H), 3.30-3.40 (m, 2H), 3.10-3.18 (m, 2H), 2.71-2.86 (m, 5H), 2.30-2.33 (m, 2H), 2.10-2.16 (m, 3H). (M+H) ⁺ 763.3

[358] Scheme for the synthesis of exemplary compound 56

[359] 5-((5-(4-(2-((1s,3s)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)ethyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[360] Step 1. (1s,3s)-3-(Benzyloxy)cyclobutan-1-ol

[361] To a solution of 3-(benzyloxy)cyclobutanone (10.0 g, 56.75 mmol) in EtOH (100 ml) was added NaBH ₄ (4.3 g, 68.1 mmol) at 0°C. The mixture was stirred at 10°C for 2 hours. After quenching the reaction mixture with 10% NH ₄ Cl, the mixture was extracted with ethyl acetate (200 ml). The combined organic layers were washed with brine (150 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product (9.5 g) as a colorless oil, which was used in the next step without further purification.

[362] Step 2. (((1s,3s)-3-(2,2-Diethoxyethoxy)cyclobutoxy)methyl)benzene

[363] To a solution of (1s,3s)-3-(benzyloxy)cyclobutan-1-ol (300 mg, crude, 1.69 mmol) in THF (10 ml) was added NaH (168 mg, 4.22 mmol, 60 %). After stirring at 5°C for 0.5 hour, 2-bromo-1,1-diethoxyethane (333 mg, 3.38 mmol) was added. The resulting mixture was stirred at 70°C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 ml) and the mixture was extracted with EA. The organic phase was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by chromatography (silica gel, PE:EA (50:1, v:v)) to obtain the desired compound (220 mg) as a yellow solid.

[364] Step 3: 2-((1s,3s)-3-(Benzyloxy)cyclobutoxy)acetaldehyde

[365] To a solution of (((1s,3s)-3-(2,2-diethoxyethoxy)cyclobutoxy)methyl)benzene (220 mg, 0.74 mmol) in CH ₃ CN (5 ml) was added HCl (2 ml, 2.5 mol/l in H ₂ O). The resulting mixture was stirred at 70°C for 2 hours. TLC (PE:EA=3:1, Rf=0.5) showed that the starting material was consumed. The mixture was diluted with water (50 ml) and extracted with EA. The organic phase was washed with NaHCO ₃ saline. The solution was dried over MgSO ₄ and concentrated to give the desired compound (170 mg, crude) as a yellow oil, which was used in the next step without further purification.

[366] Step 4. tert-Butyl 4-(2-((1s,3s)-3-(benzyloxy)cyclobutoxy)ethyl)piperazine-1-carboxylate

[367] To a solution of 2-((1s,3s)-3-(benzyloxy)cyclobutoxy)acetaldehyde (170 mg, crude, 0.772 mmol) in MeOH (10 ml) was added tert-butylpiperazine-1-carboxylate (215 mg, 1 , 16 mmol), AcOH (1 drop) and NaBH ₃ CN (97 mg, 154 mmol). The resulting mixture was stirred at 10°C for 18 hours. The reaction mixture was diluted with water (50 ml) and the mixture was extracted with EA. The organic phase was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by chromatography (silica gel, PE:EA (1:1, v:v)) to obtain the desired compound (280 mg) as a colorless oil.

[368] Convert tert-butyl-4-(2-((1s,3s)-3-(benzyloxy)cyclobutoxy)ethyl)piperazine-1-carboxylate to the title compound, 5-((5-(4-( 2-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)piperazin-1-yl) pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione, according to the scheme below using the procedures described above for exemplary compound 42 and exemplary compound 53.

[369] Exemplary compound 56: ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (s, 1H), 8.89 (s, 1H), 8.53 (s, 1H), 8.42 (s , 1H), 8.18 (d, J=8.2 Hz, 1H), 7.87 (d, J=6.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H ), 7.62 (s, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.42 (s, 1H), 7.29 (d, J=11.5 Hz, 1H ), 7.17 (d, J=6.5 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 5.34 (s, 2H), 5.00-4.87 (m, 1H), 4.07 (s, 2H), 3.75 (s, 1H), 3.57 (s, 1H), 3.04-2.49 (m, 10H), 2.20 ( m, 4H), 2.01 (s, 4H), 1.85 (s, 3H), 1.75-1.55 (m, 3H), 1.52 (s, 2H).

[370] Exemplary compound 54 and exemplary compound 58 were prepared according to the schemes below and using procedures similar to those described above.

[371] Scheme for the synthesis of exemplary compound 57

[372] Step 1. Benzyl 4-(5H-pyrido[4,3-b]indol-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[373] Mixture of 7-bromo-5H-pyrido[4,3-b]indole (492 mg, 2 mmol), benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (755 mg, 2.2 mmol), Pd(amphos)Cl ₂ (146 mg, 0.2 mmol) and CsF (1.2 g, 8 mmol) in a mixture of dioxane/H ₂ O (20 ml/2 ml) was stirred at 90°C for 16 hours. After cooling to room temperature, the reaction mixture was quenched by adding water (30 ml). The mixture was extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column, eluting with dichloromethane/methanol to give 260 mg (0.68 mmol, 34%) of the desired product.

[374] Step 2. 7-(Piperidin-4-yl)-5H-pyrido[4,3-b]indole

[375] In a solution of benzyl 4-(5H-pyrido[4,3-b]indol-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (130 mg, 0.34 mmol) and one drops of conc. HCl in CH ₃ OH (10 ml) was added to Pd/C (13 mg, 10%) at room temperature. The resulting solution was stirred at room temperature overnight at a pressure of 1 atm. H2. The solid was then filtered off and the filtrate concentrated in vacuo to give the crude product (80 mg), which was used in the next reaction without further purification.

[376] Step 3. 5-((14-(4-(5H-Pyrido[4,3-b]indol-7-yl)piperidin-1-yl)-3,6,9,12-tetraoxatetradecyl)oxy )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[377] In a solution of 7-(piperidin-4-yl)-5H-pyrido[4,3-b]indole (80 mg, 0.32 mmol) and 14-((2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecanal (175 mg, 0.36 mmol) [prepared as described for intermediate 101 above] in CH ₃ OH ( 10 ml) NaBH ₃ CN (40 mg, 0.64 mmol) and one drop of CH ₃ COOH were added at room temperature. After stirring for 2 hours, the reaction mixture was quenched by adding water (20 ml). The resulting solution was extracted with DCM (20 ml x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC using DCM/CH ₃ OH (10:1) to obtain the desired product (18 mg, 0.025 mmol, 8%). ^1H NMR (400 MHz, CD ₃ OD): δ 9.30 (s, 1H), 8.42-8.60 (m, 2H), 8.19 (d, J=8.0 Hz, 1H) , 7.60-7.65 (m, 2H), 7.52 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.19 (s, 1H), 7, 12-7.14 (m, 1H), 5.07-5.10 (m, 1H), 4.12 (t, J=4.0 Hz, 2H), 3.66-3.86 (m, 18H), 3.37 (s, 2H), 3.15-3.20 (m, 3H), 2.71-2.76 (m, 3H), 2.09-2.22 (m, 5H) . (M+H) ⁺ 728.3.

[378] Scheme for the synthesis of exemplary compound 60

[379] 5-(4-(3-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy )propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[380] Step 1. tert-Butyl 4-(3-((1r,3r)-3-((4-nitrobenzoyl)oxy)cyclobutoxy)propyl)piperazine-1-carboxylate

[381] In a solution of tert-butyl 4-(3-((1s,3s)-3-hydroxycyclobutoxy)propyl)piperazine-1-carboxylate (530 mg, 1.68 mmol), triphenylphosphine (1.32 g, 5 .06 mmol) and 4-nitrobenzoic acid (310 mg, 1.85 mmol) in THF (10 ml) was added dropwise to DIAD (1.02 g, 5.06 mmol) at room temperature under N ₂ atmosphere. After stirring at room temperature for 3 hours, the resultant was quenched with water (20 ml) and the mixture was extracted with EtOAc (20 ml x 2). The combined organic layers were concentrated in vacuo. The residue was purified by a silica gel column using PE/EA 2:1 to 1:1 as eluent to give the desired product (350 mg, 45%) as a semi-solid.

[382] Convert tert-butyl 4-(3-((1r,3r)-3-((4-nitrobenzoyl)oxy)cyclobutoxy)propyl)piperazine-1-carboxylate to the title compound, 5-(4- (3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)piperazin-1-yl )-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione, according to the following scheme and using the procedures described above for exemplary compound 53.

[383] Compound 60: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.07 (s, 1H), 9.76 (s, 1H), 8.67 (d, J=6.0 Hz , 1H), 8.60 (s, 1H), 8.52 (d, J=8.4 Hz, 1H), 8.16 (d, J=8.4 Hz, 1H), 8.80-8 .02 (m, 2H), 7.77 (t, J=8.4 Hz, 2H), 7.50 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 6 .96 (d, J=8.8 Hz, 1H), 5.36 (m, 1H), 5.07-5.11 (m, 1H), 4.24 (br, 3H), 3.62 ( br, 9H), 3.55 (s, 3H), 3.17-3.25 (m, 6H), 2.86-2.93 (m, 1H), 2.38-2.62 (m, 4H), 1.97-2.04 (m, 1H). (M+H) ⁺ 714.3.

[384] Scheme for the synthesis of exemplary compound 61

[385] 2-(2,6-Dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4 ,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindoline-1,3-dione

[386] Step 1. 7-(6-(3-((tert-Butyldimethylsilyl)oxy)propyl)pyridin-3-yl)-5H-pyrido[4,3-b]indole

[387] In a solution of 3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propan-1-ol (prepared as described for compound 55; 100 mg, 0 .33 mmol) imidazole (44.8 mg, 0.66 mmol) and TBSCl (59.6 mg, 0.40 mmol) were added to DCM (5 ml). The resulting solution was stirred at 40°C for 3 hours. The solvent was removed under reduced pressure. The residue was diluted with EA (30 ml) and the mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1, 0.2% Net ₃ ) to give the title product (100 mg, 73% yield).

[388] Step 2. 7-(6-(3-((tert-Butyldimethylsilyl)oxy)propyl)pyridin-3-yl)-5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3 -b]indole

[389] In a solution of 7-(6-(3-((tert-butyldimethylsilyl)oxy)propyl)pyridin-3-yl)-5H-pyrido[4,3-b]indole (60 mg, 0.14 mmol) NaH (8.6 mg, 0.22 mmol) was added to DMF (5 ml) at 5°C. After stirring for 20 minutes. a solution of CF ₃ CH ₂ Otf (66.6 mg, 0.29 mmol) in DMF (1 ml) was added dropwise. The mixture was stirred for another 1 hour and the reaction mixture was diluted with EtOAc (40 ml), washed with brine, dried over anhydrous sodium sulfate. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH=40:1, 0.2% NH ₃ ⋅H ₂ O) to give the title product (55 mg, 92%).

[390] Step 3. 3-(5-(5-(2,2,2-Trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propan-1- ol

[391] In a solution of 7-(6-(3-((tert-butyldimethylsilyl)oxy)propyl)pyridin-3-yl)-5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3- b]indole (110 mg, 0.22 mmol) in CH3OH (2 ml) was added a mixture of HCl/dioxane (6 N, 3 ml). The resulting solution was stirred at 5°C for 1 hour. The result was then diluted with EtOAc (40 ml) and the mixture was washed with sat. a solution of NaHCO ₃ (aq) and saline and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to obtain the crude title product (84.9 mg), which was used in the next reaction without further purification.

[392] Step 4. 3-(5-(5-(2,2,2-Trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propanal

[393] Into a solution of 3-(5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propan-1-ol (90 mg, 0.23 mmol) in DMSO (2 ml) was added IBX (130.9 mg, 0.47 ml). The resulting mixture was stirred at 40°C for 2 hours. The mixture was quenched with sat. aq. Na ₂ S ₂ O ₃ solution (5 ml) and sat. aq. NaHCO ₃ solution (5 ml). The mixture was extracted with EtOAc (20 ml x 5). The combined organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo to give the crude desired product (89.5 mg), which was used in the next reaction without further purification.

[394] Step 5. tert-Butyl 4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazine-1-carboxylate

[395] Into a solution of 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentanal (150 mg, 0.42 mmol) [prepared according to following the procedures described above] tert-butylpiperazine-1-carboxylate (77.9 mg, 0.42 mmol) and NaBH ₃ CN (52.6 mg, 0.84 mmol) were added to MeOH (5 ml). The resulting solution was stirred at 40°C for 2 hours. The solvent was evaporated under reduced pressure. The residue was diluted with EA (30 ml) and the mixture was washed with brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH=60/1) to obtain the desired product (200 mg, 90% yield).

[396] Using BOC deprotection and reductive amination procedures similar to those described above, the compounds from steps 4 and 5 were converted to the final compound, 2-(2,6-dioxopiperidin-3-yl)-5-((5- (4-(3-(5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1- yl)pentyl)oxy)isoindoline-1,3-dione.

[397] ¹ H NMR (400 MHz, CD ₃ OD) δ 9.35 (s, 1H), 8.89 (s, 1H), 8.55 (d, J=5.8 Hz, 1H), 8 .40 (d, J=8.0 Hz, 1H), 8.17-8.22 (m, 1H), 8.05 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.74 (d, J=5.6 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 5.40 (d, J=9.1 Hz, 2H), 5.08-5.16 (m, 1H), 4.95 (s, 4H), 4.59 (s, 2H), 4.18 (t, J=6.2 Hz, 1H), 2.91-3.00 (m, 2H), 2.58-2.91 (m, 9H), 2.12-2.18 ( m, 1H), 2.06 (s, 2H), 1.89 (s, 2H), 1.69 (s, 2H), 1.57 (s, 2H). (M+H) ⁺ 796.3.

[398] Scheme for the synthesis of exemplary compound 62

[399] 3-(5-((5-(4-(3-(5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl) piperazin-1-yl)pentyl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione

[400] Step 1. tert-Butyl 5-amino-4-(5-((5-hydroxypentyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate

[401] In a solution of tert-butyl-5-amino-4-(5-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (500.0 mg, 1.0 eq.), pentane-1.5 -diol (187 mg, 1.2 eq.) and PPh ₃ (590.0 mg, 1.5 eq.) in anhydrous tetrahydrofuran (50 ml) was added DIAD (455 mg, 2.25 mmol, 1.5 eq. ). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was then quenched by adding water (100 ml). The resulting solution was extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column using dichloromethane/methanol (10:1) to give the desired product (560 mg, 1.33 mmol, 89%).

[402] Step 2: 3-(5-((5-Hydroxypentyl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione

[403] In a solution of tert-butyl-5-amino-4-(5-((5-hydroxypentyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (560 mg, 1.0 eq.) in MeCN (20 ml) was added with p-TsA (253 mg, 3.0 eq.) at room temperature. The resulting solution was stirred at 90°C for 6 hours. The reaction mixture was then cooled to room temperature and quenched by adding water (10 ml). The resulting solution was extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column using dichloromethane/methanol (10:1) to give the desired product (190 mg, 0.55 mmol, 46%).

[404] Step 3: 5-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pentanal

[405] In a solution of 3-(5-((5-hydroxypentyl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (190 mg, 1.0 eq.) in DCM (20 ml) IBX (100 mg, 2 eq.) was added at room temperature. The resulting solution was stirred at room temperature for 2 hours. The solid was then filtered off and the filtrate concentrated in vacuo to give the crude product (190 mg), which was used in the next reaction without further purification.

[406] Step 4. 7-Bromo-5-methyl-5H-pyrido[4,3-b]indole

[407] To a solution of 7-bromo-5H-pyrido[4,3-b]indole (8.0 g, 32.4 mmol) in N,N-dimethylformamide (50 ml) was added sodium hydride (1.4 g, 35.6 mmol, 60% in mineral oil) at 0°C and the reaction mixture was stirred at 0°C for 30 minutes. Iodomethane (4.6 g, 32.4 mmol) was added to the resulting mixture at 0° C. and the reaction mixture was allowed to warm to room temperature and stirred overnight. TLC indicated completion of the reaction. The reaction mixture was quenched with water (30 ml) at 0°C and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with water (80 ml), then brine (90 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue, which was purified by flash chromatography on silica gel (eluting from 20 to 40% ethyl acetate in hexane) to give 7-bromo-5-methyl-5H-pyrido[4,3-b]indole (6.0 g, 71% yield) as a brown solid.

[408] Using the procedures described above for exemplary compound 61, 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pentanal was converted to the title compound, 3-(5-((5-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazine-1 -yl)pentyl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione, according to the scheme below.

[409] Exemplary compound 62: ¹ H NMR (400 MHz, MeOD): δ 9.27 (s, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.46 (d, J =6.0 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H), 7.90 (s, 1H), 7.59-7.70 (m, 3H), 7.47 (d, J=6.0 Hz, 1H), 7.03-7.09 (m, 2H), 5.06-5.12 ( m, 1H), 4.42 (d, J=5.6 Hz, 2H), 4.07 (t, J=6.4 Hz, 2H), 3.99 (s, 3H), 2.89- 2.96 (m, 3H), 2.51-2.75 (m, 13H), 2.12-2.24 (m, 1H), 2.01-2.03 (m, 3H), 1, 82-1.84 (m, 2H), 1.52-1.63 (m, 6H). (M+H) ⁺ 714.3.

[410] Illustrative connection 63

[411] 2-(2,6-Dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)-3-(trifluoromethyl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindoline-1,3-dione

[412] Step 1. 5-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[4,3-b]indole

[413] To a solution of 7-bromo-5-methyl-5H-pyrido[4,3-b]indole (150 mg, 0.577 mmol) in dioxane, KOAc (114 mg, 1.15 mmol), Pd(dppf) was added successively Cl ₂ (35 mg, 0.05 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) ( 294 mg, 1.15 mmol). The resulting solution was heated to 100°C overnight under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was quenched with water and the mixture was extracted with EtOAc (10 ml x 2). The combined organic layers were washed with brine (10 ml). The organic phase was dried over Na ₂ SO ₄ , concentrated in vacuo to give the crude desired product (180 mg, crude), which was used in the next reaction without further purification.

[414] Step 2: 7-(6-Chloro-5-(trifluoromethyl)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole

[415] In a mixture of 5-bromo-2-chloro-3-trifluoromethylpyridine (135 mg, 0.7 mmol) and 5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-5H-pyrido[4,3-b]indole (180 mg, 0.58 mmol) in a mixture of dioxane/H ₂ O (v/v = 10/1, 10 ml) was added Pd( dppf) ₂ Cl ₂ (20 mg, 10%) and CsF (180 mg, 1.16 mmol). The mixture was stirred at 80°C overnight. The solution was quenched with water. The mixture was extracted with ethyl acetate (20 ml) and the combined organic layers were washed with brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain the desired product (170 mg, 95% yield).

[416] Step 3. tert-Butyl-4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl )prop-2-yn-1-yl)piperazine-1-carboxylate

[417] In a mixture of 7-(6-chloro-5-(trifluoromethyl)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole (170 mg, 0.58 mmol) and tert. -butyl-4-(prop-2-ynyl)piperazine-1-carboxylate (156 mg, 0.69 mmol) in DMF (10 ml) was added Pd(PPh ₃ ) ₂ Cl ₂ (17 mg, 10%), Cs ₂ CO ₃ (378 mg, 1.16 mmol), DBU (30 mg, 0.116 mmol) and t-Bu ₃ P (25 mg, 0.116 mmol). The mixture was heated under microwave radiation at 150°C for 10 minutes. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain the desired product (200 mg).

[418] Step 4. tert-Butyl-4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl )propyl)piperazine-1-carboxylate

[419] Into a solution of tert-butyl-4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl) prop-2-yn-1-yl)piperazin-1-carboxylate (200 mg) in ethanol was added with Pd/C (20 mg). The mixture was stirred at 30°C in an atmosphere of H ₂ (3 MPa) for 8 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to obtain the desired product (25 mg).

[420] Using the BOC deprotection and reductive amination procedures described above, tert-butyl-4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)-3-(trifluoromethyl)pyridin-2-yl)propyl)piperazine-1-carboxylate to the title compound, 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4- (3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy )isoindoline-1,3-dione, according to the scheme below.

[421] Exemplary compound 63: ¹ H NMR (400 MHz, CD ₃ OD): δ 9.25 (s, 1H), 8.45 (s, 1H), 8.23 (d, J=7.6 Hz , 1H), 7.76 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.39 (d , J=8.4 Hz, 1H), 7.35 (s, 2H), 7.26-7.28 (m, 1H), 6.06 (s, 1H), 5.72 (s, 1H) , 5.06-5.08 (m, 1H), 4.30 (d, J=6.4 Hz, 1H), 4.11-4.15 (m, 2H), 3.90-3.94 (m, 4H), 3.70-3.74 (m, 2H), 3.03-3.06 (m, 2H), 2.82-2.88 (m, 4H), 2.71-2 .75 (m, 6H), 2.51-2.55 (m, 3H), 2.05-2.25 (m, 2H), 1.82-1.86 (m, 2H), 1.61 -1.63 (m, 2H), 1.51-1.52 (m, 2H). (M+H) ⁺ 796.2.

[422] Illustrative connection 73

[423] Step 1. 7-(6-((1s,3s)-3-(Benzyloxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole

[424] In a solution of 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (1.1 g, 4.18 mmol) and (1s,3s)-3-(benzyloxy )cyclobutanol (745 mg, 4.18 mmol) in 1-methylpyrrolidin-2-one (2 ml) was added sodium hydride (60% in mineral oil) (334 mg, 8.35 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours. TLC indicated completion of the reaction. The mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was collected, washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 2 to 5% methanol in dichloromethane) to give 7-(6-((1s,3s)-3-(benzyloxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole (1.42 g, 82%) as a white solid substances.

[425] Step 2. (1s,3s)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutan-1-ol

[426] Stir a mixture of 7-(6-((1s,3s)-3-(benzyloxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole (1.42 g, 3. 37 mmol) and palladium on carbon (10%, 150 mg) in a mixture of methanol (30 ml)-tetrahydrofuran (10 ml) at 50 ° C for 2 hours in a hydrogen atmosphere (hydrogen cylinder). TLC indicated completion of the reaction. Palladium on carbon was removed by filtration and washed with methanol (10 ml x 2). The combined filtrate was concentrated under reduced pressure to give (1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanol (1.57 g, crude) as a white solid.

[427] Step 3. tert-Butyl-7-(6-((1s,3s)-3-hydroxycyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate

[428] Into a suspension of (1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanol (1.57 g, 4 .27 mmol) and sodium carbonate (1.1 g, 10.69 mmol) in a mixture of tetrahydrofuran (20 ml) - water (5 ml) was added di-tert-butyl carbonate (1.2 g, 5.55 mmol) at room temperature. The mixture was stirred at room temperature for 17 hours. TLC indicated completion of the reaction. The mixture was concentrated and the residue was partitioned between ethyl acetate (20 ml) and water (30 ml). The organic layer was collected, washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 1 to 2% methanol in dichloromethane) to give tert-butyl-7-(6-((1s,3s)-3-hydroxycyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate (1.1 g, 73% in two stages) as a white solid.

[429] Step 4. tert-Butyl-7-(6-((1s,3s)-3-((methylsulfonyl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole -5-carboxylate

[430] Into a suspension of tert-butyl 7-(6-((1s,3s)-3-hydroxycyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate (500 mg , 1.16 mmol) and triethylamine (352 mg, 3.47 mmol) in dichloromethane (10 ml), methanesulfonyl chloride (530 mg, 4.63 mmol) was added at 0°C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 5 hours. TLC indicated completion of the reaction. The mixture was diluted with dichloromethane (10 ml) and washed with water (10 ml). The organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl-7-(6-((1s,3s)-3-hydroxycyclobutoxy)pyridin-3-yl)-5H -pyrido[4,3-b]indole-5-carboxylate (700 mg, crude), which was used in the next step without further purification.

[431] Step 5. 7-(6-((1r,3r)-3-((6-Iodopyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b ]indole

[432] Stir a mixture of tert-butyl 7-(6-((1s,3s)-3-hydroxycyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate (350 mg , 0.69 mmol), 6-iodopyridin-3-ol (155 mg, 0.69 mmol) and cesium carbonate (452 mg, 1.39 mmol) in dry N,N-dimethylformamide (4 ml) at 90°C within 12 hours. TLC indicated completion of the reaction. The mixture was partitioned between ethyl acetate (30 ml) and water (40 ml). The organic layer was collected, washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 1 to 2% methanol in dichloromethane) to give 7-(6-((1r,3r)-3-((6-iodopyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole (250 mg, 68%) as a light yellow solid.

[433] Step 6. [5-((3-(5-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2- yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione]

[434] Into a stirred solution of 7-(6-((1r,3r)-3-((6-iodopyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b ]indole (150 mg, 0.24 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1-yloxy)isoindolin-1,3-dione (111 mg, 0.35 mmol) [prepared using the procedure from step 1 for exemplary compound 180] and triethylamine (121 mg, 1.20 mmol) in N,N-dimethylformamide (2 ml) was added bis(triphenylphosphine)palladium(II) chloride ( 8 mg, 0.01 mmol) and copper iodide (2 mg, 0.01 mmol) at room temperature under nitrogen; the mixture was degassed three times with nitrogen. The resulting mixture was stirred at 65°C under nitrogen atmosphere overnight. TLC indicated completion of the reaction. The mixture was partitioned between water (30 ml) and ethyl acetate (30 ml). The organic layer was collected and washed with brine (30 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography (eluting with 2% methanol in dichloromethane) to give 5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridine -2-yl)prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (45 mg, 26% yield) as a white solid substances.

[435] ^1H NMR (400 MHz, DMSO-d6): δ 2.04-2.07 (m, 1H), 2.57-2.77 (m, 6H), 2.86-2.93 ( m, 1H), 5.10-5.14 (m, 2H), 5.32 (s, 2H), 5.39-5.48 (m, 1H), 6.97 (d, J=8, 0 Hz, 1H), 7.32-7.33 (m, 1H), 7.46 7.58 (m, 5H), 7.77 (s, 1H), 7.90 (d, J=7, 2 Hz, 1H), 8.14 (d, J=7.2 Hz, 1H), 8.25 (s, 1H), 8.30 (d, J=7.6 Hz, 1H), 8.43 (s, 1H), 8.56 (s, 1H), 9.36 (s, 1H), 11.12 (s, 1H), 11.82 (s, 1H). (M+H) ⁺ 719.4.

[436] Scheme for the synthesis of exemplary compound 77

[437] Step 1. tert-Butyl-7-(6-((1r,3r)-3-((6-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)oxy)propyl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate

[438] Into a solution of tert-butyl-7-(6-((1r,3r)-3-((6-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)prop-1-in-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate (15 mg) Pd/C was added to MeOH. The solution was stirred at 30°C for 2 hours in an atmosphere of H ₂ (2 MPa). The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified using silica gel to obtain the desired product (6 mg).

[439] Step 2. 5-(3-(5-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)cyclobutoxy)pyridin-2-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[440] Stir a solution of tert-butyl-7-(6-((1r,3r)-3-((6-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)oxy)propyl)272pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate (6 mg) in DCM/TFA (2 ml/1 ml) at room temperature for 4 hours. The solvent was removed in vacuo to give 5-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)cyclobutoxy)pyridin-2-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (5.5 mg).

[441] ¹ H NMR (400 MHz, CD ₃ OD): δ 9.56 (s, 1H), 8.54 8.56 (m, 2H), 8.45 (d, J=8.4 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H) , 7.88 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.4 Hz, 1H), 7.79 (s, 1H), 7.76-7.78 ( d, J=8 Hz, 1H), 7.29 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H) , 5.48-5.52 (m, 1H), 5.32-5.34 (m, 1H), 5.18-5.22 (m, 1H), 5.06-5.10 (m, 1H), 4.25-4.28 (m, 2H), 3.21-3.23 (m, 3H), 2.78-2.81 (m, 5H), 2.67-2.70 ( m, 2H), 2.30-2.33 (m, 2H), 2.17-2.19 (m, 1H), 1.97-2.07 (m, 3H). (M+H) ⁺ 723.5.

[442] Scheme for the synthesis of exemplary compound 94

[443] Step 1. (1r,3r)-3-((6-(5-((Triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutan-1-ol

[444] To a solution of (1r,3r)-3-((6-bromopyridin-3-yl)oxy)cyclobutan-1-ol (530 mg, 2.17 mmol) in dry THF (10 ml) was added triisopropyl(pent -4-yn-1-yloxy)silane (626 mg, 2.61 mmol), TEA (1.1 g, 10.86 mmol), CuI (45 mg, 0.24 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (110 mg, 4.34 mmol) at 25°C in an N ₂ atmosphere. The resulting solution was stirred at 45°C for 16 hours. The reaction mixture was diluted with H ₂ O (10 ml). The resulting mixture was extracted with EtOAc (10 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give the desired product, (1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy )cyclobutan-1-ol (600 mg, 68% yield), as a colorless oil.

[445] Step 2. 5-Bromo-2-((1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl) oxy)cyclobutoxy)pyridine

[446] Into a solution of (1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutan-1-ol ( 300 mg, 0.74 mmol) in DMF (5 ml) was added NaH (45 mg, 1.11 mmol) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hour and 5-bromo-2-fluoropyridine (144 mg, 0.82 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with H ₂ O solution (10 ml). The resulting mixture was extracted with EtOAc (10 ml x 2), the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give the desired product, 5-bromo-2-((1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl) pyridin-3-yl)oxy)cyclobutoxy)pyridine (240 mg, 58% yield) as a white solid.

[447] Step 3. 5-Methyl-7-(6-((1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3 -yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole

[448] Into a solution of 5-bromo-2-((1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy )cyclobutoxy)pyridine (180 mg, 0.32 mmol) in 1,4-dioxane (5 ml) and H ₂ O (1 ml) was added 5-methyl-7-(6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-5H-pyrido[4,3-b]indole (119 mg, 0.39 mmol), CsF (147 mg, 0.96 mmol) and Pd(amphos)Cl ₂ (34 mg, 0.06 mmol) at 15°C in an N ₂ atmosphere. The resulting mixture was stirred at 80°C for 5 hours. The mixture was quenched with H ₂ O (20 ml), extracted with EtOAc (10 ml x 2). The combined organic layers were then washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give the desired product, 5-methyl-7-(6-((1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yne-1 -yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole (80 mg, 38% yield).

[449] Step 4. 5-(5-((1r,3r)-3-((5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)pyridin-2-yl)pent-4-in-1-ol

[450] Into a solution of 5-methyl-7-(6-((1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3- yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole (90 mg, 0.14 mmol) in dry THF (10 ml) was added 1 M TBAF in THF (1 ml, 0.7 mmol) in an atmosphere of N ₂ at 15°C. The mixture was stirred at 40°C for 1 hour under N ₂ atmosphere using a balloon. The mixture was concentrated. The residue was purified by preparative TLC to give the desired product, 5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl) pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-ol (30 mg, 43% yield) as a white solid.

[451] Step 5: 2-(2,6-Dioxopiperidin-3-yl)-5-((5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-yl)oxy)isoindoline-1,3-dione

[452] Into a solution of 5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-ol (25 mg, 0.05 mmol) in dry THF (2 ml) was added 2-(2,6-dioxopiperidin-3-yl)- 5-hydroxyisoindoline-1,3-dione (20 mg, 0.07 mmol), PPh ₃ (40 mg, 0.14 mmol) at 15°C under N ₂ atmosphere. DIAD (32 mg, 0.14 mmol) was added to the mixture at 40° C. under N ₂ atmosphere. The resulting mixture was stirred at 40°C for 0.5 hours. The mixture was cooled to 20°C and quenched with H ₂ O (10 ml), extracted with EtOAc (10 ml x 2). The combined organic layers were then washed with brine (20 mL x 5), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give the desired product, 2-(2,6-dioxopiperidin-3-yl)-5-((5-(5-((1r,3r)-3-((5-(5- methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-in-1-yl)oxy)isoindolin-1, 3-Dione (22 mg, 58% yield) as a white solid.

[453] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ: 11.04 (s, 1H), 9.29 (s, 1H), 8.58 (d, J=2.0 Hz, 1H ), 8.43 (d, J=5.6 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.12-8.16 (m, 2H), 7.92 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.56 (d, J=6.0 Hz, 2H), 7.40 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.20-7.22 (m, 1H), 6.92 (d, J=4.4 Hz, 1H), 5.37(s, 1H) , 5.01-5.37 (m, 2H), 4.25 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 2.43-2.65 (m, 9H ), 1.98 (t, J=6.4 Hz, 3H). (M+H) ⁺ 761.5.

[454] Scheme for the synthesis of exemplary compound 117

[455] Step 1. 5-Methyl-7-(6-((1r,3r)-3-((6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yne -1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole

[456] Stir a mixture of (1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutylmethanesulfonate (480 mg , 1.1 mmol) [prepared using the procedure described in step 4 for illustrative compound 73], 6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl )pyridin-3-ol (256 mg, 1.1 mmol) and cesium carbonate (715 mg, 2.2 mmol) in N,N-dimethylformamide (15 ml) at 70°C for 16 hours. TLC indicated completion of the reaction. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (40 ml). The organic layer was collected, washed with brine (50 ml), dried over sodium sulfate and evaporated under reduced pressure to give a crude residue, which was purified by flash column chromatography on silica gel (eluting with 0 to 30% ethyl acetate in hexanes) to give 5-methyl-7-(6-((1r,3r)-3-((6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine -3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole (350 mg, 57% yield) as a white solid.

[457] Step 2. 3-(5-((1r,3r)-3-((5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-ol

[458] Into a solution of 5-methyl-7-(6-((1r,3r)-3-((6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-in- 1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole (350 mg, 0.62 mmol) in tetrahydrofuran (10 ml) was added an aqueous solution hydrogen chloride (5 ml, 2 M) and the reaction mixture was stirred at room temperature for 1 hour. TLC indicated completion of the reaction. The reaction mixture was quenched with aqueous sodium bicarbonate (20 ml) and the reaction mixture was extracted with ethyl acetate (20 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (10 ml×2). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-ol (270 mg, crude) as a white solid, which used in the next step without purification.

[459] Step 3. 3-(5-((1r,3r)-3-((5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl-4-methylbenzenesulfonate

[460] Mixture of 3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy )cyclobutoxy)pyridin-2-yl)prop-2-yn-1-ol (200 mg, crude), triethylamine (127 mg, 1.26 mmol) and 4-methylbenzenesulfonyl chloride (120 mg, 0.63 mmol) in dichloromethane (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (20 ml) and extracted with dichloromethane (30 ml). The organic layer was washed with brine (20 ml), dried over sodium sulfate and evaporated under reduced pressure to give a crude residue, which was purified by flash column chromatography on silica gel (eluting with 5% methanol in dichloromethane) to give 3-(5- ((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl) prop-2-yn-1-yl-4-methylbenzenesulfonate (130 mg, 49% yield) as a white solid.

[461] Step 4. 2-(2,6-Dioxopiperidin-3-yl)-5-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)isoindoline-1,3-dione

[462] Into a solution of 3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl-4-methylbenzenesulfonate (130 mg, 0.21 mmol), potassium carbonate (85 mg, 0.62 mmol) and 2-(2, 6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (57 mg, 0.21 mmol) in N,N-dimethylformamide (10 ml) was added potassium iodide (35 mg, 0.21 mmol) to nitrogen atmosphere. The resulting mixture was heated to 50°C and stirred for 16 hours. TLC indicated completion of the reaction. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (20 ml). The organic layer was collected, washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash column chromatography (eluting with 8% methanol in dichloromethane) to give 2- (2,6-dioxopiperidin-3-yl)-5-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole -7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione (21.3 mg, 14% yield) as a yellow solid.

[463] ¹ H NMR (400 MHz, CD ₃ OD): δ 1.92-1.94 (m, 1H), 2.02-2.10 (m, 2H), 2.62-2.65 ( m, 5H), 3.90 (s, 3H), 4.97-5.02 (m, 2H), 5.10 (s, 2H), 5.37 (t, J=6 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 7.20-7.22 (m, 1H), 7.34-7.41 (m, 2H), 7.45 (d, J= 2.0 Hz, 1H), 7.50-7.56 (m, 2H), 7.75-7.77 (m, 2H), 8.02-8.06 (m, 2H), 8.21 (d, J=8.0 Hz, 1H), 8.37 (d, J=6.0 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H), 9.18 (s , 1H). (M+H) ⁺ 733.4.

[464] Using procedures similar to those described above, compound 83 (method for compound 94), compound 95, compound 97 (method for compound 94), compound 98, compound 183 (method for compound 73), compound 204 (combination of methods for connection 73 and connection 176).

[465] Scheme for the synthesis of exemplary compound 102 and exemplary compound 110

[466] 2-(2,6-Dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione (illustrative compound 102) and 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3- b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hexyl)oxy)isoindoline-1,3-dione (illustrative compound 110)

[467] Step 1. 7-(6-((1r,3r)-3-((5-Iodopyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4 ,3-b]indole

[468] Into a solution of (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanol (100 mg , 0.29 mmol) [prepared using procedures similar to those described for steps 1 and 2 for compound 73] in 1-methylpyrrolidin-2-one (5 ml) was added sodium hydride (60% in mineral oil) (58 mg, 1 .45 mmol) at 0°C and the reaction mixture was stirred for 1 hour. 2-Fluoro-5-iodopyridine (65 mg, 0.29 mmol) was then added to the reaction mixture and the mixture was stirred at room temperature for 2 hours. TLC indicated completion of the reaction. The reaction mixture was quenched with water (10 ml) at 0°C and extracted with ethyl acetate (20 ml × 2). The combined organic layers were washed with water (20 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 5% methanol in dichloromethane) to give 7-( 6-((1r,3r)-3-((5-iodopyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole (100 mg , yield 63%) as a white solid.

[469] Using the procedures described for compound 73, 7-(6-((1r,3r)-3-((5-iodopyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)-5- methyl-5H-pyrido[4,3-b]indole to the title compounds, 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3 -((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hex-5-yne-1- yl)oxy)isoindolin-1,3-dione (compound 102) and 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-(( 5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hexyl)oxy)isoindoline-1,3-dione (connection 110), according to the diagram below.

[470] Compound 102: 1H NMR (400 MHz, DMSO-d6): δ 1.73 (d, J=7.2 Hz, 2H), 1.91 (d, J=7.2 Hz, 2H), 2.01-2.08 (m, 1H), 2.51-2.67 (m, 8H), 2.83-2.94 (m, 1H), 3.96 (s, 3H), 4.24 ( t, J=6.0 Hz, 2H), 5.12 (dd, J=12.8, 5.2 Hz, 1H), 5.31-5.52 (m, 2H), 6.99 (d , J=8.4 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.44 (s, 1H ), 7.75-7.58 (m, 3H), 7.82 (d, J=8.2 Hz, 1H), 7.99 (s, 1H), 8.10-8.28 (m, 2H), 8.33 (d, J=8.2 Hz, 1H), 8.52 (s, 1H), 8.64 (d, J=1.6 Hz, 1H), 9.40 (s, 1H), 11.11 (s, 1H). (M+H) ⁺ 775.5

[471] Compound 110: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.36 (d, J=7.6 Hz, 2H), 1.45 (d, J=6.8 Hz, 2H ), 1.52-1.61 (m, 2H), 1.70-1.80 (m, 2H), 1.98-2.02 (m, 3H), 2.54-2.70 (m , 6H), 2.89 (t, J=16.6 Hz, 1H), 3.96 (s, 3H), 4.16 (d, J=5.0 Hz, 2H), 5.12 (dd , J=12.8, 4.4 Hz, 1H), 5.36 5.43 (m, 2H), 6.77 (d, J=8.4 Hz, 1H), 6.99 (d, J =8.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.42 (s, 1H), 7.60-7.64 (m, 3H), 7.83 (d, J=8.0 Hz, 1H), 7.97 (dd, J=14.0, 6.4 Hz, 2H), 8.33 (d, J=8.4 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.50 (d, J=4.8 Hz, 1H), 8.65 (s, 1H), 9.37 (s, 1H), 11.11 (s, 1H). (M+H) ⁺ 779.5

[472] Scheme for the synthesis of exemplary compound 173

[473] 5-(2-((3-(5-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[474] Step 1: 2-(Prop-2-yn-1-yloxy)ethan-1-ol

[475] Ethane-1,2-diol (3.9 g, 63 mmol) and stirred at 0°C for 0.5 hour. 3-bromoprop-1-yne (5.0 g, 42 mmol) was added to the resulting mixture at 0°C and stirred at 50°C overnight. TLC indicated completion of the reaction. The reaction mixture was quenched with ice water (20 ml) and partitioned between ethyl acetate (80 ml) and water (100 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 0 to 20% ethyl acetate in hexane) to give 2 -(prop-2-yn-1-yloxy)ethanol (3.4 g, 80% yield) as a colorless oil.

[476] Step 2: 2-(Prop-2-yn-1-yloxy)ethyl-4-methylbenzenesulfonate

[477] Into a stirred solution of 2-(prop-2-yn-1-yloxy)ethanol (1 g, 10 mmol), triethylamine (3 g, 3 mmol) and N,N-dimethylpyridin-4-amine (20 mg, 1 mmol) in dichloromethane (20 ml) p-toluenesulfonic acid (2.9 g, 15 mmol) was added at 0°C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (20 ml), washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue. The result was purified by silica gel flash column chromatography (eluent: 10 to 20% ethyl acetate in hexane) to give 2-(prop-2-yn-1-yloxy)ethyl-4-methylbenzenesulfonate (700 mg, yield: 40% ) as a light yellow oil.

[478] Step 3: 2-(2,6-Dioxopiperidin-3-yl)-5-(2-(prop-2-yn-1-yloxy)ethoxy)isoindoline-1,3-dione

[479] Into a stirred solution of 2-(prop-2-yn-1-yloxy)ethyl-4-methylbenzenesulfonate (700 mg, 2.8 mmol) and potassium carbonate (1.1 g, 8.3 mmol) in N, N-dimethylformamide (15 ml) was added 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (755 mg, 2.8 mmol) at room temperature. The resulting mixture was stirred at 50°C overnight. TLC indicated completion of the reaction. The mixture solution was cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (30 ml); the organic layer was collected and the aqueous layer was extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 0 to 50% ethyl acetate in hexane) to give 2 -(2,6-dioxopiperidin-3-yl)-5-(2-(prop-2-yn-1-yloxy)ethoxy)isoindoline-1,3-dione (290 mg, 30% yield) as light yellow solid.

[480] 2-(2,6-Dioxopiperidin-3-yl)-5-(2-(prop-2-yn-1-yloxy)ethoxy)isoindolin-1,3-dione was reacted with 7-(6 -((1r,3r)-3-((6-iodopyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole using the procedure described for compound 73 , to obtain the title compound, 5-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl) pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3- diona.

[481] ^1H NMR (400 MHz, DMSO-d6): δ 2.02-2.08 (m, 1H), 2.52-2.76 (m, 6H), 2.85-2.93 ( m, 1H), 3.89-3.95 (m, 2H), 4.37-4.42 (m, 2H), 4.49 (s, 2H), 5.06-5.14 (m, 2H), 5.40-5.47 (m, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.30-7.33 (m, 1H), 7.38-7 .40 (m, 1H), 7.46-7.48 (m, 2H), 7.62-7.64 (m, 2H), 7.82-7.84 (m, 2H), 8.14 -8.17 (m, 1H), 8.24 (d, J=2.8 Hz, 1H), 8.36 8.38 (m, 1H), 8.49 (d, J=6 Hz, 1H ), 8.58 (d, J=2.0 Hz, 1H), 9.47 (s, 1H), 11.11 (s, 1H), 12.14-12.28 (m, 1H). (M+H) ⁺ 763.5.

[482] Compounds 110 (process for compound 102), 124, 144 (process for compound 102), 145, 146, 147 (process for compound 94), 172 (process for compound 73) were prepared using procedures similar to those described above. , 179 (method for connection 173), 188 (method for connection 173), 189 (method for connection 73).

[483] Scheme for the synthesis of exemplary compound 180

[484] Step 1. tert-Butyl-(S)-5-amino-5-oxo-4-(1-oxo-5-(prop-2-yn-1-yloxy)isoindolin-2-yl)pentanoate

[485] Into a stirred solution of (S)-tert-butyl-5-amino-4-(5-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (450 mg, 1.35 mmol) and 3-bromoprop -1-yne (192 mg, 1.62 mmol) in N,N-dimethylformamide (4 ml), potassium carbonate (372 mg, 2.69 mmol) and potassium iodide (22.4 mg, 0.135 mmol) were added and the mixture was stirred at 50°C overnight under nitrogen atmosphere. LCMS showed the formation of the desired product. The mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 50% ethyl acetate in hexanes with 5% methanol) to give (S)-tert-butyl-5-amino-5-oxo-4-(1-oxo-5-(prop-2-yn-1-yloxy)isoindolin-2-yl)pentanoate (489 mg, 97% yield ) in the form of a colorless oil.

[486] Step 2: 3-(1-Oxo-5-(prop-2-yn-1-yloxy)isoindolin-2-yl)piperidin-2,6-dione

[487] Into a stirred solution of (8)-tert-butyl-5-amino-5-oxo-4-(1-oxo-5-(prop-2-yn-1-yloxy)isoindolin-2-yl)pentanoate ( 325 mg, 0.873 mmol) in anhydrous tetrahydrofuran (20 ml) was added dropwise potassium tert-butoxide (1N, in THF) (107.7 mg, 0.96 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 20 minutes. LCMS showed the formation of the desired product. The reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (50 ml). The organic layer was collected, washed with water (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 50% ethyl acetate in hexanes with 10% methanol) with yielding 3-(1-oxo-5-(prop-2-yn-1-yloxy)isoindolin-2-yl)piperidin-2,6-dione (128 mg, 49% yield) as a white solid.

[488] Step 3. 3-(5-((3-(5-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin- 2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione

[489] Into a stirred solution of 3-(1-oxo-5-(prop-2-yn-1-yloxy)isoindolin-2-yl)piperidin-2,6-dione (50 mg, 0.168 mmol), 7-( 6-((1r,3r)-3-((6-iodopyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole (74 mg, 0.14 mmol) and triethylamine (70.7 mg, 0.70 mmol) in N,N-dimethylformamide (1 ml), trans-dichlorobis(triphenylphosphine)palladium(II) (4.91 mg, 0.007 mmol) and copper iodide (1 .33 mg, 0.007 mmol) at room temperature in a nitrogen atmosphere; the mixture was degassed three times with nitrogen. The resulting mixture was stirred at 65°C for 12 hours. TLC indicated completion of the reaction. TLC indicated completion of the reaction. The mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by preparative TLC (eluting with 10% methanol in dichloroethane) to give 3-(5-((3- (5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop -2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (19 mg, 16%) as a white solid.

[490] ^1H NMR (400 MHz, DMSO-d6): δ 1.97-2.00 (m, 1H), 2.33-2.44 (m, 2H), 2.55-2.67 ( m, 4H), 2.86-2.96 (m, 1H), 4.29 (d, J=17.2 Hz, 1H), 4.42 (d, J=16.8 Hz, 1H), 5.06-5.10 (m, 2H), 5.18 (s, 2H), 5.42-5.45 (m, 1H), 6.99 (d, J=8.4 Hz, 1H) , 7.17 (d, J=8.0 Hz, 1H), 7.29-7.33 (m, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.68 ( d, J=8.0 Hz, 2H), 7.74 (d, J=5.6 Hz, 1H), 7.89 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 8.24 (s, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.53-8.59 (m, 2H), 9.56 (s, 1H), 10.97 (s, 1H), 12.54 (br, 1H). (M+H) ⁺ 705.4.

[491] Scheme for the synthesis of exemplary compound 64

[492] 5-(4-(3-(5-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)cyclobutoxy)pyridin-2-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[493] The title compound was prepared according to the scheme below using the procedures described above for the other target compounds and conventional procedures known to those skilled in the art. The original tert-butyl-7-(6-((1r,3r)-3-((6-(3-hydroxyprop-1-in-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3- yl)-5H-pyrido[4,3-b]indole-5-carboxylate was prepared according to the procedures described for compound 117.

[494] 5-(4-(3-(5-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)cyclobutoxy)pyridin-2-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[495] ¹ H NMR (400 MHz, CD ₃ OD) δ 9.42 (s, 1H), 8.53 (d, J=2.3 Hz, 1H), 8.50 (d, J=6, 1 Hz, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.13 (d, J=8.0 Hz, 2H), 7.87 (s, 1H), 7.71 -7.78 (m, 2H), 7.68 (d, J=8.3 Hz, 1H), 7.42 (s, 1H), 7.33 (s, 2H), 7.29 (d, J=8.6 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 5.51 (s, 2H), 5.06-5.14 (m, 2H), 3, 55 (s, 4H), 2.58-3.03 (m, 15H), 2.04 (m, 3H).

[496] Scheme for the synthesis of exemplary compound 67

[497] Step 1. 14-((5-Bromo-3-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol

[498] To a solution of pentaethylene glycol (330 mg, 1.38 mmol) in THF (5 ml) was added NaH (30 mg, 0.76 mmol) at 0°C. The solution was stirred at room temperature for 1 hour. 5-bromo-2-chloro-3-(trifluoromethyl)pyridine (180 mg, 0.69 mmol) was then added. The resulting solution was stirred at 80°C for 2 hours. The reaction solution was quenched with water. The mixture was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the desired compound (400 mg, crude), which was used in the next step without further purification.

[499] Step 2. 14-((5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-3, 6,9,12-tetraoxatetradecane-1-ol

[500] A mixture of 14-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol was stirred

[501] (180 mg, 0.39 mmol), 5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[4,3 -b]indole (120 mg, 0.39 mmol) [prepared as described in step 1 for compound 63], Pd(amphos)Cl ₂ (20 mg, 10%) and CsF (118 mg, 0.78 mmol) in mixture of dioxane/H ₂ O (10/1.5 ml) at 80°C for 2 hours. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (20 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired compound (85 mg, 47% yield).

[502] Step 3. 2-(2,6-Dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )-3-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione

[503] Into a solution of 14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-3,6 ,9,12-tetraoxatetradecan-1-ol (85 mg, 0.15 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindolin-1,3-dione (41 mg, 0.15 mmol) and PPh ₃ (47 mg, 0.18 mmol) in THF was added DIAD (45 mg, 0.22 mmol) at 40°C. The mixture was stirred at 40°C for 1 hour. The reaction solution was quenched with water. The mixture was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (10 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (34 mg, 28% yield).

[504] ¹ H NMR (400 MHz, CD ₃ OD): δ 9.25 (s, 1H), 8.79 (s, 1H), 8.37-8.39 (d, J=8.0 Hz , 1H), 8.28-8.30 (d, J=8.0 Hz, 2H), 7.89 (s, 1H), 7.63-7.65 (d, J=8.0 Hz, 1H), 7.54-7.56 (m, 2H), 7.26 (s, 1H), 7.18-7.20 (m, 1H), 5.02-5.05 (m, 1H) , 4.62-4.64 (m, 2H), 4.17-4.19 (m, 2H), 3.95 (s, 3H), 3.88-3.90 (m, 2H), 3.82 -3.84 (m, 2H), 3.61-3.71 (m, 13H), 2.55-2.81 (m, 3H), 2.95-2.99 (m, 1H). (M+H) ⁺ 820.5.

[505] Using the procedures for compound 67, the following compounds were prepared: compound 69, compound 113.

[506] Scheme for the synthesis of exemplary compound 65

[507] Step 1: 4-((1r,3r)-3-(Benzyloxy)cyclobutoxy)pyridine

[508] A solution of pyridin-4-ol (3.20 g, 33.66 mmol, 1.5 eq.) and 3-benzyloxycyclobutanol (4 g, 22.44 mmol, 1 eq.) in tetrahydrofuran (200 ml) add triphenylphosphine (7.06 g, 26.93 mmol, 1.2 eq.) and diisopropyl azodicarboxylate (5.45 g, 26.93 mmol, 1.2 eq.) in one portion at 10°C under nitrogen atmosphere. The mixture was stirred at 50°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. Water (50 ml) was poured into the mixture and it was stirred for 1 minute. The aqueous phase was extracted with dichloromethane (50 ml x 3). The combined organic phase was washed with brine (50 ml x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran, 20:1 to 5:1). HPLC showed 41% product at 254 mm. The residue was purified by flash chromatography on a C18 column [acetonitrile:water (0.5% ammonium hydroxide) = 5% to 50%]. The compound was obtained as 4-(3-benzyloxycyclobutoxy)pyridine (3.2 g, 12.53 mmol, 55% yield) as a white solid.

[509] Step 2: 1-Benzyl-4-((1r,3r)-3-(benzyloxy)cyclobutoxy)pyridinium-1-ium bromide

[510] To a solution of 4-(3-benzyloxycyclobutoxy)pyridine (4.2 g, 16.45 mmol, 1 eq.) in toluene (65 ml) was added benzyl bromide (2.81 g, 16.45 mmol, 1 eq. ). The mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove toluene. The crude product was triturated with petroleum ether (80 ml). The compound was obtained as 1-benzyl-4-((1r,3r)-3-(benzyloxy)cyclobutoxy)pyridinium-1-ium bromide (6.5 g, 15.25 mmol, 92% yield), as white solid matter.

[511] Step 3: 1-Benzyl-4-((1r,3r)-3-(benzyloxy)cyclobutoxy)-1,2,3,6-tetrahydropyridine

[512] A solution of 1-benzyl-4-((1r,3r)-3-(benzyloxy)cyclobutoxy)pyridinium-1-ium bromide (6.5 g, 15.25 mmol, 1 eq.) in ethanol (120 ml) sodium borohydride (3.46 g, 91.47 mmol, 6 eq.) was added at 0°C. The mixture was stirred at 15°C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol. The residue was diluted with water (25 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with brine (40 ml x 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The compound was obtained as 1-benzyl-4-(3-benzyloxycyclobutoxy)-3,6-dihydro-2H-pyridine (4.5 g, 12.88 mmol, 84% yield) as a colorless oil.

[513] Step 4. (1r,3r)-3-((1-Benzylpiperidin-4-yl)oxy)cyclobutan-1-ol

[514] A solution of 1-benzyl-4-(3-benzyloxycyclobutoxy)-3,6-dihydro-2H-pyridine (4.5 g, 12.88 mmol, 1 eq.) in tetrahydrofuran (95 ml) and ethanol ( 70 ml) a catalyst of palladium on activated carbon (0.5 g, 10% purity) was added under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen 3 times. The mixture was stirred under a hydrogen atmosphere (50 psi) at 25°C for 24 hours. LCMS indicated that the reaction was not complete. The mixture was then stirred at 35°C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol:ammonium hydroxide, 20:1:0 to 10:1:0.1). The compound was obtained as 3-[(1-benzyl-4-piperidyl)oxy]cyclobutanol (2.8 g, 10.71 mmol, 83% yield) as a colorless oil.

[515] Step 5. tert-Butyl 4-((1r,3r)-3-hydroxycyclobutoxy)piperidine-1-carboxylate

[516] To a solution of 3-[(1-benzyl-4-piperidyl)oxy]cyclobutanol (1.1 g, 4.21 mmol, 1 eq.) in methanol (10 ml) was added palladium hydroxide (591 mg) and di -tert-butyl carbonate (1.84 g, 8.42 mmol, 2 eq.) under nitrogen. The suspension was degassed and purged with hydrogen 3 times. The mixture was stirred under a hydrogen atmosphere (50 psi) at 25°C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 20:1 to 2:1). The compound was obtained as tert-butyl 4-(3-hydroxycyclobutoxy)piperidine-1-carboxylate (820 mg, 3.02 mmol, 71% yield) as a colorless oil.

[517] Step 6. tert-Butyl-4-((1r,3r)-3-((5-bromopyridin-2-yl)oxy)cyclobutoxy)piperidine-1-carboxylate

[518] In a mixture of tert-butyl 4-(3-hydroxycyclobutoxy)piperidine-1-carboxylate (400 mg, 1.47 mmol, 1 eq.) and 5-bromo-2-fluoropyridine (285 mg, 1.62 mmol , 1.1 eq.) in dimethylformamide (8 ml), cesium carbonate (960 mg, 2.95 mmol, 2 eq.) was added in one portion at 25°C under a nitrogen atmosphere. The mixture was stirred at 100°C for 2 hours. The reaction mixture was poured into water (30 ml) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (20 ml x 3). The combined organic phase was washed with brine (30 ml x 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel 1000 mesh, petroleum ether/ethyl acetate, 200:1 to 20:1). The product was obtained as tert-butyl 4-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]piperidine-1-carboxylate (560 mg, 1.30 mmol, 88% yield) as a colorless oils

[519] Step 7. tert-Butyl-4-((1r,3r)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin- 2-yl)oxy)cyclobutoxy)piperidine-1-carboxylate

[520] Into a suspension of tert-butyl 4-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]piperidine-1-carboxylate (560 mg, 1.31 mmol, 1 eq.), 4.4 ,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (432 mg, 1.70 mmol, 1.3 eq.) and potassium acetate (257 mg, 2.62 mmol, 2 eq.) in dioxane (20 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (95 mg, 0.13 mmol, 0.1 eq.). The mixture was degassed in vacuo and purged with nitrogen 3 times. The mixture was heated to 80°C and stirred at 80°C for 15 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20:1 to 10:1). We obtained tert-butyl-4-[3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]cyclobutoxy]piperidin-1- carboxylate (500 mg, 1.05 mmol, 80% yield) as a colorless oil.

[521] Step 8. tert-Butyl-4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) cyclobutoxy)piperidine-1-carboxylate

[522] Into a solution of tert-butyl-4-[3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]cyclobutoxy] piperidine-1-carboxylate (240 mg, 0.50 mmol, 1 eq.), 7-bromo-5H-pyrido[4,3-b]indole (125 mg, 0.50 mmol, 1 eq.) and potassium carbonate (140 mg, 1.01 mmol, 2 eq.) in a mixture of dimethylformamide (8 ml) and water (2 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05 mmol, 0.1 eq.). The mixture was degassed in vacuo and purged with nitrogen three times. The mixture was stirred at 100°C for 3 hours. The mixture was poured into 50 ml of saturated saline and then extracted with ethyl acetate (50 ml x 2). The combined organic layer was washed with brine (50 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol = 20:1). This gave tert-butyl 4-[3-[[5-(5H-pyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]piperidine-1-carboxylate (175 mg, 0 .34 mmol, 67% yield) as an off-white solid.

[523] Step 9. 7-(6-((1r,3r)-3-(Piperidin-4-yloxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole

[524] Stirred tert-butyl 4-[3-[[5-(5H-pyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]piperidine-1-carboxylate (170 mg, 0.33 mmol, 1 eq.) in hydrochloric acid (4M in dioxane, 8 ml, 100 eq.) at 25°C for 10 minutes. The mixture was concentrated in vacuo. The product was obtained as 7-[6-[3-(4-piperidyloxy)cyclobutoxy]-3-pyridyl]-5H-pyrido[4,3-b]indole (190 mg, crude, hydrochloride) as a brown solid substance and was directly used in the next step without further purification.

[525] Step 10: 5-((5,5-Dimethoxypentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[526] In a solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (548 mg, 2.00 mmol, 1 eq.) and 5-bromo-1,1- dimethoxypentane (506 mg, 2.40 mmol, 1.2 eq.) in a mixture of acetone (3 ml) and dimethylformamide (3 ml) was added potassium carbonate (552 mg, 4.00 mmol, 2 eq.). The mixture was heated to 50°C and stirred at 50°C for 2 hours. The mixture was poured into 50 ml of 0.1 M hydrochloric acid aqueous solution and then extracted with ethyl acetate (50 ml x 2). The combined organic layer was washed with brine (50 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol = 20:1). 5-((5,5-dimethoxypentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (120 mg, 0.30 mmol, 14% yield) was obtained as a colorless oils

[527] Step 11. 5-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentanal

[528] In a mixture of 5-(5,5-dimethoxypentoxy)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (120 mg, 0.29 mmol, 1 eq.) in tetrahydrofuran (10 ml) sulfuric acid (2M in water, 7 ml, 50 eq.) was added in one portion at 25°C under nitrogen atmosphere. The mixture was stirred at 70°C for 1 hour. The aqueous phase was extracted with ethyl acetate (20 ml x 3). The combined organic phase was washed with saturated aqueous sodium bicarbonate (20 ml x 2) and then brine (20 ml x 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was obtained as 5-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-5-yl]oxypentanal (93 mg, crude) as a light yellow solid.

[529] Step 12. 5-((5-(4-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[530] In a mixture of 7-[6-[3-(4-piperidyloxy)cyclobutoxy]-3-pyridyl]-5H-pyrido[4,3-b]indole (110 mg, 0.24 mmol, 1 eq. hydrochloride) in dichloroethane (2 ml) and methanol (5 ml) was added in one portion sodium acetate (40 mg, 0.49 mmol, 2 eq.) at 20°C. The mixture was stirred at 20°C for 10 minutes. 5-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-5-yl]oxypentanal (88 mg, 0.24 mmol, 1 eq.) was added. The mixture was stirred at 20°C for 10 minutes. And then acetic acid (0.02 ml) and sodium cyanoborohydride (31 mg, 0.49 mmol, 2 eq.) were added in one portion. The mixture was stirred at 35°C for 40 minutes. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified using semipreparative reverse phase HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; V%: 3% to 33%, 10 min. ). The product obtained was 2-(2,6-dioxo-3-piperidyl)-5-[5-[4-[3-[[5-(5H-pyrido[4,3-b]indol-7-yl )-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]pentoxy]isoindoline-1,3-dione triformate (50.2 mg, 0.05 mmol, 21% yield) as an off-white solid.

[531] ^1H NMR: (400 MHz, DMSO-d6) δ: 11.80 (s, 1H), 11.11 (s, 1H), 9.35 (s, 1H), 8.55 (d, J=2.4 Hz, 1H), 8.42 (d, J=5.6 Hz, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.18 (s, 3H) , 8.11 (dd, J=2.4, 8.8 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.55 ( d, J=8.4 Hz, 1H), 7.48 (d, J=5.6 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.35 (dd, J=2.0, 8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 5.30 (d, J=3.6 Hz, 1H), 5.11 ( dd, J=5.6, 13.2 Hz, 1H), 4.35 (t, J=6.4 Hz, 1H), 4.17 (t, J=6.4 Hz, 2H), 2, 93-2.84 (m, 2H), 2.77 (s, 2H), 2.63-2.54 (m, 3H), 2.37 (d, J=6.0 Hz, 4H), 2 .22-1.98 (m, 4H), 1.87-1.74 (m, 4H), 1.53-1.38 (m, 6H). (M+H) ⁺ 757.5

[532] Using procedures similar to those described above, the following compounds were prepared: compounds 82, 123 (as described for compounds 65 and 67 and detailed in the scheme below).

[533] Scheme for the synthesis of exemplary compound 66

[534] 5-(4-(2-(4-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)cyclobutoxy)piperidin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[535] Step 1: Benzyl 4-(2,2-diethoxyethyl)piperazine-1-carboxylate

[536] To a solution of benzylpiperazine-1-carboxylate (1.0, 4.54 mmol) in DMF (20 ml) was added K ₂ CO ₃ (1.25 g, 9.0 mmol) and 2-bromo-1,1 -diethoxyethane (1.0 g, 4.54 mmol). The resulting mixture was stirred at 80°C for 20 hours. The reaction mixture was then diluted with water (50 ml) and extracted with EA. The organic phase was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by chromatography (silica gel, PE:EA=1:1) to obtain the desired compound as benzyl 4-(2,2-diethoxyethyl)piperazine-1-carboxylate (1.55 g) as a colorless oil .

[537] Step 2: 1-(2,2-Diethoxyethyl)piperazine

[538] Pd(OH) ₂ /C (0.3 g, 20%). The resulting mixture was stirred at 30°C for 3 hours. The reaction mixture was then filtered and concentrated to give the desired compound 1-(2,2-diethoxyethyl)piperazine (0.9 g, crude) as a white solid, which was used in the next step without further purification.

[539] Step 3: 5-(4-(2,2-Diethoxyethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[540] To a solution of 1-(2,2-diethoxyethyl)piperazine (0.9 g, 4.45 mmol) in NMP (15 ml) was added DIEA (2.3 g, 17.8 mmol) and 2-(2 ,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.35 g, 4.9 mmol). The resulting mixture was stirred at 90°C for 20 hours. The reaction mixture was then diluted with water (50 ml) and extracted with DCM/MeOH (10/1). The organic phase was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by chromatography (silica gel, DCM:MeOH (20:1)) to obtain the desired compound (1.4 g) as a yellow solid.

[541] Step 4: 2-(4-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetaldehyde

[542] 5-(4-(2,2-Diethoxyethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione solution (300 mg, 0.65 mmol) in HCl (5 ml in H ₂ O, 2.5 mol/l) was stirred at 50°C for 20 hours. The mixture was rebasified with NaHCO ₃ (20 ml) and extracted with EA. The organic phase was washed with brine, dried over MgSO ₄ and concentrated to give the desired compound (220 mg, crude) as a yellow solid, which was used in the next step without further purification.

[543]

[544] Step 5. 5-(4-(2-(4-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2 -yl)oxy)cyclobutoxy)piperidin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[545] Into a solution of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetaldehyde (180 mg, 0.41 mmol ) in MeOH/DMSO (8 ml, 1/1) was added 7-(6-((1r,3r)-3-(piperidin-4-yloxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4, 3-b]indole (97 mg, 0.24 mmol) [prepared as described for compound 65], AcOH (1 drop) and NaBH ₃ CN (60 mg, 0.94 mmol). The resulting mixture was stirred at 10°C for 2 hours. The reaction mixture was then diluted with water (10 ml) and extracted with EA. The organic phase was washed with brine and filtered and the crude material was purified by preparative HPLC to give the title compound (21.2 mg) as a yellow solid.

[546] ^1H NMR (400 MHz, DMSO- _d6 ): δ 13.21 (s, 1H), 11.08 (s, 2H), 9.76 (s, 1H), 8.67 (d, J=6.6 Hz, 1H), 8.61 (s, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.17 (d, J=8.3 Hz, 1H) , 8.02 (d, J=7.1 Hz, 2H), 7.82-7.72 (m, 3H), 7.46 (s, 2H), 7.35 (s, 2H), 6, 96 (d, J=8.5 Hz, 1H), 5.34 (s, 1H), 5.08 (d, J=1.1 Hz, 2H), 4.40 (s, 2H), 3, 23 (s, 4H), 3.15 (s, 4H), 3.02 (s, 4H), 2.95-2.83 (m, 4H), 2.59 (d, J=15.7 Hz , 4H), 2.44 (s, 2H), 2.01 (s, 5H), 1.77 (d, J=14.7 Hz, 2H). (M+H) ⁺ 783.6.

[547] Scheme for the synthesis of exemplary compound 171

[548] 5-((4,4-Difluoro-5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[549] Step 1. O5-tert-Butyl-O1-ethyl-2,2-difluoropentanedioate

[550] Heat a mixture of tert-butylprop-2-enoate (10 g, 78.02 mmol, 1.00 eq), ethyl 2-bromo-2,2-difluoroacetate (28.51 g, 140.44 mmol, 1.8 eq.) and copper (10.41 g, 163.85 mmol, 2.10 eq.) in tetrahydrofuran (100 ml) to 55°C with vigorous stirring; then N,N,N',N'-tetramethylethylenediamine (4.53 g, 39.01 mmol, 0.50 eq.) was added followed by acetic acid (4.22 g, 70.22 mmol, 0.90 eq. .). The dark blue-brown reaction mixture was stirred for 1 hour at 55°C. 10% aqueous ammonium chloride (100 ml) and ethyl acetate (500 ml) were added. The resulting mixture was stirred for 0.5 hours at room temperature and filtered through celite. The organic phase was washed with another ammonium chloride solution (100 mL x 5) to remove any remaining copper complexes (blue). The solution was dried with anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 500/1, 100/1) to give O5-tert-butyl-O1-ethyl-2,2-difluoropentanedioate (18.6 g, 73.74 mmol, yield 95%) as a yellow oil.

[551] Step 2: tert-Butyl 4,4-difluoro-5-hydroxypentanoate

[552] Cool a suspension of sodium borohydride (3.24 g, 85.63 mmol, 1.20 eq.) in ethanol (100 ml) to 0° C. in an ice bath and add dropwise using a dropping funnel a solution of O5-tert- butyl O1-ethyl-2,2-difluoropentanedioate (18 g, 71.36 mmol, 1.00 eq.) in ethanol (100 ml) with vigorous stirring. The rate of addition of drops was carefully controlled while maintaining the temperature of the reaction mixture at 0-15°C. The mixture was then stirred at 15°C for 1 hour. The reaction mixture was quenched by adding dropwise 5% aqueous citric acid solution (40 ml) with cooling. The aqueous phase was extracted with ethyl acetate (200 ml x 3). The combined organic phase was washed with brine (200 ml x 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 20/1, 10/1) to give tert-butyl 4,4-difluoro-5-hydroxypentanoate (14.2 g, 67.55 mmol, 95% yield %) in the form of a colorless oil.

[553] Step 3: tert-Butyl 4,4-difluoro-5-tetrahydropyran-2-yloxypentanoate

[554] In a mixture of tert-butyl 4,4-difluoro-5-hydroxypentanoate (14.2 g, 67.55 mmol, 1.00 eq.) and 4-methylbenzenesulfonic acid (642 mg, 3.38 mmol, 0 .05 eq.) in dichloromethane (50 ml) was added 3,4-dihydro-2H-pyran (17.05 g, 202.65 mmol, 3.00 eq.) at -10°C under nitrogen atmosphere. The mixture was then heated to 25°C and stirred for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 ml) and then extracted with dichloromethane (50 ml x 3). The combined organic phase was washed with brine (50 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 500/1, 100/1) to give tert-butyl 4,4-difluoro-5-tetrahydropyran-2-yloxypentanoate (17.2 g, crude) in the form of a colorless oil.

[555] Step 4: 4,4-Difluoro-5-tetrahydropyran-2-yloxypentan-1-ol

[556] To a solution of lithium aluminum hydride (2.66 g, 70.12 mmol, 1.20 eq.) in tetrahydrofuran (300 ml) was added dropwise a solution of tert-butyl-4,4-difluoro-5-tetrahydropyran-2- yloxypentanoate (17.2 g, 58.44 mmol, 1.00 eq.) in tetrahydrofuran (60 ml) at 0°C under a nitrogen atmosphere, while the temperature was maintained below 0°C. The reaction mixture was stirred at 0°C within 1 hour. The reaction mixture was quenched with water (2.6 ml), a solution of sodium hydroxide in water (15%, 5.2 ml) and water (8 ml) at 0° C. The suspension was filtered through a pad of celite. The precipitate was washed with ethyl acetate (500 ml). The combined organic phase was washed with brine (200 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 20/1 to 10:1). 4,4-Difluoro-5-tetrahydropyran-2-yloxypentan-1-ol (10.9 g, 48.61 mmol, 83% yield) was obtained as a colorless oil.

[557] Step 5: (4,4-Difluoro-5-tetrahydropyran-2-yloxypentyl)-4-methylbenzenesulfonate

[558] In a mixture of 4,4-difluoro-5-tetrahydropyran-2-yloxypentan-1-ol (10.9 g, 48.61 mmol, 1.00 eq.) and p-toluenesulfonyl chloride (13.90 g, 72 .91 mmol, 1.50 eq.) in dichloromethane (100 ml), triethylamine (9.84 g, 97.22 mmol, 2.00 eq.) was added in one portion at 0°C under nitrogen atmosphere. The mixture was heated to 25°C and stirred for 16 hours. The mixture was poured into ice water (w/w = 1/1) (30 ml) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (50 ml x 3). The combined organic phase was washed with brine (50 ml x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 20/1, 10/1) to give (4,4-difluoro-5-tetrahydropyran-2-yloxypentyl)-4-methylbenzenesulfonate (16.6 g, 43. 87 mmol, yield 90%) as a colorless oil.

[559] Step 6: Dimethyl 4-(4,4-difluoro-5-hydroxypentoxy)benzene-1,2-dicarboxylate

[560] To a solution of (4,4-difluoro-5-tetrahydropyran-2-yloxypentyl)-4-methylbenzenesulfonate (1 g, 2.64 mmol, 1 eq.) in N,N-dimethylformamide (6 ml) was added cesium carbonate (1.72 g, 5.28 mmol, 2 eq.) and dimethyl 4-hydroxybenzene-1,2-dicarboxylate (555 mg, 2.64 mmol, 1 eq.). The mixture was stirred at 50°C for 12 hours. LCMS indicated that the starting material was consumed and the desired compound was detected. The mixture was filtered and poured into hydrochloric acid (1 N, 30 ml), the aqueous phase was extracted with dichloromethane (20 ml x 3). The combined organic phase was washed with brine (20 ml x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 20/1, 5/1). Dimethyl 4-(4,4-difluoro-5-hydroxypentoxy)benzene-1,2-dicarboxylate (700 mg, 2.11 mmol, 79% yield) was obtained as a colorless oil.

[561] Step 7: Dimethyl 4-[4,4-difluoro-5-(trifluoromethylsulfonyloxy)pentoxy]benzene-1,2-dicarboxylate

[562] To a solution of dimethyl 4-(4,4-difluoro-5-hydroxypentoxy)benzene-1,2-dicarboxylate (600 mg, 1.81 mmol, 1 eq.) in dichloromethane (10 ml) add 2 ,6-dimethylpyridine (580 mg, 5.42 mmol, 3 eq.) at 0°C. After addition, the mixture was stirred at this temperature for 10 minutes and then trifluoromethylsulfonyltrifluoromethanesulfonate (2.55 g, 9.03 mmol, 5 eq.) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 50 minutes. LCMS showed that the starting material had disappeared and the desired compound was detected. The mixture was concentrated in vacuo. The residue was further purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 4:1). Dimethyl 4-[4,4-difluoro-5-(trifluoromethylsulfonyloxy)pentoxy]benzene-1,2-dicarboxylate (600 mg, 1.29 mmol, 71% yield) was obtained as a white solid.

[563] Step 8: Dimethyl-4-[4,4-difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl ]oxy]cyclobutoxy]-1-piperidyl]pentoxy]benzene-1,2-dicarboxylate

[564] In a solution of dimethyl 4-[4,4-difluoro-5-(trifluoromethylsulfonyloxy)pentoxy]benzene-1,2-dicarboxylate (150 mg, 0.3 mmol, 1 eq.) in acetonitrile (1 ml) and dimethyl sulfoxide (0.5 ml) was added potassium carbonate (133 mg, 1 mmol, 3 eq.) and 5-methyl-7-[6-[3-(4-piperidyloxy)cyclobutoxy]-3-pyridyl]pyrido[4, 3-b]indole (138 mg, 0.3 mmol, 1 eq.) [prepared as described for compound 82]. The mixture was stirred at 50°C for 16 hours. LCMS showed that the starting material had virtually disappeared and the desired compound was detected. The mixture was poured into water (20 ml) and the aqueous phase was extracted with ethyl acetate (20 ml x 3). The combined organic phase was washed with brine (20 ml x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was further purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 4:1). Dimethyl-4-[4,4-difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy] was obtained -1-piperidyl]pentoxy]benzene-1,2-dicarboxylate (160 mg, 0.2 mmol, 66% yield) as a yellow oil.

[565] Step 9: 4-[4,4-Difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy ]cyclobutoxy]-1-piperidyl]pentoxy]phthalic acid

[566] Into a solution of dimethyl-4-[4,4-difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl] oxy]cyclobutoxy]-1-piperidyl]pentoxy]benzene-1,2-dicarboxylate (120 mg, 0.16 mmol, 1 eq.) in methanol (3 ml) and water (1.5 ml) was added potassium hydroxide (36 mg, 0.6 mmol, 4 eq.). The mixture was stirred at 55°C for 2 hours. LCMS indicated that the starting material was consumed and the desired compound was detected. The reaction mixture was adjusted to pH = (7) with hydrochloric acid (1 M) and concentrated under reduced pressure to remove methanol and water. The residue was directly used for the next step without further purification. 4-[4,4-difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]-1 was obtained -piperidyl]pentoxy]phthalic acid (110 mg, 0.1 mmol, 95% yield) as a yellow solid.

[567] Step 10: 5-[4,4-Difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy ]cyclobutoxy]-1-piperidyl]pentoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

[568] Into a solution of 4-[4,4-difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy] cyclobutoxy]-1-piperidyl]pentoxy]phthalic acid (110 mg, 0.2 mmol, 1 eq.) in acetic acid (2 ml) was added sodium acetate (37 mg, 0.5 mmol, 3 eq.), the mixture was stirred at 25°C for 1 hour. 3-Aminopiperidine-2,6-dione (30 mg, 0.2 mmol, 1.2 eq., in hydrochloric acid) was then added to the mixture and heated to 120° C., stirred for an additional 11 hours. LCMS indicated that the starting material was consumed and the desired compound was detected. The mixture was concentrated in vacuo. The residue was purified using preparative high-performance liquid chromatography on a column: Phenomenex Synergi C18 150*25*10 µm; mobile phase: [water (0.225% formic acid) - acetonitrile]; In%: from 14% to 35%), 7 minutes. 5-[4,4-difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]-1 was obtained -piperidyl]pentoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (67 mg, 0.08 mmol, 50% yield, 98% purity), formic acid) as gray solid matter.

[569] ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ=11.11 (s, 1H), 8=9.35 (s, 1H) δ=8.64 (s, 1H), 8, 49-8.48 (d, J=4 Hz 1H), 8.33-8.31 (d, J=8 Hz 1H), δ=8.17 (s, 1H), δ=7.97 (s , 1H) 7.85-7.83 (d, J=8 Hz 1H), 7.62-7.61 (d, J=4 Hz 2H), 7.43 (s, 1H), 6.94- 6.92 (d, J=8 Hz 1H), 5.31-5.29 (m, 1H), 5.12-5.10 (m, 1H), 4.34 (s, 5H), 4, 25-4.23 (d, J=8 Hz 1H), 3.95 (s, 3H), 2.77 (m, 2H), 2.73 (m, 4H), 2.53-2.52 ( m, 1H), 2.39-2.38 (m, 4H), 1.91-1.90 (m, 4H), 1.75 (m, 2H), 1.43 (m, 2H), 1 .41 (m, 2H). (M+H) ⁺ 807.5.

[570] Scheme for the synthesis of exemplary compound 164

[571] Step 1: Benzyl 6-(tosyloxy)hexanoate

[572] To a mixture of benzyl 6-hydroxyhexanoate (1.1 g, 4.95 mmol) and triethylamine (1.0 g, 9.90 mmol) in dichloromethane (10 ml), 4-toluenesulfonyl chloride (1.88 g, 9.90 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. TLC indicated completion of the reaction. The reaction mixture was diluted with dichloromethane (20 ml), washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash chromatography on silica gel (eluting with 30 to 50% ethanol). l acetate in hexane) to obtain benzyl 6-(tosyloxy)hexanoate (960 mg, 54% yield) as a colorless oil.

[573] Step 2: Benzyl 6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)hexanoate

[574] A mixture of benzyl 6-(tosyloxy)hexanoate (200 mg, 0.53 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (146 mg, 0.53 mmol), potassium carbonate (147 mg, 1.06 mmol) and potassium iodide (9 mg, 0.05 mmol) in N,N-dimethylformamide (3 ml) at 50°C for 12 hours. TLC indicated completion of the reaction. The reaction mixture was partitioned between water (15 ml) and ethyl acetate (15 ml). The organic layer was collected, washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 2 to 5% methanol in dichloromethane) to give benzyl 6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)hexanoate (100 mg, 40% yield) as a yellow solid.

[575] Step 3: 6-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)hexanoic acid

[576] A mixture of benzyl 6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)hexanoate (100 mg, 0.21 mmol) and palladium on activated carbon ( 20%, 50 mg) in methanol (2 ml) at room temperature for 1 hour in a hydrogen atmosphere (hydrogen cylinder). TLC indicated completion of the reaction. The reaction mixture was filtered and concentrated under reduced pressure to give 6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)hexanoic acid (70 mg, 86% yield) as yellow oil, which was directly used in the next step without further purification.

[577] Step 4: 5-(6-(4-((1r,3r)-3-(5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)cyclobutoxy )piperidin-1-yl)-6-oxohexyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[578] In a mixture of 6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)hexanoic acid (70 mg, 0.18 mmol), and 7-(6- ((1r,3r)-3-(piperidin-4-yloxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole (75 mg, 0.18 mmol) [prepared as described for compound 65], and triethylamine (56 mg, 0.56 mmol) in N,N-dimethylformamide (2 ml) was added (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3 -tetramethyluronium hexafluorophosphate) (212 mg, 0.56 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. TLC indicated completion of the reaction. The reaction mixture was diluted with dichloromethane (50 ml), washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 2 to 5% methanol in dichloromethane) to give the title compound (6.6 mg, 5% yield) as a white solid.

[579] ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.52 1.57 (m, 3H), 1.61 1.65 (m, 2H), 1.70-1.74 (m, 2H ), 1.98-2.01 (m, 2H), 2.13-2.17 (m, 1H), 2.34-2.41 (m, 2H), 2.47-2.50 (m , 2H), 2.78-2.88 (m, 2H), 3.20-3.28 (m, 2H), 3.54-3.72 (m, 3H), 4.00-4.10 (m, 3H), 4.39-4.44 (m, 1H), 4.95 (dd, J=5.2, 12.0 Hz, 1H), 5.31-5.42 (m, 4H ), 6.82 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.31-7.34 (m, 2H), 7.48 -7.51 (m, 2H), 7.68 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.87 (d, J=7.2 Hz, 1H) , 8.11 (d, J=8.0 Hz, 1H), 8.32 (s, 1H), 8.41-8.45 (m, 2H), 9.23 (s, 1H).

[580] Scheme for the synthesis of exemplary compounds 198 and 205

[581] 2-(2,6-Dioxopiperidin-3-yl)-5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione

[582] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)propoxy)isoindoline-1,3-dione

[583] Compounds 198 and 205 were prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[584] Scheme for the synthesis of exemplary compound 68

[585] 2-(2,6-Dioxopiperidin-3-yl)-5-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)piperazin-1-yl)isoindolin-1,3-dione

[586] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[587] ^1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 9.37 (s, 1H), 8.64 (s, 1H), 8.50 (d, J =4.0 Hz, 1H), 8.33 (d, J=12.0 Hz, 1H), 8.00 (s, 1H), 7.68-7.60 (m, 3H), 7.34 (d, J=4.0 Hz, 1H), 7.25 (dd, J=8.0 Hz, 4.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 5.32 (t, J=4.0 Hz, 1H), 5.07 (dd, J=12.0 Hz, 8.0 Hz, 1H), 4.20-4.17 (m, 1H), 3.96 (s, 3H), 4.46 (s, 6H), 2.88-2.84 (m, 1H), 2.59-2.54 (m, 7H), 2.43-2, 32 (m, 6H), 2.02-1.98 (m, 1H), 1.57-1.49 (m, 4H), 1.38-1.34 (m, 2H). (M+H) ⁺ 756.6

[588] Scheme for the synthesis of exemplary compound 70

[589] 2-(2,6-Dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H -pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione

[590] Step 1. 2-((1r,3r)-3-(Benzyloxy)cyclobutoxy)-5-bromopyridine

[591] To a solution of (1r,3r)-3-(benzyloxy)cyclobutan-1-ol (500 mg, 2.8 mmol) in DMF (15 ml) was added NaH (336 mg, 8.4 mmol, 60%) at 0°C. The solution was stirred at 0°C for 30 minutes. Add 5-bromo-2-fluoropyridine (1.0 g, 5.6 mmol) in DMF (3 ml). The resulting solution was heated at 80°C overnight. After cooling to room temperature, the mixture was quenched with water. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 100:1) to give the desired compound (630 mg, 67% yield) as a colorless oil.

[592] Step 2. (1r,3r)-3-((5-Bromopyridin-2-yl)oxy)cyclobutan-1-ol

[593] To a solution of 2-((1r,3r)-3-(benzyloxy)cyclobutoxy)-5-bromopyridine (630 mg, 1.88 mmol) in DCM (15 ml) was added BBr ₃ (1.42 g, 5 .65 mmol) at 78°C. The resulting solution was stirred at 78°C for 0.5 hours. The solution was quenched with NaHCO ₃ . The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were concentrated to give the desired compound (390 mg, crude) as a yellow solid, which was directly used in the next step without further purification.

[594] Step 3: 5-Bromo-2-((1r,3r)-3-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)cyclobutoxy)pyridine

[595] To a solution of (1r,3r)-3-((5-bromopyridin-2-yl)oxy)cyclobutan-1-ol (390 mg, 1.64 mmol) in THF (15 ml) was added NaH (262 mg , 60%) at 0°C. The solution was stirred at 10°C for 0.5 hour and then 13-bromo-1-phenyl-2,5,8,11-tetraoxatridecane (570 mg, 1.64 mmol) was added. The resulting solution was stirred at 70°C for 20 hours. The solution was quenched with water. The layers were separated and the aqueous layer was extracted with EA. The combined organic layers were washed with brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography using PE:EA (1:1) to obtain the desired compound (350 mg) as a yellow solid.

[596] Convert 5-bromo-2-((1r,3r)-3-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)cyclobutoxy)pyridine to the final compound, 2- (2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione, according to the following scheme and using the procedures described above and conventional procedures , known to those skilled in the art.

[597] Compound 70: ^1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 9.36 (s, 1H), 8.62 (s, 1H), 8.50 ( s, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 7.81 ( d, J=8.3 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.43 (s, 1H), 7.35 (d, J=7.8 Hz, 1H), 6.93 (d, J=8.7 Hz, 1H), 5.31 (s, 1H), 5.11 (dd, J=12.8, 5.1 Hz, 1H), 4, 31 (s, 2H), 4.22 (s, 1H), 3.95 (s, 3H), 3.79 (s, 2H), 3.64-3.48 (m, 10H), 3.45 (d, J=4.9 Hz, 3H), 2.86 (d, J=13.2 Hz, 1H), 2.45-2.40 (m, 2H), 2.37-2.30 ( m, 2H), 2.02 (d, J=6.5 Hz, 1H). (M+H) ⁺ 778.5.

[598] Scheme for the synthesis of exemplary compound 71

[599] 2-(2,6-Dioxopiperidin-3-yl)-5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2 -yl)-3,6,9,12-tetraoxapentadec-14-in-1-yl)oxy)isoindoline-1,3-dione

[600] Step 1. 15-(5-Bromopyridin-2-yl)-3,6,9,12-tetraoxapentadec-14-in-1-ol

[601] To a solution of 3,6,9,12-tetraoxapentadec-14-yn-1-ol (570 mg, 2.45 mmol) in dry THF (10 ml) 2,5-dibromopyridine (697.6 mg , 2.94 mmol), CuI (51.4 mg, 0.27 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (80 mg, 0.24 mmol) at 15°C in an N ₂ atmosphere. The solution was stirred at 40°C for 1.5 hours. The solution was quenched with H ₂ O (10 ml) and the mixture was extracted with EtOAc (10 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired compound (530 mg, 56% yield) as a yellow oil.

[602] Convert 15-(5-bromopyridin-2-yl)-3,6,9,12-tetraoxapentadec-14-yn-1-ol to the final compound, 2-(2,6-dioxopiperidin-3-yl) -5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)-3,6,9,12-tetraoxapentadec-14- in-1-yl)oxy)isoindoline-1,3-dione, according to the following scheme and using the procedures described above and conventional procedures known to those skilled in the art.

[603] Compound 71: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.39 (s, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.30 (d , J=2.0 Hz, 1H), 8.28 (d, J=3.0 Hz, 1H), 8.11 (s, 1H), 7.80 (d, J=8.4 Hz, 1H ), 7.72 (d, J=7.6 Hz, 1H), 7.63-7.68 (m, 2H), 7.44 (d, J=2.0 Hz, 1H), 7.34 -7.36 (m, 1H), 5.08-5.12 (m, 1H), 4.48 (s, 2H), 4.31 (t, J=3.6 Hz, 2H), 3, 98 (s, 3H), 3.80 (s, 3H), 3.53-3.79 (m, 12H), 1.95-2.08 (m, 2H). (M+H) ⁺ 746.5.

[604] Scheme for the synthesis of exemplary compound 74

[605] 2-(2,6-Dioxopiperidin-3-yl)-5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2 -yl)-3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione

[606] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[607] Compound 74: ^1H NMR (400 MHz, _CDCl3 ): δ 9.65 (s, 1H), 9.22 (s, 1H), 8.67-8.73 (m, 2H), 8 .47 (d, J=7.6 Hz, 1H), 8.36 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.83 (s, 1H), 7 .81 (s, 1H), 7.59-7.71 (m, 2H), 7.04 (d, J=9.2 Hz, 2H), 4.93-4.96 (m, 1H), 4.10 (s, 5H), 3.87 (s, 1H), 3.55-3.76 (m, 18H), 3.26 (s, 2H), 2.12-2.16 (m, 2H). (M+H) ⁺ 750.5.

[608] Scheme for the synthesis of exemplary compound 72

[609] 5-((14-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy )-2-(2,6-dioxopiperidin-3-yl)-4,6,7-trifluoroisoindoline-1,3-dione

[610] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[611] 2-(2,6-Dioxopiperidin-3-yl)-4,5,7-trifluoro-6-hydroxyisoindoline-1,3-dione was prepared as described below.

[612] Step 1: 3,4,6-Trifluoro-5-hydroxyphthalic acid

[613] To a solution of 3,4,5,6-tetrafluorophthalic acid (1.18 g, 5 mmol) in water (20 ml) was added potassium hydroxide (2.24 g, 40 mmol, 8 eq.). The resulting solution was heated to 90°C for 9 hours. The reaction mixture was then cooled to room temperature and neutralized with HCl (1 N). The resulting solution was extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude desired product (1.15 g) as a white solid, which was used in the next step without purification.

[614] Step 2: 2-(2,6-Dioxopiperidin-3-yl)-4,5,7-trifluoro-6-hydroxyisoindoline-1,3-dione

[615] AcONa ( 209 mg, 2.54 mmol). The resulting solution was stirred at 120°C for 4 hours. After cooling to room temperature, the solvent was removed under vacuum. Then the resulting mixture was quenched with water (30 ml). The resulting solution was extracted with EA (30 ml x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate and concentrated in vacuo to give 2-(2,6-dioxopiperidin-3-yl)-4,5,7-trifluoro-6-hydroxyisoindolin- 1,3-dione (400 mg, 1.22 mmol, 58%).

[616] Compound 72: ^1H NMR (400 MHz, CD ₃ OD): δ 13.19 (s, 1H), 9.77 (s, 1H), 8.62-8.68 (m, 2H), 8.52 (d,J=8.0 Hz, 1H), 8.16 (s, 1H), 8.01-8.02 (m, 2H), 7.80-7.81 (m, 1H) , 7.15-7.28 (m, 1H), 6.99 (d,J=8.0 Hz, 1H), 5.15-5.23 (m, 1H), 4.43-4.45 (m, 2H), 3.77-3.89 (m, 4H), 3.49-3.60 (m, 12H), 2.86-3.05 (m, 3H), 1.99-2 .01 (m, 1H). (M+H) ⁺ 792.5.

[617] Scheme for the synthesis of exemplary compound 81

[618] 5-((14-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy )-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[619] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[620] Compound 81: ^1H NMR (400 MHz, _CDCl3 ): δ 9.31 (s, 1H), 8.51 (s, 1H), 8.40 (s, 1H), 8.11 (d , J=8.0 Hz, 1H), 7.82-7.83 (m, 1H), 7.60 (s, 1H), 7.37-7.45 (m, 3H), 6.84 ( d, J=8.0 Hz, 1H), 4.92-4.95 (m, 1H), 4.53 (t, J=4.8 Hz, 2H), 4.24 (t, J=4 .8 Hz, 2H), 3.89-3.91 (m, 4H), 3.67-3.75 (m, 12H), 2.74-2.92 (m, 3H), 2.12- 2.16 (m, 1H). (M+H) ⁺ 756.5.

[621] Scheme for the synthesis of exemplary compound 75

[622] 2-(2,6-Dioxopiperidin-3-yl)-5-(4-(5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol- 7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)piperidin-1-yl)isoindoline-1,3-dione

[623] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[624] Compound 75: ^1H NMR (400 MHz, DMSO- _d6 ): δ=11.07 (s, 1H), 9.38-9.32 (m, 1H), 8.66-8.63 (d, J=12 Hz 1H), 8.50-8.48 (m, J=8 Hz 1H), 8.36 (s, 2H), 8.34-8.29 (m, 1H), 8 .21-8.14 (m, 1H), 7.99-7.94 (m, 1H), 7.61 (s, 3H), 7.28-7.22 (m, 1H), 7.19 -7.12 (m, 1H), 6.96-6.89 (m, 1H), 5.09-5.00 (m, 1H), 4.36-4.29 (m, 2H), 3 .95 (s, 5H), 3.34 (s, 4H), 2.87 (s, 2H), 2.99-2.78 (m, 1H), 2.82-2.73 (m, 1H ), 2.04-1.93 (m, 1H), 1.82-1.65 (m, 4H), 1.61-1.52 (m, 2H), 1.52-1.41 (m , 5H), 1.28 (s, 4H), 1.22-1.05 (m, 4H). (M+H) ⁺ 771.6.

[625] Scheme for the synthesis of exemplary compound 76

[626] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(3-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indole -7-yl)pyridin-2-yl)prop-2-in-1-yl)piperazin-1-yl)propoxy)azetidin-1-yl)isoindolin-1,3-dione

[627] Prepared according to the synthesis scheme below using the procedures described above and those routine to those skilled in the art.

[628] Compound 76: ¹ H NMR (400 MHz, CD ₃ OD): δ 9.32 (s, 1H), 8.96 (s, 1H), 8.45-8.52 (m, 2H), 8.37 (d, J=8.0 Hz, 1H), 8.27-8.31 (m, 1H), 7.98 (s, 1H), 7.61-7.98 (m, 4H) , 6.82 (s, 1H), 6.65-6.67 (m, 1H), 5.01-5.05 (m, 1H), 4.59 (m, 1H), 4.27 (t , J=8.4 Hz, 1H), 4.02 (s, 3H), 3.88-3.91 (m, 2H), 3.70 (s, 2H), 3.57 (t, J= 6.0 Hz, 2H), 3.41 (m, 1H), 3.13-3.17 (m, 2H), 2.66-2.86 (m, 11H), 2.02-2.03 (m, 3H). (M+H) ⁺ 751.5.

[629] Scheme for the synthesis of exemplary compound 78

[630] 2-(2,6-Dioxopiperidin-3-yl)-5-(4-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)piperazin-1-yl)isoindolin-1,3-dione

[631] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[632] Compound 78: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 9.35 (s, 1H), 8.64 (t, J=3.9 Hz , 1H), 8.49 (d, J=4.7 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.19 (dd, J=8.6, 2, 5 Hz, 1H), 7.98 (s, 1H), 7.68-7.48 (m, 3H), 7.31 (d, J=7.8 Hz, 1H), 7.20 (t, J=9.5 Hz, 1H), 6.94 (d,J=8.6 Hz, 1H), 5.07 (dd, J=12.9, 5.3 Hz, 1H), 4.33 ( t, J=6.5 Hz, 2H), 3.95 (s, 3H), 3.65 (m, 1H), 3.51-3.41 (m, 3H), 3.36-3.23 (m, 5H), 2.95-2.83 (m, 1H), 2.43-2.28 (m, 6H), 2.05-1.96 (m, 1H), 1.79-1 .73 (m, 1H), 1.67-1.61 (m, 1H), 1.42 (m, 7H). (M+H) ⁺ 770.6.

[633] Scheme for the synthesis of exemplary compound 85

[634] 2-(2,6-Dioxopiperidin-3-yl)-5-((1r,3r)-3-((5-((5-((5-(5-methyl-5H-pyrido[4 ,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)oxy)cyclobutoxy)isoindoline-1,3-dione

[635] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[636] Compound 85: ^1H NMR (400 MHz, CDCl ₃ ): δ 9.32 (s, 1H), 8.58-8.59 (d, J=4.0 Hz, 2H), 8.48 (s, 1H), 8.16-8.18 (d, J=8.0 Hz, 1H), 7.89-7.91 (d, J=8.0 Hz, 1H), 7.74- 7.76 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.47-7.49 (d, J=8.0 Hz, 1H), 7.32-7 .33 (d, J=4.0 Hz, 1H), 7.19 (s, 1H), 7.06-7.08 (d, J=8.0 Hz, 1H), 6.84-6, 86 (d, J=8.0 Hz, 1H), 4.93 (m, 2H), 4.35-4.38 (m, 2H), 4.21 (s, 1H), 3.90 (s , 3H), 3.35-3.49 (m, 7H), 2.68-2.95 (m, 3H), 2.44-2.51 (m, 4H), 2.15 (m, 1H ), 1.88 (m, 2H), 1.56-1.68 (m, 9H), 1.44 (d,J=8.0 Hz, 2H). (M+H) ⁺ 774.6.

[637] Scheme for the synthesis of exemplary compound 79

[638] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-((5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indole -7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)oxy)azetidin-1-yl)isoindoline-1,3-dione

[639] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[640] Compound 79: ^1H NMR (400 MHz, CDCl ₃ ): δ 9.35 (s, 1H), 8.59 (d, J=5.7 Hz, 1H), 8.49 (s, 1H ), 8.28 (s, 1H), 8.21 (d, J=10.6 Hz, 1H), 8.00 (s, 1H), 7.91 (d, J=11.0 Hz, 1H ), 7.63 (d, J=8.2 Hz, 1H), 7.57 (s, 1H), 7.51 (d, J=9.3 Hz, 1H), 7.37 (d, J =5.9 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H), 6.77 (s, 1H), 4.92 (m, 1H), 4.45 (s, 1H ), 4.36 (t, J=6.6 Hz, 2H), 4.16-4.26 (m, 2H), 3.83-3.98 (m, 4H), 3.44 (m, 4H), 2.63-2.92 (m, 3H), 2.11 (d, J=6.4 Hz,2H), 1.79-1.89 (m, 3H), 1.44-1 .70 (m, 10H). (M+H) ⁺ 759.6.

[641] Scheme for the synthesis of exemplary compound 80

[642] 2-(2,6-Dioxopiperidin-3-yl)-5-((1-(5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indole -7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)azetidin-3-yl)oxy)isoindoline-1,3-dione

[643] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[644] Compound 80: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.12 (s, 1H), 9.35 (s, 1H), 8.63 (d, J=2.3 Hz , 1H), 8.50 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 8.18 (dd, J=8.6, 2.5 Hz, 1H), 7 .96 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.60 (d, J=6.8 Hz, 2H), 7.23 (d, J=7, 2 Hz, 2H), 6.93 (d, J=8.6 Hz, 1H), 5.10 (m, 1H), 5.02-4.95 (m, 1H), 4.32 (t, J=6.6 Hz, 2H), 3.95 (s, 3H), 3.70 (t, J=6.8 Hz, 2H), 2.99-2.95 (m, 2H), 2, 86 (d, J=12.1 Hz, 2H), 2.64 (br, 1H), 2.55 (br, 2H), 2.33 (s, 2H), 2.06-1.96 (m , 3H), 1.81-1.70 (m, 3H), 1.60-1.40 (m, 8H). (M+H) ⁺ 759.6.

[645] Scheme for the synthesis of exemplary compound 84

[646] 2-(2,6-Dioxopiperidin-3-yl)-5-((6-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenoxy)hexyl)oxy)isoindoline-1,3-dione

[647] Step 1. 2-((6-(3-(Benzyloxy)phenoxy)hexyl)oxy)tetrahydro-2H-pyran

[648] Stir a solution of 3-(benzyloxy)phenol (1.13 g, 5.66 mmol), 2-((6-bromohexyl)oxy)tetrahydro-2H-pyran (1.0 g, 3.77 mmol) and CS ₂ CO ₃ (2.45 g, 7.55 mmol) in acetone (30 ml) at 70°C overnight. The mixture was cooled to room temperature and quenched with water. The mixture was extracted with EA (200 ml) and the solution was washed with water (30 ml x 3) and saline (30 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified to give the desired product (PE:EA = 20:1) (1.2 g, yield = 83%) as a colorless oil.

[649] Step 2: 3-((6-((Tetrahydro-2H-pyran-2-yl)oxy)hexyl)oxy)phenol

[650] Pd/C ( 200 mg) at room temperature. The resulting solution was stirred at room temperature overnight under a H ₂ pressure of 1 atm. The mixture was filtered and the filtrate was concentrated in vacuo to give the crude desired product (900 mg) as a light yellow oil, which was used directly in the next step.

[651] Step 3. 2-((6-(3-((1r,3r)-3-(Benzyloxy)cyclobutoxy)phenoxy)hexyl)oxy)tetrahydro-2H-pyran

[652] In a solution of 3-((6-((tetrahydro-2H-pyran-2-yl)oxy)hexyl)oxy)phenol (100 mg, 0.34 mmol), (1s,3s)-3-(benzyloxy )cyclobutanol (91 mg, 0.51 mmol), PPh ₃ (267 mg, 1.02 mmol) in THF (5.0 ml) was added DIAD (206 mg, 1.02 mmol) at 40°C under nitrogen atmosphere. The resulting mixture was heated to 80°C overnight. After cooling to room temperature, the reaction mixture was quenched with water. The mixture was extracted with EA (50 ml) and the organic phase was washed with water (20 ml x 3), brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified to give the desired product (PE:EA = 5:1) (130 mg, yield = 84%) as a colorless oil.

[653] Converted 2-((6-(3-((1r,3r)-3-(benzyloxy)cyclobutoxy)phenoxy)hexyl)oxy)tetrahydro-2H-pyran to the final compound, 2-(2,6-dioxopiperidine -3-yl)-5-((6-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridine -2-yl)oxy)cyclobutoxy)phenoxy)hexyl)oxy)isoindoline-1,3-dione, according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[654] Compound 84: 1H NMR (400 MHz, CDCl ₃ ): δ 93.4 (s, 1H), 8.58 (d, J=5.6 Hz, 1H), 8.21-8.48 ( m, 2H), 8.20 (d, J=8.4 Hz, 1H), 7.88-7.91 (m, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.51 (d,J=8.0 Hz, 1H), 7.33-7.36 (m, 2H), 7.16-7.18 (m, 2H) , 6.86 (d, J=8.4 Hz, 1H), 6.39-6.51 (m, 3H), 5.52-5.54 (m, 1H), 4.94-4.96 (m, 2H), 4.07-4.10 (m, 2H), 3.91-3.97 (m, 5H), 3.22-3.24 (m, 1H), 2.69-2 .76 (m, 7H), 2.14-2.16 (m, 1H), 1.82-1.86 (m, 4H), 1.54-1.57 (m, 4H). (M+H) ⁺ 794.5.

[655] Scheme for the synthesis of exemplary compound 86

[656] 4-((14-(4-(5H-Pyrido[4,3-b]indol-7-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[657] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[658] Compound 86: ^1H NMR (400 MHz, CDCl ₃ ): δ 9.28 (s, 2H), 8.50 (s, 1H), 8.08 (s, 1H), 7.35-7 .57 (m, 6H), 6.94-6.96 (m, 3H), 6.77 (s, 1H), 6.38 (s, 1H), 4.88-4.90 (m, 1H ), 4.14 (s, 2H), 3.60-3.86 (m, 17H), 3.31-3.34 (m, 2H), 2.66-2.86 (m, 3H), 2.03-2.05 (m, 1H). (M+H) ⁺ 736.5.

[659] Synthesis plan for illustrative compound 87

[660] 6-((14-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy )-2-(2,6-dioxopiperidin-3-yl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione

[661] Step 1. 6-((14-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12- tetraoxatetradecyl)oxy)pyridine-3,4-dicarboxylic acid

[662] Into a solution of 14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol (200.0 mg, 0.42 mmol) and 6-chloropyridine-3,4-dicarboxylic acid (166 mg, 0.83 mmol) in anhydrous tetrahydrofuran (4 ml) was added sodium hydride (162.0 mg, 4.2 mmol). The resulting solution was stirred at 100°C under the influence of microns. izl. for 2 hours in an N ₂ atmosphere. The solution was cooled to room temperature and quenched with water (20 ml). The mixture was extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired compound (50 mg, 0.077 mmol, 9% yield).

[663] Step 2. 6-((14-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12- tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione

[664] Into a solution of 6-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl )oxy)pyridine-3,4-dicarboxylic acid (50 mg, 0.077 mmol) and 3-aminopiperidine-2,6-dione (12 mg, 0.092 mmol) in AcOH (6 ml) added NaOAc (6 mg, 0.092 mmol) . The resulting solution was stirred at 120°C for 16 hours. After cooling to room temperature, the reaction mixture was quenched by adding water (20 ml). The mixture was extracted with EA (20 ml x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC using DCM/CH ₃ OH (10:1) to give the title compound (4.0 mg, 0.005 mmol, 7% yield).

[665] Compound 87: ^1H NMR (400 MHz, _CDCl3 ): δ 9.28 (s, 1H), 8.42 (s, 1H), 8.37-8.39 (m, 2H), 8 .06 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.40-7.45 (m, 3H), 6.09 (s, 1H), 6.82 (d, J=8.8 Hz, 1H), 4.94-4.99 (m, 1H), 4.54 (t, J=4 .8 Hz, 4H), 3.86-3.91 (m, 4H), 3.66-3.75 (m, 12H), 2.73-2.92 (m, 3H), 2.20- 2.22 (m, 1H). (M+H) ⁺ 739.5.

[666] Scheme for the synthesis of exemplary compound 88

[667] 2-(2,6-Dioxopiperidin-3-yl)-5-((14-((5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione

[668] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[669] Compound 88: ^1H NMR (400 MHz, CDCl ₃ ): δ 9.35 (s, 1H), 8.63 (d, J=7.6 Hz, 1H), 8.45 (s, 1H ), 8.21 (d, J=8.0 Hz, 1H), 8.16 (s, 1H), 7.87-7.90 (m, 1H), 7.75 (d, J=8, 4 Hz, 1H), 7.53-7.58 (m, 2H), 7.39 (s, 1H), 7.35 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.87-4.92 (m, 3H), 4.55 (t, J=4.8 Hz, 2H), 4, 24 (t, J=4.8 Hz, 2H), 3.90 (t, J=4.4 Hz, 3H), 3.66-3.73 (m, 12H), 2.76-2.87 (m, 3H), 2.09-2.16 (m, 1H). (M+H) ⁺ 820.5

[670] Synthesis scheme for exemplary compound 89

[671] 2-(2,6-Dioxopiperidin-3-yl)-5-(4-(3,3,3-trifluoro-2-(2-((5-((5-(5-methyl-5H -pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)ethoxy)propyl)piperidin-1-yl)isoindolin-1,3-dione

[672] Step 1: 2-(5-Benzyloxypentoxy)acetate

[673] To a solution of 5-benzyloxypentan-1-ol (1 g, 5.15 mmol, 1.0 eq.) in dichloromethane (20 ml) was added ethyl 2-diazoacetate (704 mg, 6.18 mmol, 1.0 eq. 2 equiv.) and dirhodium tetraacetate (11 mg, 0.03 mmol). The mixture was then stirred at 20°C for 0.5 hour. The mixture was quenched with ethyl alcohol (10 ml) and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 4:1) to give ethyl 2-(5-benzyloxypentoxy)acetate (700 mg, 2.50 mmol, 49% yield) as yellow oil.

[674] Step 2: 2-(5-Benzyloxypentoxy)ethanol

[675] To a mixture of 1 LiAlH ₄ (189 mg, 4.99 mmol, 2.0 eq.) in tetrahydrofuran (4 ml) was added a solution of ethyl 2-(5-benzyloxypentoxy) acetate (700 mg, 2.50 mmol, 1.0 eq.) in tetrahydrofuran (10 ml) at 0°C. The mixture was then stirred at 20°C for 2 hours. The mixture was quenched with water (0.2 ml), aqueous sodium hydroxide (1 M, 0.2 ml) and additional water (0.8 ml). Then the result was filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to give 2-(5-benzyloxypentoxy)ethanol (400 mg, 1.68 mmol, 67% yield) obtained as white oil.

[676] Step 3: 2-(5-Benzyloxypentoxy)ethyl-4-methylbenzenesulfonate

[677] In a mixture of 2-(5-benzyloxypentoxy)ethanol (400 mg, 1.68 mmol, 1.0 eq.) and toluenesulfonyl chloride (640 mg, 3.36 mmol, 2.0 eq.) in tetrahydrofuran (3 ml ) potassium hydroxide (2.83 g, 50.35 mmol, 30.0 eq.) was added. The mixture was then stirred at 20°C for 0.5 hour. The mixture was diluted with water (10 ml), extracted with ethyl acetate (20 ml), washed with brine (20 ml), dried over anhydrous sodium sulfate and then concentrated. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to give 2-(5-benzyloxypentoxy)ethyl-4-methylbenzenesulfonate (570 mg, 1.45 mmol, 86% yield) in the form of white oil.

[678] Step 4. tert-Butyl 4-(3,3,3-trifluoro-2-hydroxypropyl)piperidine-1-carboxylate

[679] In a mixture of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1.9 g, 8.36 mmol, 1.0 eq.) and trimethyl(trifluoromethyl)silane (1.43 g, 10.03 mmol, 1.2 eq.) in tetrahydrofuran (20 ml), tetrabutylammonium fluoride (1 M, 0.1 ml) was added at 0°C. The mixture was then stirred at 20°C for 1 hour. Aqueous hydrochloric acid (1 M, 17 mL, 2.0 eq.) was then added to the mixture and stirred at 20° C. for an additional 2 hours. The mixture was extracted with dichloromethane (100 ml), washed with brine (50 ml), dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to give tert-butyl 4-(3,3,3-trifluoro-2-hydroxypropyl)piperidine-1-carboxylate ( 2.0 g, 6.73 mmol, 80% yield) as a white solid.

[680] Step 5. tert-Butyl 4-[2-[2-(5-benzyloxypentoxy)ethoxy]-3,3,3-trifluoropropyl]piperidine-1-carboxylate

[681] In a solution of tert-butyl 4-(3,3,3-trifluoro-2-hydroxypropyl)piperidine-1-carboxylate (216 mg, 0.73 mmol, 1.0 eq.) in dimethylformamide (2 ml) sodium hydride (58 mg, 1.46 mmol, 60% in mineral oil, 2.0 eq.) was added at 15°C. The mixture was then stirred at 15°C for 0.5 hour under a nitrogen atmosphere. 2-(5-benzyloxypentoxy)ethyl-4-methylbenzenesulfonate (200 mg, 0.51 mmol, 0.7 eq.) was added to the mixture and stirred at 50° C. for an additional 2.5 hours. The mixture was quenched with water (5 ml), extracted with ethyl acetate (20 ml x 2), washed with brine (20 ml), dried over anhydrous sodium sulfate and then concentrated. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 200:1 to 10:1) to give tert-butyl-4-[2-[2-(5-benzyloxypentoxy)ethoxy]-3,3,3 -trifluoropropyl]piperidine-1-carboxylate (300 mg, 0.58 mmol, 80% yield) as a white oil.

[682]

[683] Convert tert-butyl 4-[2-[2-(5-benzyloxypentoxy)ethoxy]-3,3,3-trifluoropropyl]piperidine-1-carboxylate to the title compound, 2-(2,6- dioxopiperidin-3-yl)-5-(4-(3,3,3-trifluoro-2-(2-((5-((5-(5-methyl-5H-pyrido[4,3-b]indole -7-yl)pyridin-2-yl)oxy)pentyl)oxy)ethoxy)propyl)piperidin-1-yl)isoindolin-1,3-dione, according to the synthesis scheme below using the procedures described above and conventional procedures, known to those skilled in the art.

[684] Compound 89: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 11.09 (s, 1H), 9.36 (s, 1H), 8.61 (d, J=2.4 Hz , 1H), 8.50 (d, J=5.6 Hz, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.21 (s, 1H), 8.15 (dd , J=2.8, 8.8 Hz, 1H), 7.95 (s, 1H), 7.65-7.57 (m, 3H), 7.29 (s, 1H), 7.23- 7.18 (m, 1H), 6.90 (d, J=8.8 Hz, 1H), 5.04 (dd, J=5.6, 12.8 Hz, 1H), 4.31 (t , J=6.4 Hz, 2H), 4.14 (br s, 1H), 4.10-3.99 (m, 3H), 3.96 (s, 3H), 3.87 (d, J =11.6 Hz, 2H), 3.74 (dd, J=5.6, 10.8 Hz, 2H), 3.02-2.81 (m, 4H), 1.98-1.86 ( m, 2H), 1.85-1.72 (m, 4H), 1.63-1.15 (m, 9H). (M+H) ⁺ 841.6.

[685] Scheme for the synthesis of exemplary compound 90

[686] 2-(2,6-Dioxopiperidin-3-yl)-5-(4-(4-((4-((5-(5-methyl-5H-pyrido[4,3-b]indol- 7-yl)pyridin-2-yl)oxy)but-2-in-1-yl)oxy)butoxy)butoxy)isoindoline-1,3-dione

[687] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[688] Compound 90: ^1H NMR (400 MHz, _CDCl3 ): δ 9.35 (s, 1H), 8.60 (s, 1H), 8.50 (s, 1H), 8.20 (d , J=8.0 Hz, 2H), 7.75 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J=8.0 Hz, 1H ), 7.32 (d,J=10.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 1H), 6.92 (d,J=8.4 Hz, 1H), 5.10 (s, 2H), 4.98-5.00 (m, 1H), 4.21 (s, 2H), 4.07-4.10 (m, 2H), 3.90 (s, 3H), 3.44-3.54 (m, 7H), 2.76-2.87 (m, 3H), 2.18-2.23 (m, 2H), 1.88-1.92 ( m, 3H), 1.72-1.75 (m, 4H). (M+H) ⁺ 744.5.

[689] Scheme for the synthesis of exemplary compound 91

[690] 2-(2,6-Dioxopiperidin-3-yl)-5-(4-(8-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)octyl)piperazin-1-yl)isoindolin-1,3-dione

[691] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[692] Compound 91: 1H NMR (400 MHz, CD ₃ OD): δ 9.33 (s, 1H), 8.51-8.53 (m, 2H), 8.33-8.34 (m, 1H), 8.09-8.11 (m, 1H), 7.84 (s, 1H), 7.59-7.62 (m, 3H), 7.30 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 5.32-5.35 (m, 1H), 3.99 (s, 3H) , 3.40-3.47 (m, 13H), 2.69-2.71 (m, 6H), 2.50-2.52 (m, 4H), 2.03-2.18 (m, 5H), 1.59-1.60 (m, 6H). (M+H) ⁺ 798.6.

[693] Scheme for the synthesis of exemplary compound 92

[694] 5-((14-((3-Chloro-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6 ,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[695] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[696] Compound 92: ^1H NMR (400 MHz, _CDCl3 ): δ 9.32 (s, 1H), 8.68 (s, 1H), 8.58 (s, 1H), 8.35 (s , 1H), 8.18 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.52 (s , 1H), 7.45 (d, J=8.0 Hz, 1H), 7.27-7.34 (m, 2H), 7.20 (d, J=7.6 Hz, 1H), 4 .92-4.96 (m, 1H), 4.61 (s, 2H), 4.23 (s, 2H), 3.89-3.94 (m, 8H), 3.68-3.78 (m, 11H), 2.72-2.90 (m, 3H), 2.01-2.12 (m, 1H). (M+H) ⁺ 786.5, 788.5.

[697] Scheme for the synthesis of exemplary compound 93

[698] 5-((6-((5-(2,2-Difluoro-2-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2- yl)ethoxy)pentyl)oxy)hexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[699] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[700] Compound 93: ^1H NMR (400 MHz, _CDCl3 ): δ 9.35 (br, 1H), 8.94 (s, 1H), 8.59 (s, 1H), 8.21 (d , J=8.0 Hz, 1H), 8.01-8.09 (m, 2H), 7.73 (d, J=8.4 Hz, 1H), 7.69 (d, J=8, 0 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31 (d, J=5.2 Hz, 1H), 7.24 (s, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H), 4.85-4.90 (m, 1H), 4.10 (t, J=8.0 Hz, 1H), 3.98 (t, J=6.4 Hz, 1H), 3.87 (s, 3H), 3.51 (t, J=6.4 Hz, 1H), 3.27- 3.32 (m, 4H), 2.65-2.85 (m, 3H), 2.04-2.08 (m, 1H), 1.71-1.76 (m, 4H), 1. 45-1.52 (m, 8H), 0.75-0.85 (m, 4H). (M+H) ⁺ 782.5.

[701] Synthesis scheme for exemplary compound 96

[702] 2-(2,6-Dioxopiperidin-3-yl)-5-(4-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)-3-(trifluoromethyl)piperazin-1-yl)isoindolin-1,3-dione

[703] Prepared in accordance with the synthesis schemes below using the procedures described above and conventional procedures known to those skilled in the art.

[704] Compound 96: ^1H NMR: 400 MHz, DMSO-d6 δ: 11.09 (s, 1H), 9.38 (s, 1H), 8.64 (d, J=2.4 Hz, 1H ), 8.51 (d, J=5.6 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.19 (dd, J=2.4, 8.8 Hz , 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.72-7.59 (m, 3H), 7.21 (d, J=2.0 Hz, 1H) , 7.12 (dd,J=2.0, 8.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 5.38-5.26 (m, 1H), 5.06 (dd, J=5.3, 12.9 Hz, 1H), 4.24-4.13 (m, 1H), 3.96 (s, 3H), 3.95-3.88 ( m, 1H), 3.72 (d, J=15.2 Hz, 1H), 3.68-3.63 (m, 1H), 3.53 (d, J=7.2 Hz, 1H), 3.31 (s, 2H), 3.07-2.75 (m, 4H), 2.74-2.54 (m, 4H), 2.44-2.29 (m, 4H), 2. 06-1.94 (m, 1H), 1.50 (td, J=7.0, 13.8 Hz, 4H), 1.33 (s, 4H). (M+H) ⁺ 838.6.

[705] Synthesis scheme for exemplary compound 99

[706] 2-(2,6-Dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)isoindoline-1,3-dione

[707] Step 1: 2-(3-Bromopropoxy)tetrahydro-2H-pyran

[708] Stir a mixture of 3-bromopropan-1-ol (5.56 g, 40 mmol), dihydropyran (4.0 g, 48 mmol) and p-toluenesulfonic acid (0.76 g, 4 mmol) in tetrahydropyrane (80 ml) at room temperature overnight. The reaction mixture was quenched with aqueous sodium bicarbonate (saturated, 10 ml) and extracted with t-butyl methyl ether (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 10% ethyl acetate in hexanes) to give 2-(3 -bromopropoxy)tetrahydro-2H-pyran (6.4 g, 72% yield) as a colorless oil.

[709] Step 2: 3-(3-((Tetrahydro-2H-pyran-2-yl)oxy)propoxy)propan-1-ol

[710] To a solution of propane-1,3-diol (4.6 g, 60 mmol) in N,N-dimethylformamide (50 ml) was added sodium hydride (60% in mineral oil) (0.88 g, 222 mmol) at 0°C and the resulting mixture was stirred at 0°C for 30 minutes. 2-(3-bromopropoxy)tetrahydro-2H-pyran (2.2 g, 20 mmol) was added to the reaction mixture, and the resulting reaction mixture was stirred at 65° C. for 16 hours. The reaction mixture was quenched with water (150 ml) at 0°C and extracted with ethyl acetate (200 ml x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel flash chromatography (eluting with 30% ethyl acetate in hexane) to give 3- (3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)propan-1-ol (0.9 g, 45%o yield) as a colorless oil.

[711] Step 3: 3-(3-((Tetrahydro-2H-pyran-2-yl)oxy)propoxy)propyl-4-methylbenzenesulfonate

[712] Into a stirred solution of 3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)propan-1-ol (900 mg, 4.1 mmol), triethylamine (1.1 mL, 8 .25 mmol) in dichloromethane (30 ml) was added tosyl chloride (0.94 g, 4.95 mmol) and 4-dimethylaminopyridine (50 mg, 0.4 mmol) at 0°C. The resulting solution was allowed to warm to room temperature and stirred at room temperature for 2 hours. The mixture was poured into water (20 ml) and extracted with dichloromethane (20 ml x 2). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography on silica gel (eluting with 10 to 20% ethyl acetate in hexanes) to give 3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)propyl-4-methylbenzenesulfonate (1.2 g, 78% yield) as a colorless oil.

[713] Step 4: 2-(3-(3-((1r,3r)-3-(Benzyloxy)cyclobutoxy)propoxy)propoxy)tetrahydro-2H-pyran

[714] To a solution of (1r,3r)-3-(benzyloxy)cyclobutanol (200 mg, 1.12 mmol) in N,N-dimethylformamide (6 ml) was added sodium hydride (60% in mineral oil) (63 mg, 1.57 mmol) at 0°C and the resulting mixture was stirred at room temperature for 30 minutes. 3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)propyl-4-methylbenzenesulfonate (501 mg, 1.34 mmol) was added and the resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (30 ml) at 0°C and extracted with ethyl acetate (60 ml x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (eluting with 30% ethyl acetate in hexane) to give 2-(3- (3-((1r,3r)-3-(benzyloxy)cyclobutoxy)propoxy)propoxy)tetrahydro-2H-pyran (234 g, 47% yield) as a colorless oil.

[715] Step 5. (1r,3r)-3-(3-(3-Hydroxypropoxy)propoxy)cyclobutanol

[716] Stir a mixture of 2-(3-(3-((1r,3r)-3-(benzyloxy)cyclobutoxy)propoxy)propoxy)tetrahydro-2H-pyran (468 g, 1.23 mmol), palladium on carbon ( 10%, 60 mg) in methanol (30 ml) at room temperature overnight under a hydrogen atmosphere (hydrogen balloon). Palladium on carbon was removed by filtration and washed with methanol (5 ml x 2). The combined filtrates were concentrated under reduced pressure to give (1r,3r)-3-(3-(3-hydroxypropoxy)propoxy)cyclobutanol (240 mg, yield: 95%) as a colorless oil.

[717] Step 6. 3-(3-((1r,3r)-3-((5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)propoxy)propan-1-ol

[718] Sodium hydride (60% in mineral oil) (28 mg, 0.69 mmol) at 0°C and the resulting mixture was stirred at room temperature for 30 minutes. 7-(6-fluoropyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole (96 mg, 0.35 mmol) was added and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (30 ml) at 0°C and extracted with ethyl acetate (60 ml x 2). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (eluting with 5% methanol in dichloromethane) to give 3-(3- ((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propan-1- ol (75 mg, 34% yield) as a white solid.

[719] Step 7. 3-(3-((1r,3r)-3-((5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)propoxy)propanal

[720] Into a stirred solution of 3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)propoxy)propan-1-ol (70 mg, 0.15 mmol) in dichloromethane (5 ml) was added Dess-Martin periodinane (129 mg, 0.3 mmol) at 0°C. The resulting reaction mixture was allowed to warm to room temperature and stirred at this temperature for an additional 30 minutes. The reaction mixture was quenched with aqueous sodium bicarbonate (10 ml) and extracted with dichloromethane (20 ml x 2), washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 3-(3-((1r ,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propanal (80 mg, crude) as a white solid, which was used in the next step without further purification.

[721] Step 8. 2-(2,6-Dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl- 5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)isoindoline-1,3-dione

[722] Stir a mixture of 5-(azetidin-3-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride (70 mg, 0.17 mmol) [prepared as shown in the diagram below, using the procedures described above and conventional procedures known to those skilled in the art], N-ethyl-N-isopropylpropan-2-amine (44 mg, 0.35 mmol), acetic acid (1 drop) and 3 -(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy) propanal (80 mg, 0.17 mmol) in methanol (5 ml) at room temperature for 30 min. followed by the addition of sodium cyanoborohydride (22 mg, 0.35 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with aqueous sodium bicarbonate (sat., 10 ml) and extracted with ethyl acetate (20 ml), washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue, which was purified using preparative TLC (eluting with 10% methanol in dichloromethane) to give 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5 -(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)isoindoline-1,3- dione (20 mg, yield: 15%) as a white solid.

[723] Compound 99: 1H NMR (400 Hz, DMSO-d6): δ 1.40-1.56 (m, 2H), 1.62-1.75 (m, 2H), 1.83-2, 09 (m, 2H), 2.34-2.50 (m, 3H), 2.58-2.73 (m, 2H), 2.83- 2.93 (m, 1H), 3.01- 3.13 (m, 2H), 3.37-3.52 (m, 8H), 3.77 (s, 2H), 3.95 (s, 3H), 4.18 (s, 1H), 5 .02-5.13 (m, 2H), 5.29-5.37 (m, 1H), 6.94 (d, J=8.0 Hz, 1H), 7.21-7.29 (m , 2H), 7.59-7.65 (m, 2H), 7.80 (d, J=7.2 Hz, 1H), 7.97 (s, 1H), 8.18 (d, J= 7.6 Hz, 1H), 8.31 (d, J=7.6 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.63 (s, 1H), 9 .35 (s, 1H), 11.11 (s, 1H). (M+H) ⁺ 773.5.

[724] Scheme for the synthesis of exemplary compound 100

[725] 2-(2,6-Dioxopiperidin-3-yl)-5-(6-(4-(4-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)butoxy)butoxy)-2-azaspiro[3.3]heptan-2-yl)isoindoline-1,3-dione

[726] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[727] Compound 100: ^1H NMR (400 MHz, CDCl ₃ ): δ 1.65-1.67 (m, 6H), 1.74-1.81 (m, 2H), 1.87-1, 94 (m, 2H), 2.00-2.06 (m, 1H), 2.09-2.14 (m, 1H), 2.18- 2.24 (m, 2H), 2.54- 2.59 (m, 2H), 2.68-2.90 (m, 3H), 3.37-3.53 (m, 5H), 3.91 (t, J=7.6 Hz, 3H) , 3.98 (d, J=8.0 Hz, 3H), 4.39 (t,J=6.4 Hz, 2H), 4.90-4.94 (m, 1H), 6.45 ( d,J=1.6 Hz, 1H), 6.72 (d,J=1.6 Hz, 1H), 6.85 (d,J=8.4 Hz, 1H), 7.35 (d, J=6 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7 .91 (d,J=2.4 Hz, 1H), 8.05 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.49 (d, J=2, 4 Hz, 1H), 8.60 (d, J=5.6 Hz, 1H), 9.34 (s, 1H). (M+H) ⁺ 771.6.

[728] Scheme for the synthesis of exemplary compound 101

[729] 5-((1-(3-(3-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl )pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[730] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[731] Compound 101: 1H NMR (400 Hz, D6-DMSO): δ 1.56-1.59 (m, 2H), 1.71-1.77 (m, 2H), 1.95-2, 05 (m, 2H), 2.34-2.46 (m, 3H), 2.50-2.67 (m, 3H), 2.83- 2.93 (m, 1H), 3.32- 3.49 (m, 9H), 3.88-3.92 (m, 1H), 4.17-4.20 (m, 1H), 4.55 (t, J=5.6 Hz, 1H) , 5.05-5.13 (m, 2H), 5.46-5.49 (m, 1H), 7.25-7.28 (m, 2H), 7.52 (d, J=5, 6 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.39 (s, 1H), 8.45 (d, J=6.0 Hz, 1H), 8.83 (s, 1H), 9.39 (s, 1H), 11.11 (s, 1H), 11.86 (s, 1H). (M+H) ⁺ 827.5.

[732] Using similar procedures, the following compound was prepared: Compound 105.

[733] Scheme for the synthesis of exemplary compound 103

[734] 5-((14-((5-(8,9-Difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9 ,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[735] Step 1. 5-Bromo-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine

[736] To a solution of the compound 5-bromo-2-fluoropyridine (2.0 g, 9.5 mmol) in DMF (20 ml) was added 1-phenyl-2,5,8,11,14-pentaoxahexadecane -16-ol (2.6 g, 7.91 mmol) and NaH (950 mg, 24 mmol, 60%) at 0°C. The resulting mixture was stirred at 20°C for 18 hours. TLC (PE:EA = 1:1, Rf = 0.5) showed that 5-bromo-2-fluoropyridine was consumed. The mixture was diluted with EA (30 ml), washed with water (3 * 30 ml) and saline (30 ml). The organic layer was dried and concentrated to give the crude product, which was purified by silica gel column chromatography using PE:EA (1:1) to give the desired product (3.6 g) as a colorless oil.

[737] Step 2. 2-((1-Phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)pyridine

[738] In a solution of 5-bromo-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine (3.6 g, 7.22 mmol) in dioxane ( 50 ml) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.7 g, 14.45 mmol), Pd(dppf)Cl ₂ (530 mg) and AcOK (1.42 g, 14.45 mmol). The resulting solution was stirred at 90°C for 18 hours. The mixture was filtered and concentrated. The crude material was purified by silica gel column chromatography using PE:EA (1:1) to give the desired product (3.0 g, yield = 78%) as a yellow oil.

[739] Step 3: 5-(4-Bromo-2,3-difluorophenyl)-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine

[740] Into a solution of 2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)pyridine (2.8 g, 5.27 mmol) in a mixture of dioxane/H ₂ O (55 ml, 10/1, v/v) was added 1,4-dibromo-2,3 -difluorobenzene (1.72 g, 6.32 mmol), CsF (1.6 g, 10.54 mmol) and Pd(PPh ₃ ) (300 mg). The resulting solution was stirred at 90°C for 18 hours under N ₂ atmosphere. After completion of the reaction, the mixture was quenched with EA and extracted with EA. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by silica gel column chromatography using PE:EA (1:1) to give the desired product (1.5 g, yield = 48%) as a brown oil.

[741] Step 4: 5-(2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((1-phenyl -2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine

[742] In a solution of 5-(4-bromo-2,3-difluorophenyl)-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine (1.0 g, 1.68 mmol) in dioxane (20 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane ) (640 mg, 2.52 mmol), Pd(dppf)Cl ₂ (120 mg) and AcOK (330 mg, 3.36 mmol). The resulting solution was stirred at 90°C for 18 hours. LCMS showed that 5-(4-bromo-2,3-difluorophenyl)-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine was completely consumed . The mixture was filtered and concentrated. The crude material was purified by silica gel column chromatography using PE:EA (3:2) to give the desired product (660 mg, yield = 95%) as a brown oil.

[743] Step 5: 5-(2,3-Difluoro-4-(4-nitropyridin-3-yl)phenyl)-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecane-16 -yl)oxy)pyridine

[744] Into a solution of 5-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((1-phenyl- 2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine (350 mg, 0.544 mmol) in a mixture of dioxane/H ₂ O (11 ml, 10/1, v/v) was added 3- bromo-4-nitropyridine (121 mg, 0.6 mmol), Na ₂ CO ₃ (120 mg, 1.1 mmol) and Pd(PPh ₃ ) ₄ (63 mg). The mixture was stirred at 110°C for 1 hour under N ₂ atmosphere. After completion of the reaction, the mixture was extracted with ethyl acetate (20 ml) and washed with brine (30 ml). The organic solution was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography using PE/EA (1:3) to give the desired product (170 mg) as a yellow oil.

[745] Step 6. 8,9-Difluoro-7-(6-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridin-3-yl)-5H- pyrido[4,3-b]indole

[746] A solution of 5-(2,3-difluoro-4-(4-nitropyridin-3-yl)phenyl)-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecane-16-) was stirred yl)oxy)pyridine (340 mg, 0.53 mmol) in P(Oet) ₃ (3 ml) at 110°C for 3 hours. After completion of the reaction, the mixture was purified by silica gel column chromatography using DCM/MeOH ( 30:1) to obtain the desired product (205 mg) as a brown solid.

[747] Converted 8,9-difluoro-7-(6-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridin-3-yl)-5H-pyrido[ 4,3-b]indole

[748] to the final compounds, 5-((14-((5-(8,9-difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3 ,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 103) and 5-((14-((5-(8, 9-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2 ,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (compound 112), according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[749] Compound 103: ^1H NMR (400 MHz, CD ₃ OD): δ 9.46 (s, 1H), 8.63 (d, J=6.8 Hz, 1H), 8.38 (s, 1H), 8.00 (d, J=6.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H) , 7.61 (d, J=4.8 Hz, 1H), 7.29 (s, 1H), 7.23 (d, J=8.4 Hz, 1H), 6.93 (d, J= 8.8 Hz, 1H), 5.05 (m, 1H), 4.54-4.45 (m, 2H), 4.26-4.19 (m, 2H), 3.86 (m, 4H ), 370-3.65 (m, 12H), 2.86-2.62 (m, 3H), 2.10-2.04 (m, 1H). (M+H) ⁺ 774.5.

[750] Compound 112: ^1H NMR (400 MHz, _CDCl3 ): δ: 11.09 (s, 1H), 9.25 (s, 1H), 8.50 (s, 1H), 8.59 ( s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.69-7.73 (m, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.02 (d, J=8 ,4 Hz, 1H), 5.08-5.13 (m, 1H), 4.46 (d, J=4.4 Hz, 2H), 4.30-4.34 (m, 2H), 3 .95 (s, 3H), 3.79 (s, 4H), 3.60 (s, 4H), 3.56 (s, 4H), 3.53 (s, 4H), 2.85-2, 88 (m, 1H), 2.61 (s, 2H). (M+H) ⁺ 788.5.

[751] Scheme for the synthesis of exemplary compound 104

[752] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)isoindolin-1,3-dione

[753] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[754] Compound 104: ^1H NMR (400 MHz, DMSO- _d6 ): δ 1.73-1.79 (m, 4H), 1.97-1.99 (m, 2H), 2.31- 2.37 (m, 2H), 2.40-2.49 (m, 2H), 2.54-2.59 (m, 1H), 2.83-2.88 (m, 1H), 3, 38 (t, J=6.4 Hz, 2H), 3.43-3.49 (m, 6H), 3.82-3.85 (m, 2H), 3.75 (s, 3H), 4 .16-4.18 (m, 1H), 4.20-4.26 (m, 2H), 4.43-4.47 (m, 1H), 5.02-5.07 (m, 1H) , 5.31-5.34 (m, 1H), 6.62-6.64 (m, 1H), 6.78-6.79 (m, 1H), 6.93 (t, J=8, 4 Hz, 1H), 7.59-6.72 (m, 3H), 7.96 (s, 1H), 8.17-8.19 (m, 1H), 8.30 (d, J=8 .0 Hz, 1H), 8.49 (d, J=6.4 Hz, 1H), 8.62-8.63 (m, 1H), 9.35 (s, 1H), 11.06 (s , 1H). (M+H) ⁺ 773.5.

[755] Using procedures similar to those described above, the following compounds were prepared: 125 (also using the procedures described for compound 67), 148 (also using the procedures described for compound 67), compound 170.

[756] Scheme for the synthesis of exemplary compound 106

[757] Prepared according to the synthesis schemes below using the procedures described above and conventional procedures known to those skilled in the art.

[758] Compound 106: ^1H NMR (400 MHz, DMSO-d6): δ 1.54-1.68 (m, 10H), 1.84-1.88 (m, 2H), 2.12-2 .14 (m, 1H), 2.77-2.93 (m, 5H), 3.40-3.45 (m, 4H), 3.64-3.75 (m, 4H), 3.91 (s, 3H), 4.09 (t, J=6.4 Hz, 2H), 4.39-4.46 (m, 1H), 4.89-4.99 (m, 1H), 5, 41-5.50 (m, 1H), 6.90 (d, J=8.4 Hz, 1H), 7.14-7.2 (m, 1H), 7.32-7.35 (m, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.92-8, 00 (m, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.59 (d, J=5.6 Hz, 1H), 9.33 (s, 1H). (M+H) ⁺ 759.6.

[759] Scheme for the synthesis of exemplary compound 107

[760] 2-(2,6-Dioxopiperidin-3-yl)-5-(4-(4-(6-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)butoxy)butoxy)isoindoline-1,3-dione

[761] Prepared according to the synthesis schemes below using the procedures described above and conventional procedures known to those skilled in the art.

[762] Compound 107: 1H NMR (400 MHz, CDCl ₃ ): δ 1.61-1.65 (m, 2H), 1.72-1.77 (m, 4H), 1.90-1.93 (m, 2H), 1.99-2.04 (m, 1H), 2.14-2.22 (m, 3H), 2.44-2.49 (m, 2H), 2.78-3 .01 (m, 6H), 3.44-3.49 (m, 4H), 3.92 (s, 3H), 3.99-4.05 (m, 2H), 4.14 (t, J =6.2 Hz, 2H), 4.94-4.98 (m, 1H), 5.17-5.20 (m, 1H), 6.81 (d, J=8.4 Hz, 1H) , 7.19-7.21 (m, 1H), 7.33-7.37 (m, 2H), 7.49 (d, J=8.4 Hz, 1H), 7.56 (s, 1H ), 7.78 (d, J=8.4 Hz, 1H), 7.90-7.93 (m, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.35 (br, 1H), 8.45 8.46 (m, 1H), 8.59 (d, J=5.6 Hz, 1H), 9.34 (s, 1H). (M+H) ⁺ 771.6.

[763] Scheme for the synthesis of exemplary compound 108

[764] 2-(2,6-Dioxopiperidin-3-yl)-5-((6-((6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4 ,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)oxy)hexyl)oxy)isoindoline-1,3-dione

[765] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[766] Compound 108: ^1H NMR (400 MHz, DMSO-d6): δ 1.43-1.44 (m, 4H), 1.70-1.74 (m, 4H), 1.98-2 .04 (m, 1H), 2.44-2.47 (m, 1H), 2.56-2.60 (m, 1H), 2.65 (t, J=6.0 Hz, 4H), 2.83-2.92 (m, 1H), 3.95 (s, 3H), 4.10 (t, J=6.0 Hz, 2H), 4.22 (t, J=6.4 Hz , 2H), 5.07-5.11 (m, 1H), 5.30-5.35 (m, 1H), 5.39-5.45 (m, 1H), 6.34-6.37 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 7.24-7.26 (m, 1H), 7.33 (d, J=2.0 Hz, 1H) , 7.59-7.65 (m, 3H), 7.72 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 8.17-8.21 (m, 1H ), 8.31 (d, J=8.0 Hz, 1H), 8.50 (d, J=6.0 Hz, 1H), 8.65 (d, J=2.0 Hz, 1H), 9.36 (s, 1H), 11.10 (s, 1H). (M+H) ⁺ 795.5.

[767] Scheme for the synthesis of exemplary compound 109

[768] 2-(2,6-Dioxopiperidin-3-yl)-5-((6-((4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4 ,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)oxy)hexyl)oxy)isoindoline-1,3-dione

[769] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[770] Compound 109: ^1H NMR (400 MHz, DMSO-d6): δ 1.47 (s, 4H), 1.72-1.78 (m, 4H), 2.02-2.05 (m , 2H), 2.33 (s, 1H), 2.63-2.66 (m, 4H), 2.88-2.89 (m, 1H), 3.41-3.49 (m, 2H ), 3.96 (s, 2H), 4.18-4.23 (m, 3H), 5.04-5.12 (m, 2H), 5.42 (br, 1H), 6.19 ( s, 1H), 6.55-6.56 (m, 1H), 6.98 (d, J=8.4 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.41 (s, 1H), 6.63 (s, 2H), 7.81-7.83 (m, 1H), 7.95-7.97 (m, 2H), 8.21 (d, J=8.4 Hz, 1H), 8.32 (d, J=7.2 Hz, 1H), 8.50 (d, J=4.0 Hz, 1H), 8.64 (s, 1H) , 9.36 (s, 1H), 11.11 (s, 1H). (M+H) ⁺ 795.5.

[771] Scheme for the synthesis of exemplary compound 111

[772] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)azetidin-1-yl)isoindolin-1 ,3-dione

[773] Step 1. tert-Butyl-3-(prop-2-yn-1-yloxy)azetidine-1-carboxylate

[774] To a stirred solution of tert-butyl-3-hydroxyazetidine-1-carboxylate (1.0 g, 12.2 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in mineral oil) (255 mg, 6.36 mmol) at 0°C and the resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred for an additional 30 minutes, then 3-bromoprop-1-yne (818 mg, 6.94 mmol) was added and the resulting reaction mixture was stirred at 50°C overnight. Completion of the reaction was indicated by LCMS. The reaction mixture was quenched with water (10 ml) at 0°C and extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel flash chromatography (eluting with 10% ethyl acetate in hexane) to give tert-butyl -3-(prop-2-yn-1-yloxy)azetidine-1-carboxylate (1.03 g, 84% yield) as a colorless oil.

[775] Step 2. tert-Butyl-3-((3-(5-hydroxypyridin-2-yl)prop-2-yn-1-yl)oxy)azetidine-1-carboxylate

[776] Into a stirred solution of tert-butyl-3-(prop-2-yn-1-yloxy)azetidine-1-carboxylate (900 mg, 4.27 mmol) and 6-bromopyridin-3-ol (734 mg, 4 .27 mmol) in acetonitrile (10 ml) was added triethylamine (863 mg, 8.54 mmol) followed by the addition of bis(triphenylphosphine) palladium(II) chloride (150 mg, 0.214 mmol) and cuprous iodide (41 mg, 0.214 mmol ) at room temperature in a nitrogen atmosphere; the mixture was degassed three times with nitrogen. The reaction mixture was heated to 65°C and stirred overnight. TLC indicated completion of the reaction. The mixture was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography on silica gel (eluting with 100% ethyl acetate in hexanes) to give tert-butyl- 3-((3-(5-hydroxypyridin-2-yl)prop-2-yn-1-yl)oxy)azetidine-1-carboxylate (550 mg, 42% yield) as a brown oil.

[777] Step 3. tert-Butyl-3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7 -yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)azetidine-1-carboxylate

[778] Stir a solution of tert-butyl 3-((3-(5-hydroxypyridin-2-yl)prop-2-yn-1-yl)oxy)azetidine-1-carboxylate (100 mg, 0.325 mmol), ( 1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutylmethanesulfonate (137 mg, 0.325 mmol) and carbonate cesium (211 mg, 0.65 mmol) in dry N,N-dimethylformamide (2 ml) at 70°C for 36 hours. TLC indicated completion of the reaction. The mixture was partitioned between ethyl acetate (50 ml) and water (25 ml). The organic layer was collected, washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography (eluting with 3% methanol in dichloromethane) to give tert. butyl-3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl )oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidine-1-carboxylate (60 mg, 29% yield) as a white solid.

[779] Converted tert-butyl-3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-carboxylate to the final compound, 2-(2,6-dioxopiperidin-3-yl) )-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin- 2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione, according to the synthesis scheme below using those described above procedures and routine procedures known to those skilled in the art.

[780] Compound 111: ^1H NMR (400 MHz, DMSO-d6): δ 1.98-2.02 (m, 1H), 2.54-2.73 (m, 6H), 2.83-2 .92 (m, 1H), 3.95-3.97 (m, 5H), 4.31-4.34 (m, 2H), 4.50 (s, 2H), 4.67-4.72 (m, 1H), 5.04-5.13 (m, 2H), 5.42-5.48 (m, 1H), 6.67-6.69 (m, 1H), 6.82 (s , 1H), 6.69-7.01 (m, 1H), 7.33-7.36 (m, 1H), 7.53-7.55 (m, 1H), 7.63-7.67 (m, 3H), 8.01 (s, 1H), 8.21-8.26 (m, 2H), 8.33-8.37 (m, 1H), 8.51-8.55 (m , 1H), 8.65-8.66 (m, 1H), 9.39 (s, 1H), 11.07 (s, 1H). (M+H) ⁺ 788.5.

[781] The following illustrative compounds were prepared using similar procedures: 194.

[782] Scheme for the synthesis of exemplary compound 114

[783] 2-(2,6-Dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)pentyl)oxy)isoindoline-1,3-dione

[784] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[785] Compound 114: ^1H NMR (400 MHz, CDCl ₃ ): δ 1.52-1.59 (m, 2H), 1.63-1.67 (m, 5H), 1.83-1, 90 (m, 1H), 2.11-2.16 (m, 2H), 2.43-2.54 (m, 4H), 2.71-2.92 (m, 4H), 3.39- 3.49 (m, 6H), 3.95 (s, 3H), 4.08 (t, J=6.4 Hz, 2H), 4.23-4.29 (m, 1H), 4.94 (dd, J=5.2, 12.0 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 7.17 (dd, J=2.0, 8.0 Hz, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.44 (d, J=6.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H) , 7.60 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.91 (dd, J=2.4, 8.8 Hz, 1H), 8.14 ( m, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.58 (d, J=5.2 Hz, 1H), 9.34 (s, 1H). (M+H) ⁺ 760.5.

[786] Using procedures similar to those for compound 140, the following compound was prepared: compound 115.

[787] Scheme for the synthesis of exemplary compound 116

[788] 2-(2,6-Dioxopiperidin-3-yl)-5-((2-(4-(4-((5-(5-methyl-5H-pyrido[4,3-b]indol- 7-yl)pyridin-2-yl)oxy)butoxy)butyl)-2-azaspiro[3.3]heptan-6-yl)oxy)isoindoline-1,3-dione

[789] Prepared in accordance with the synthesis schemes below using the procedures described above and conventional procedures known to those skilled in the art.

[790] Compound 116: 1H NMR (400 MHz, CDCl ₃ ): δ 1.39 1.42 (m, 2H), 1.47-1.52 (m, 2H), 1.64-1.70 ( m, 2H), 1.77-1.82 (m, 2H), 2.01-2.07 (m, 1H), 2.21-2.26 (m, 2H), 2.54-2, 64 (m, 3H), 2.75-2.90 (m, 5H), 3.42-3.45 (m, 3H), 3.61-3.71 (m, 4H), 3.95 ( s, 3H), 4.35 (t, J=6.2 Hz, 2H), 4.78-4.82 (m, 1H), 5.09-5.13 (m, 1H), 6.94 (d, J=8.4 Hz, 1H), 7.20-7.25 (m, 2H), 7.60-7.63 (m, 2H), 7.79 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 8.18-8.20 (m, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.48 (d, J =5.2 Hz, 1H), 8.65 (s, 1H), 9.34 (s, 1H), 11.11 (s, 1H). (M+H) ⁺ 771.6.

[791] Scheme for the synthesis of compound 118

[792] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)azetidin-1 -yl)isoindoline-1,3-dione

[793] Prepared according to the synthesis schemes below using the procedures described above and conventional procedures known to those skilled in the art.

[794] Compound 118: ^1H NMR (400 MHz, DMSO-d6): δ 1.98-2.03 (m, 1H), 2.09-2.15 (m, 1H), 2.20-2 .24 (m, 1H), 2.70-2.87 (m, 5H), 4.01-4.04 (m, 4H), 4.29-4.34 (m, 1H), 4.46 (s, 2H), 4.75-4.79 (m, 1H), 4.89-4.95 (m, 1H), 5.00-5.06 (m, 1H), 5.33-5 .40 (m, 2H), 5.65-5.70 (m, 1H), 6.53-6.55 (m, 1H), 6.79 (s, 1H), 7.08-7.11 (m, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.56-7.65 (m, 4H), 7.95 (s, 1H), 8.19-8, 30 (m, 3H), 8.60-8.64 (m, 2H), 9.38 (s, 1H). (M+H) ⁺ 856.5.

[795] Scheme for the synthesis of exemplary compound 121

[796] (2S,4R)-1-((S)-20-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2- (tert-butyl)-4-oxo-6,9,12,15,18-pentaoxa-3-azaeicosanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[797] Step 1: 14-((5-Bromopyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol

[798] To a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (20 g, 83.93 mmol) in N,N-dimethylformamide (100 ml) was added sodium hydride (60% in mineral oil) ( 1.36 g, 34.09 mmol) at 0°C and the resulting mixture was stirred at 0°C for 30 minutes. Then 5-bromo-2-fluoropyridine (5 g, 28.41 mmol) was added and the resulting reaction mixture was stirred at 50°C for 2 hours. TLC indicated completion of the reaction. The reaction mixture was quenched with water (150 ml) at 0°C and extracted with ethyl acetate (150 ml x 2). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 2% methanol in dichloromethane) to give 14- ((5-bromopyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol (8 g, 72% yield) as a colorless oil.

[799] Step 2. tert-Butyl-17-((5-bromopyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecane-1-oate

[800] Into a stirred solution of 14-((5-bromopyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol (2.00 g, 5.07 mmol) and tetrabutylammonium chloride (1 .41 g, 5.07 mmol) in dichloromethane (20 ml) and sodium hydroxide (20 ml, 35% in water) was added tert-butyl-2-bromoacetate (2.97 g, 15.22 mmol) at 0°C . The reaction mixture was then allowed to warm to room temperature and stirred at room temperature overnight. The organic layer was collected, the aqueous layer was extracted with dichloromethane (20 ml). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography (eluting with 50% ethyl acetate in hexane) to give tert-butyl -17-((5-bromopyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecane-1-oate (1.64 g, 64% yield) as a colorless oil.

[801] Step 3. tert-Butyl-17-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12, 15-pentaoxaheptadecane-1-oate

[802] In a stirred solution of 7-bromo-5H-pyrido[4,3-b]indole (300 mg, 1.22 mmol), 4,4,4',4',5,5,5',5' 1,G- bis(diphenylphosphino)ferrocenepalladium(II) dichloride (176 mg, 0.24 mmol) at room temperature under nitrogen, the mixture was degassed with nitrogen three times. The resulting mixture was stirred at 90°C overnight. Completion of the reaction was indicated by LCMS. 14-((5-bromopyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol (930 mg, 1.83 mmol), aqueous sodium carbonate (2 N) was added to the reaction mixture. , 3.2 ml) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol); the mixture was degassed three times with nitrogen. The resulting mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 2% methanol in dichloromethane) to give tert-butyl- 17-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecane-1-oate (260 mg , yield 36%) as a gray oil.

[803] Step 4. 17-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecane- 1-oic acid

[804] Stir a mixture of tert-butyl-17-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15 -pentaoxaheptadecane-1-oate (130 mg, 0.22 mmol) and 2,2,2-trifluoroacetic acid (2 ml) in dichloromethane (1 ml) at room temperature for one hour. The volatiles were evaporated under reduced pressure to give 17-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15- pentaoxaheptadecano-1-oic acid (120 mg, crude) as a brown solid, which was directly used in the next step without further purification.

[805] Step 5. (2S,4R)-1-((S)-20-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) -2-(tert-butyl)-4-oxo-6,9,12,15,18-pentaoxa-3-azaeicosan-1-oil)-4-hydroxy-N-((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[806] Into a stirred solution of 17-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecane- 1-oic acid (120 mg, crude), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4 -(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (105 mg, 0.22 mmol) and N-ethyl-N-isopropylpropan-2-amine (142 mg, 1.10 mmol) in anhydrous N,N-dimethylformamide (3 ml) add HATU (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (167 mg, 0.44 mmol) at room temperature and stirred for 20 minutes. The mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was collected, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by preparative TLC (eluting with 10% methanol in dichloromethane) to give (2S,4R )-1-((S)-20-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-(tert-butyl)-4 -oxo-6,9,12,15,18-pentaoxa-3-azaeicosan-1-oil)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl )ethyl)pyrrolidine-2-carboxamide (28 mg, 13% yield) as a white solid.

[807] ^1H NMR (400 MHz, DMSO-d6): δ 0.93 (s, 9H), 1.36-1.47 (m, 3H), 1.73-1.80 (m, 1H) , 1.96-2.09 (m, 2H), 3.23-3.60 (m, 16H), 3.79 (t, J=3.6 Hz, 2H), 3.96 (s, 2H ), 4.28 (s, 1H), 4.42-4.46 (m, 3H), 4.54 (d, J=9.6 Hz, 1H), 4.90 (t, J=1, 6 Hz, 1H), 5.12 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 7.35-7.43 (m, 5H), 7.65-7, 69 (m, 2H), 7.87 (s, 1H), 8.12-8.15 (m, 1H), 8.37-8.43 (m, 2H), 8.51 (d, J= 5.6 Hz, 1H), 8.59 (d, J=1.6 Hz, 1H), 8.97 (s, 1H), 9.51 (s, 1H), 12.28 (s, 1H) . (M+H) ⁺ 966.7.

[808] Using similar procedures, the following compound was prepared: Compound 1, Compound 5, Compound 6, Compound 120, and Compound 122.

[809] Scheme for the synthesis of exemplary compound 119

[810] (2S,4R)-1-((S)-17-((5-(5H-Pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl )oxy)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[811] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[812] Compound 119: ^1H NMR (400 MHz, DMSO- _d6 ): δ 0.93 (s, 9H), 1.35 (t, J=6.8 Hz, 3H), 1.77 1, 78 (s, 1H), 2.02 2.04 (m, 1H), 2.44 (s, 3H), 3.53 3.64 (m, 14H), 3.80-3.85 (m, 2H), 3.95 (s, 2H), 4.28 (s, 1H), 4.44 (d, J=8.2 Hz, 1H), 4.54 (d, J=9.6 Hz, 1H), 4.58-4.63 (m, 2H), 4.90 (s, 1H), 5.12 (s, 1H), 7.26-7.50 (m, 5H), 7.54 (d, J=5.8 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.90 (s, 1H), 8.35 (d, J=8.0 Hz , 1H), 8.42-8.45 (m, 3H), 8.85 (s, 1H), 8.97 (s, 1H), 9.41 (s, 1H), 11.92 (s, 1H). (M+H) ⁺ 990.7.

[813] Scheme for the synthesis of exemplary compound 126

[814] 2-(2,6-Dioxopiperidin-3-yl)-5-((5-(6-(methyl-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)pentyl)oxy)isoindoline-1,3-dione

[815] Step 1. (1r,3r)-3-(Methylamino)cyclobutanol

[816] To a solution of tert-butyl-((1r,3r)-3-hydroxycyclobutyl)carbamate (2 g, 10.7 mmol) in tetrahydrofuran (30 ml) was added lithium aluminum hydride (1.6 g, 42.7 mmol) at 0°C. The mixture was stirred at 65°C for 2 hours. TLC indicated completion of the reaction. The mixture was quenched with water (1.6 ml), sodium hydroxide (1.6 ml, 15% in water) and water (4.8 ml) at 0°C. The mixture was stirred at room temperature for 15 minutes and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude (1r,3r)-3-(methylamino)cyclobutanol (1.3 g) as a colorless oil, which was used in the next step without further purification.

[817] Step 2. tert-Butyl-((1r,3r)-3-hydroxycyclobutyl)(methyl)carbamate

[818] To a solution of (1r,3r)-3-(methylamino)cyclobutanol (1.3 g, 12.8 mmol) and triethylamine (2.6 g, 25.7 mmol) in dichloromethane (10 ml), di- tert-butyl carbonate (4.2 g, 19.28 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours. TLC indicated completion of the reaction. The mixture was diluted with dichloromethane (10 ml) and washed with aqueous hydrochloric acid (1 N, 10 ml). The organic layer was collected, washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 33 to 50% ethyl acetate in hexanes) to give tert-butyl-((1r,3r)-3-hydroxycyclobutyl)(methyl)carbamate (1.2 g, 56% in two steps) as a colorless oil.

[819] Step 3. tert-Butylmethyl-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) hydroxy)cyclobutyl)carbamate

[820] In a solution of 7-(6-fluoropyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole (300 mg, 1.1 mmol) and tert-butyl-((1r, 3r)-3-hydroxycyclobutyl)(methyl)carbamate (218 mg, 1.1 mmol) in 1-methylpyrrolidin-2-one (3 ml) was added sodium hydride (60% in mineral oil) at 0°C. The mixture was allowed to cool to room temperature and stirred at room temperature for 30 minutes. Completion of the reaction was indicated by LC-MS. The mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was collected, washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 1 to 2% methanol in dichloromethane) to give tert-butylmethyl-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)carbamate ( 450 mg, 91%) as a light yellow oil.

[821] Step 4. Preparation of tert-butyl-6-(methyl-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl) pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

[822] Stir a mixture of tert-butylmethyl-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy )cyclobutyl)carbamate (450 mg, 0.98 mmol) and 2,2,2-trifluoroacetic acid (2 ml) in dichloromethane (2 ml) at room temperature for 1 hour. TLC indicated completion of the reaction. Volatiles were evaporated under reduced pressure. The residue was taken up in methanol (5 ml) followed by sequential addition of N-ethyl-N-isopropylpropan-2-amine (380 mg, 2.94 mmol), tert-butyl-6-oxo-2-azaspiro[3.3]heptane-2- carboxylate (207 mg, 0.98 mmol) and acetic acid (71 mg, 1.18 mmol) at 0°C. The resulting mixture was stirred at room temperature for 30 minutes and sodium cyanoborohydride (124 mg, 1.96 mmol) was added. The mixture was stirred at room temperature for 18 hours. TLC indicated completion of the reaction. The mixture was concentrated and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was collected, washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 2 to 5% methanol in dichloromethane) to give tert-butyl-6-(methyl-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy )cyclobutyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (240 mg, 44% in two steps) as a white solid.

[823] Step 5. N-Methyl-N-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2- yl)oxy)cyclobutyl)-2-azaspiro[3.3]heptan-6-amine

[824] A mixture of tert-butyl-6-(methyl-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin- 2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (100 mg, 0.18 mmol) and 2,2,2-trifluoroacetic acid (0.5 ml) in anhydrous dichloromethane ( 0.5 ml) at room temperature for 1 hour. TLC indicated completion of the reaction. The mixture was concentrated under reduced pressure to obtain crude N-methyl-N-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin- 2-yl)oxy)cyclobutyl)-2-azaspiro[3.3]heptan-6-amine (100 mg), which was used in the next step without further purification.

[825] Step 6. 2-(2,6-Dioxopiperidin-3-yl)-5-((5-(6-(methyl-((1r,3r)-3-((5-(5-methyl- 5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)pentyl)oxy)isoindoline-1,3 -dion

[826] K N-methyl-N-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) oxy)cyclobutyl)-2-azaspiro[3.3]heptan-6-amine (100 mg, crude) and N-ethyl-N-isopropylpropan-2-amine (70 mg, 0.54 mmol) in methanol (10 ml) were added 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentanal (65 mg, 0.18 mmol) and acetic acid (13 mg, 0.21 mmol) at 0°C. The mixture was stirred at room temperature for 30 minutes and then sodium cyanoborohydride (23 mg, 0.36 mmol) was added. The mixture was stirred at room temperature for 16 hours. TLC indicated completion of the reaction. The mixture was concentrated under reduced pressure to give a crude residue, which was purified by HPLC to give 2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl-((1r,3r)- 3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2- yl)pentyl)oxy)isoindoline-1,3-dione (57.3 mg, 40% in two steps) as a white solid.

[827] ¹ H NMR (400 MHz, DMSO-d6): δ 1.42-1.51 (m, 4H), 1.75-1.79 (m, 2H), 2.03-2.06 ( m, 1H), 2.54 (s, 3H), 2.58-2.68 (m, 5H), 2.81-2.94 (m, 2H), 3.11-3.17 (m, 2H), 3.61-3.71 (m, 3H), 3.98-4.11 (m, 6H), 4.15 (s, 3H), 4.17-4.23 (m, 3H) , 5.10-5.14 (m, 1H), 5.25-5.31 (m, 1H), 7.03 (d, J=8.4 Hz, 1H), 7.33-7.42 (m, 2H), 7.84-7.89 (m, 1H), 8.22-8.32 (m, 3H), 8.55 (d, J=8.0 Hz, 1H), 8, 71 (s, 1H), 8.78 (d, J=6.4 Hz, 1H), 9.78 (s, 1H), 10.05 (brs, 1H), 10.51 (brs, 1H), 11.11(s, 1H). (M+H) ⁺ 796.6.

[828] Scheme for the synthesis of exemplary compound 127

[829] 3-(5-(4-((1-(5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl )methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione

[830] Step 1. (1-(5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)methanol

[831] In a mixture of 7-(6-fluoropyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole (200 mg, 0.72 mmol) and piperidin-4-ylmethanol (108 mg , 0.93 mmol) in 1-methylpyrrolidin-2-one (5 ml) was added potassium carbonate (298 mg, 2.16 mmol) and the result was stirred at 100°C overnight under nitrogen atmosphere. The cooled reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was collected, washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 2 to 5% methanol in dichloromethane) to give (1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)methanol (205 mg, 76% yield) as light yellow solid.

[832] Step 2: 1-(5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-carbaldehyde

[833] To a solution of Dess-Martin periodinane (136 mg, 0.32 mmol) in dichloromethane (3 ml) was added (1-(5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)pyridin-2-yl)piperidin-4-yl)methanol (60 mg, 0.16 mmol) and stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction mixture was partitioned between dichloromethane (20 ml) and water (20 ml). The organic layer was collected, washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by preparative TLC (eluting with 3% methanol in dichloromethane) to give 1-(5-( 5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-carbaldehyde (58 mg, 97% yield) as a white solid.

[834] Step 3: tert-Butyl 4-(1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate

[835] In a solution of 5-bromo-3H-isobenzofuran-1-one (45 g, 211.24 mmol, 1.00 eq.) and tert-butylpiperazine-1-carboxylate (39.34 g, 211.24 mmol, 1.00 eq.) in dioxane (500 ml) was added tris(dibenzylideneacetone)dipalladium(0) (19.34 g, 21.12 mmol, 0.10 eq.), 4,5-bis(diphenylphosphino)-9, 9-dimethylxanthene (12.22 g, 21.12 mmol, 0.10 eq.) and potassium phosphate (89.68 g, 422.48 mmol, 2.00 eq.). The mixture was heated to 100°C for 16 hours under a protective nitrogen atmosphere. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was triturated in a mixture of ethyl acetate: petroleum ether (500 ml, v/v = 1:2). tert-Butyl 4-(1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (50 g, 122.5 mmol, 58% yield, 78% purity) was obtained as a yellow solid.

[836] Step 4: 4-(4-tert-Butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)benzoic acid

[837] A mixture of tert-butyl 4-(1-oxo-3H-isobenzofuran-5-yl)piperazin-1-carboxylate (47.8 g, 150.14 mmol, 1.00 eq.) in tetrahydrofuran (150 ml), methanol (150 ml) and water (150 ml), sodium hydroxide (24 g, 600 mmol, 4.00 eq.) was added. The mixture was stirred at 25°C for 1 hour. The solution was adjusted to pH=4-5 with aqueous hydrochloride solution (1 M) and extracted with ethyl acetate (100 ml x 5). The organic layers were concentrated in vacuo. The crude substance was triturated in a mixture of ethyl acetate: petroleum ether (450 ml, v:v = 1:2). 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)benzoic acid (40 g, 118.91 mmol, 79% yield) was obtained as a yellow solid.

[838] Step 5: tert-Butyl 4-[3-(hydroxymethyl)-4-methoxycarbonylphenyl]piperazine-1-carboxylate

[839] A solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)benzoic acid (20 g, 59.46 mmol, 1.00 eq.) in methanol (100 ml) and ethyl acetate ( 100 ml) TMS-diazomethane (2 M, 89 ml, 3.00 eq.) was added at -10°C. The solution was stirred at 10°C for 0.25 h. The solution was quenched with water (300 ml) and extracted with ethyl acetate (150 ml x 3). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated. tert-Butyl 4-[3-(hydroxymethyl)-4-methoxycarbonylphenyl]piperazine-1-carboxylate (20.84 g, crude) was obtained as a brown oil.

[840] Step 6: tert-Butyl 4-[3-(bromomethyl)-4-methoxycarbonylphenyl]piperazine-1-carboxylate

[841] A solution of tert-butyl 4-[3-(hydroxymethyl)-4-methoxycarbonylphenyl]piperazine-1-carboxylate (20.84 g, 59.47 mmol, 1.00 eq.) in tetrahydrofuran (200 ml) triphenylphosphine (23.4 g, 89.21 mmol, 1.50 eq) and tetrabromomethane (29.58 g, 89.21 mmol, 1.50 eq) were added. The solution was stirred at 25°C for 1 hour. The solution was quenched with water (200 ml) and extracted with ethyl acetate (100 ml x 2). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:50 to 1:8). tert-Butyl 4-[3-(bromomethyl)-4-methoxycarbonylphenyl]piperazine-1-carboxylate (12 g, 29.03 mmol, 49% yield) was obtained as a pale yellow oil.

[842] Step 7: tert-Butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxoisoindolin-5-yl]piperazine-1-carboxylate

[843] To a solution of tert-butyl 4-[3-(bromomethyl)-4-methoxycarbonylphenyl]piperazine-1-carboxylate (12 g, 29.03 mmol, 1.00 eq.) in acetonitrile (300 ml) was added 3 -Aminopiperidine-2,6-dione hydrochloride (7.17 g, 43.55 mmol, 1.50 eq.) and N-ethyl-N-isopropylpropan-2-amine (11.26 g, 87.09 mmol, 15 ml, 3.00 eq.). The solution was stirred at 80°C for 16 hours. Using LCMS it was shown that the reaction was almost complete. The reaction mixture was cooled to 20°C and filtered. The solid was washed with acetonitrile (30 ml). Tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxoisoindolin-5-yl]piperazine-1-carboxylate (6 g, 14 mmol, 48% yield) was obtained as a white solid. substances.

[844] Step 8: 3-(1-Oxo-5-piperazin-1-ylisoindolin-2-yl)piperidin-2,6-dione

[845] To a mixture of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxoisoindolin-5-yl]piperazine-1-carboxylate (6 g, 14 mmol, 1.00 eq. .) in dioxane (70 ml), a mixture of hydrochloride/dioxane (4 M, 100 ml, 28.57 eq.) was added. The mixture was stirred at 25°C for 2 hours. The mixture was poured into ethyl acetate (400 ml) and stirred for 30 minutes. The suspension was filtered and the solid was collected. 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidin-2,6-dione (5 g, 13.71 mmol, 98% yield, hydrochloride salt) was obtained as a white solid. .

[846] Step 9. 3-(5-(4-((1-(5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin- 4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione

[847] Stir a mixture of 1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-carbaldehyde (58 mg, 0.15 mmol ), N-ethyl-N-isopropylpropan-2-amine (32 mg, 0.23 mmol), 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidin-2,6 -dione (51 mg, 0.15 mmol) and acetic acid (0.5 ml) in methanol (4 ml) at room temperature for 30 minutes. This was followed by the addition of sodium cyanoborohydride (21 mg, 2.10 mmol) and stirring for 1 hour at room temperature. The mixture was partitioned between ethyl acetate (30 ml) and brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by preparative TLC (eluting with 10% methanol in dichloromethane) to give 3- (5-(4-((1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (57 mg, 53% yield) as a light yellow solid.

[848] ¹ H NMR (400 MHz, DMSO-d6): δ 1.11-1.23 (m, 4H), 1.82-1.99 (m, 4H), 2.30-2.39 ( m, 3H), 2.60 (br, 4H), 2.86-2.94 (m, 3H), 3.17 (s, 2H), 3.98 (s, 3H), 4.10 (br , 1H), 4.21 (d, J=16.8 Hz, 1H), 4.32-4.41 (m, 3H), 5.05 (dd, J=13.2 Hz, 1H), 6 .96 (d, J=9.2 Hz, 1H), 706-7.08 (m, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.62 (d, J= 8.0 Hz, 1H), 7.69 (d, J=6.0 Hz, 1H), 7.95 (s, 1H), 8.02 (dd, J=9.2 Hz, 1H), 8 .30 (dd, J=8.4 Hz, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.64 (s, 1H), 9.38 (s, 1H), 10 .95 (s, 1H). (M+H) ⁺ 683.5.

[849] Scheme for the synthesis of exemplary compound 128

[850] 3-(5-(4-(2-(1-(5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4 -yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione

[851] Prepared according to the synthesis scheme below using the procedures described for compound 127.

[852] Compound 128: ^1H NMR (400 MHz, DMSO-d6) δ 1.16-1.23 (m, 3H), 1.40-1.50 (m, 2H), 1.61 (br, 1H), 1.76-1.78 (m, 2H), 1.94-1.96 (m, 1H), 2.38-2.41 (s, 3H), 2.51-2.56 ( m, 4H), 2.82-2.90 (m, 3H), 3.29-3.33 (m, 4H), 3.95 (s, 3H), 4.18-4.22 (m, 1H), 4.30-4.39 (m, 3H), 5.02-5.08 (m, 1H), 6.95 (d, J=8.8 Hz, 1H), 7.05-7 .06 (m, 2H), 7.50-7.69 (m, 3H), 7.91 (s, 1H), 8.00 (dd, J=8.8, 2.2 Hz, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.48 (d, J=5.8 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H), 9, 33 (s, 1H), 10.95 (s, 1H). (M+H) ⁺ 697.6.

[853] Scheme for the synthesis of exemplary compound 130

[854] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(3-(3-(4-((5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)propoxy)propoxy)azetidin-1-yl)isoindolin-1,3-dione

[855] Prepared according to the synthesis scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[856] Compound 130: ^1H NMR (400 MHz, DMSO-d6): δ 1.74 1.80 (m, 4H), 1.85-1.92 (m, 2H), 1.97-2, 02 (m, 2H), 2.02-2.15 (m, 2H), 2.54-2.58 (m, 2H), 2.67-2.91 (m, 4H), 3.41- 3.50 (m, 8H), 3.81-3.88 (m, 2H), 3.98 (s, 3H), 4.25 (t, J=7.8 Hz, 2H), 4.44 -4.49 (m, 1H), 5.05 (dd, J=5.2, 12.8 Hz, 1H), 5.33-5.40 (m, 1H), 6.66 (dd, J =1.6, 8.4 Hz, 1H), 6.80 (d, J=1.2 Hz, 1H), 7.63-7.72 (m, 3H), 8.10 (s, 1H) , 8.36 (d, J=8.4 Hz, 1H), 8.51 (d, J=4.8 Hz, 2H), 8.92 (s, 1H), 9.39 (s, 1H) , 11.06 (s, 1H). (M+H) ⁺ 854.6.

[857] Scheme for the synthesis of exemplary compound 129

[858] 2-(2,6-Dioxopiperidin-3-yl)-5-((1,1,1-trifluoro-6-(2-(2-(2-((5-(5-methyl-5H -pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)hexan-2-yl)oxy)isoindolin-1,3-dione

[859] Step 1: 6-(2-(2-(2-(5-Bromopyridin-2-yloxy)ethoxy)ethoxy)ethoxy)-1,1,1-trifluorohexan-2-ol

[860] Into a solution of 5-(2-(2-(2-(5-bromopyridin-2-yloxy)ethoxy)ethoxy)ethoxy)pentanal (575 mg, 1.47 mmol) [prepared according to the scheme below and with using the procedures described above and conventional procedures known to those skilled in the art] and CF ₃ Si(CH ₃ ) ₃ (320 mg, 2.21 mmol) in THF was added TBAF (1 M, 2.2 ml, 2.20 mmol ) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After quenching with 1 N. HCl (3 ml) the mixture was extracted with EA (30 ml), washed with saline. The organic phase was dried and concentrated under vacuum. The residue was purified with silica gel (PE:EA = 2:1) to give 6-(2-(2-(2-(5-bromopyridin-2-yloxy)ethoxy)ethoxy)ethoxy)-1,1,1-trifluorohexane -2-ol (400 mg, 60% yield).

[861] Step 2: 6-(2-(2-(2-(5-Bromopyridin-2-yloxy)ethoxy)ethoxy)ethoxy)-1,1,1-trifluorohexan-2-yltrifluoromethanesulfonate

[862] Into a solution of 6-(2-(2-(2-(5-bromopyridin-2-yloxy)ethoxy)ethoxy)ethoxy)-1,1,1-trifluorohexan-2-ol (130 mg, 0.28 mmol) and pyridine (67 mg, 0.85 mmol) in DCM was added Tf ₂ O (120 mg, 0.42 mmol) at 0°C. The resulting solution was heated to room temperature for 1 hour. The reaction mixture was diluted with DCM (10 ml), washed with water, brine and concentrated in vacuo to give 6-(2-(2-(2-(5-bromopyridin-2-yloxy)ethoxy)ethoxy)ethoxy)-1 ,1,1-trifluorohexan-2-yltrifluoromethanesulfonate (160 mg, 96%).

[863] Compound 129: ^1H NMR (400 MHz, _CDCl3 ): δ 9.25 (s, 1H), 8.48 (s, 1H), 8.39 (s, 1H), 8.09 (d , J=8.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.46 (s, 1H ), 7.36-7.41 (m, 2H), 7.19-7.24 (m, 2H), 6.82 (d, J=8.8 Hz, 1H), 4.86-4, 91 (m, 1H), 4.58-4.63 (m, 1H), 4.45-4.48 (m, 2H), 3.78-3.82 (m, 5H), 3.55- 3.80 (m, 9H), 3.39-3.50 (m, 3H), 2.69-2.82 (m, 6H), 1.96-2.05 (m, 2H), 1, 81-1.89 (m, 2H). (M+H) ⁺ 818.5.

[864] Scheme for the synthesis of exemplary compound 131

[865] 2-(2,6-Dioxopiperidin-3-yl)-5-((17-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin- 2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecyl)oxy)isoindoline-1,3-dione

[866] Prepared according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[867] Using procedures similar to those for compound 131, the following compound was prepared: compound 132.

[868] Scheme for the synthesis of exemplary compound 133

[869] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(6-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol- 7-yl)pyridin-2-yl)oxy)pentyl)oxy)hexyl)azetidin-1-yl)isoindolin-1,3-dione

[870] Step 1. (6-(Benzyloxy)hexyl)magnesium bromide

[871] Stir a suspension of (((6-bromohexyl)oxy)methyl)benzene (10 g, 0.037 mol), magnesium (1.33 g, 0.055 mol) and iodine (200 mg) in anhydrous tetrahydrofuran (100 ml) at 50 °C for 2 hours. The iodine disappeared and the mixture was stirred for a further 1 hour to obtain (6-(benzyloxy)hexyl)magnesium bromide (crude), which was used in the next step without further purification.

[872] Step 2: tert-Butyl 3-(6-(benzyloxy)hexyl)-3-hydroxyazetidine-1-carboxylate

[873] To a solution of tert-butyl-3-oxoazetidine-1-carboxylate (5.2 g, 0.031 mol) in anhydrous tetrahydrofuran (50 ml) was added (6-(benzyloxy)hexyl)magnesium bromide at 0°C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between ethyl acetate (50 ml) and water (100 ml). The organic layer was collected, washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 33 to 50% ethyl acetate in hexanes) to give tert-butyl 3-(6-(benzyloxy)hexyl)-3-hydroxyazetidine-1-carboxylate (1.7 g, 12% in two steps) as a colorless oil.

[874] Step 3: tert-Butyl 3-(6-(benzyloxy)hexylidene)azetidine-1-carboxylate

[875] To a stirred solution of tert-butyl 3-(6-(benzyloxy)hexyl)-3-hydroxyazetidine-1-carboxylate (800 mg, 2.2 mmol) in toluene (10 ml) was added 1-methoxy-N- triethylammoniosulfonylmethanimidate (Burgess reagent) (1.57 g, 6.6 mmol). The resulting solution was heated to 90°C and stirred at this temperature for 2 hours. The mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography (eluting with 30% ethyl acetate in hexane) to give tert-butyl -3-(6-(benzyloxy)hexylidene)azetidine-1-carboxylate (125 mg, 16% yield) as a colorless oil.

[876] Step 4: tert-Butyl 3-(6-hydroxyhexyl)azetidine-1-carboxylate

[877] Stir a mixture of tert-butyl 3-(6-(benzyloxy)hexylidene)azetidine-1-carboxylate (125 mg, 0.36 mmol), palladium on carbon (10%, 50 mg) in methanol (30 ml) at room temperature for 3 hours in a hydrogen atmosphere (hydrogen cylinder). TLC indicated completion of the reaction. Palladium on carbon was removed by filtration and washed with methanol (5 ml x 2). The combined filtrates were concentrated under reduced pressure to give tert-butyl 3-(6-hydroxyhexyl)azetidine-1-carboxylate (88 mg, yield: 95%) as a colorless oil.

[878] Convert tert-butyl-3-(6-hydroxyhexyl)azetidine-1-carboxylate to the final compound, 2-(2,6-dioxopiperidin-3-yl)-5-(3-(6-((5- ((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)hexyl)azetidin-1-yl)isoindolin-1,3 -dione, in accordance with the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.

[879] Compound 133: 1H NMR (400 Hz, D6-DMSO): δ 1.24 1.35 (m, 7H), 1.46-1.57 (m, 8H), 1.72-1.82 (m, 2H), 1.98-2.01 (m, 3H), 2.57-2.74 (m, 3H), 2.81-2.99 (m, 2H), 3.57-3 .59 (m, 2H), 3.98 (s, 3H), 4.06-4.08 (m, 2H), 4.33 (s, 2H), 5.03-5.06 (m, 1H ), 6.54-6.66 (m, 1H), 6.69 (s, 1H), 6.93-6.95 (m, 1H), 7.57-7.71 (m, 3H), 8.02 (s, 1H), 8.19-8.21 (m, 1H), 8.34-8.36 (m, 1H), 8.53-8.58 (m, 1H), 8. 66 (s, 1H), 9.41 (s, 1H), 11.08 (s, 1H). (M+H) ⁺ 757.6.

[880] Scheme for the synthesis of exemplary compound 134

[881] 2-(2,6-Dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)hex-5-in-1-yl)oxy)isoindolin-1,3-dione

[882] Step 1: 3,6-Diiodopyridazine

[883] Stir a mixture of 3,6-dichloropyridazine (5.0 g, 34.0 mmol) and sodium iodide (50 g, 0.68 mol) in acetone (50 ml) at 65°C for 3 hours. The reaction mixture was quenched with water (100 ml) and extracted with ethyl acetate (200 ml x 2). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel flash column chromatography (eluting with 40% ethyl acetate in hexane) to give 3. 6-Diiodopyridazine (5.4 g, 4.9 mol, 48% yield) as a brown solid.

[884] Step 2. 3-Fluoro-6-iodopyridazine

[885] Stir a mixture of 3,6-dichloropyridazine (1 g, 3.0 mmol), cesium fluoride (413 mg, 0.9 mol) in dimethyl sulfoxide (10 ml) at 140°C overnight. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic layer was collected, washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel flash column chromatography (eluting with 20% ethyl acetate in hexane) to give 3-fluoro -6-iodopyridazine (840 mg).

[886] Step 3. 7-(6-((1r,3r)-3-((6-Iodopyridazin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4 ,3-b]indole

[887] To (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanol (100 mg, 0.29 mmol), 3-fluoro-6-iodopyridazine (300 mg, 0.10 mmol) in 1-methylpyrrolidin-2-one (5 ml) was added sodium hydride (60% in mineral oil) (110 mg, 2. 7 mmol) at 0°C. The resulting mixture was heated to room temperature for 1 hour. The reaction mixture was quenched with water (10 ml) at 0°C and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 20% methanol in dichloromethane) to give 7-(6 -((1r,3r)-3-((6-iodopyridazin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole (70 mg, 0.13 mmol, 44% yield) as a brown solid.

[888] Converted 7-(6-((1r,3r)-3-((6-iodopyridazin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4,3 -b]indole to the final compound, 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H -pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)hex-5-yn-1-yl)oxy)isoindolin-1,3-dione , according to the scheme below and using the procedures described above (step 6 for compound 73 and step 1 for compound 180).

[889] Compound 134: 1H NMR (400 MHz, DMSO- _d6 ): δ 1.74-1.78 (m, 2H), 1.92-1.95 (m, 2H), 2.03-2 .07 (m, 1H), 2.54-2.62 (m, 4H), 2.68-2.71 (m, 4H), 2.85-2.93 (m, 1H), 3.96 (s, 3H), 4.23-4.27 (m, 2H), 5.09-5.14 (m, 1H), 5.45-5.48 (m, 1H), 5.55-5 .58 (m, 1H), 7.01 (d, J=8.8 Hz, 1H), 7.24-7.26 (m, 1H), 7.36-7.38 (m, 1H), 7.45 (m, 1H), 7.62-7.68 (m, 3H), 7.82 (d, J=8.0 Hz, 1H), 7.99 (s, 1H), 8.21 -8.24 (m, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.49 8.51 (m, 1H), 8.64 8.65 (m, 1H), 9.37 (s, 1H), 11.12 (s, 1H). (M+H) ⁺ 776.5.

[890] Compound 149 was further prepared from compound 134 using the hydrogenation procedure described previously to convert compound 102 to compound 110.

[891] Scheme for the synthesis of exemplary compound 145

[892] 2-(2,6-Dioxopiperidin-3-yl)-5-(4-((2-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4 ,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione

[893] Prepared in accordance with the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.

[894] Compound 135: ^1H NMR (400 MHz, DMSO- _d6 ): 1.60-1.80 (m, 6H), 1.92-2.07 (m, 5H), 2.16-2 .26 (m, 3H), 2.34-2.40 (m, 2H), 2.55-2.67 (m, 4H), 2.84-2.93 (m, 1H), 3.26 -3.31 (m, 4H), 3.78-3.82 (m, 1H), 3.96 (s, 3H), 4.18 (t, J=6.0 Hz, 2H), 5, 05-5.27 (m, 2H), 6.90-6.94 (m, 1H), 7.33-7.35 (m, 1H), 7.42 (s, 1H), 7.60- 7.63 (m, 2H), 7.83 (d, J=8.4 Hz, 1H), 7.98 (s, 1H), 8.17-8.20 (m, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.51 (d, J=6.0 Hz, 1H), 8.62 (s, 1H), 9.36 (s, 1H), 11.12 (s, 1H). (M+H) ⁺ 783.6.

[895] Scheme for the synthesis of exemplary compound 136

[896] 2-(2,6-Dioxopiperidin-3-yl)-5-(4-((2-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutan-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione

[897] Prepared in accordance with the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.

[898] Compound 136: 1H NMR (400 MHz, DMSO- _d6 ): δ 1.61 1.65 (m, 2H), 1.77-1.80 (m, 2H), 1.99-2, 08 (m, 4H), 2.14-2.20 (m, 2H), 2.44-2.46 (m, 3H), 2.55-2.61 (m, 4H), 2.72- 2.76 (m, 1H), 2.85-2.93 (m, 1H), 3.79-3.84 (m, 3H), 3.96 (s, 3H), 4.04-4, 09 (m, 2H), 4.17-4.20 (m, 2H), 5.10-5.14 (m, 2H), 6.93 (d, J=8.4 Hz, 1H), 7 ,34-7.42 (m, 2H), 7.61-7.65 (m, 2H), 7.83 (d, J=8.0 Hz, 1H), 7.99 (s, 1H), 8.18-8.20 (m, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.50 (d, J=6.0 Hz, 1H), 8.62 (d , J=0.8 Hz, 1H), 9.37 (s, 1H), 11.12 (s, 1H). (M+H) ⁺ 797.5.

[899] Scheme for the synthesis of exemplary compound 137

[900] 2-(2,6-Dioxopiperidin-3-yl)-5-((5-(6-(methyl-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)-5-oxopentyl)oxy)isoindoline-1,3 -dion

[901] Step 1: Benzyl 5-hydroxypentanoate

[902] Stir a mixture of tetrahydro-2H-pyran-2-one (1 g, 10 mmol) and sodium hydroxide (400 mg, 10 mmol) in water (15 ml) at 70°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude residue, which was dissolved in acetone (20 ml), followed by sequential addition of tetrabutylammonium bromide (161 mg, 0.5 mmol) and benzyl bromide (2 g, 12 mmol) at room temperature. The mixture was stirred at 60°C for 4 hours. TLC indicated completion of the reaction. The mixture was concentrated and the residue was partitioned between ethyl acetate (30 ml) and water (50 ml). The organic layer was collected, washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 33 to 50% ethyl acetate in hexanes) to give benzyl 5-hydroxypentanoate (500 mg, 24%) as a light yellow solid.

[903] Convert benzyl 5-hydroxypentanoate to the final compound, 2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl-((1r,3r)-3-(( 5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)-5 -oxopentyl)oxy)isoindoline-1,3-dione, in accordance with the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.

[904] Compound 137: ^1H NMR (400 MHz, DMSO-d6): δ 1.58-1.63 (m, 2H), 1.72-1.77 (m, 2H), 2.03-2 .11 (m, 3H), 2.33-2.47 (m, 8H), 2.54-2.62 (m, 2H), 2.78-2.90 (m, 3H), 3.41 -3.48 (m, 3H), 3.75-3.79 (m, 1H), 3.80-3.87 (m, 1H), 4.02 (s, 3H), 4.06 (s , 1H), 4.13-4.18 (m, 3H), 5.10-5.14 (m, 1H), 5.25-5.28 (m, 1H), 6.96-7.00 (m, 1H), 7.33-7.42 (m, 2H), 7.70 (d, J=8.4 Hz, 1H), 7.80-7.84 (m, 2H), 8, 06 (s, 1H), 8.23-8.26 (m, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.57-8.67 (m, 2H), 9 .49 (s, 1H), 11.12 (s, 1H). (M+H) ⁺ 810.6.

[905] Scheme for the synthesis of exemplary compound 138

[906] 5-((14-((5-(5-(Difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9 ,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[907] Step 1. 5-(Difluoromethyl)-7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole

[908] To a solution of 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (500 mg, 1.90 mmol) in dry N,N-dimethylformamide (6 ml) was added the hydride sodium (60% in mineral oil) (380 mg, 9.50 mmol) at 0°C and the resulting mixture was stirred at room temperature for 30 minutes. Sodium 2-chloro-2,2-difluoroacetate (580 mg, 3.80 mmol) was then added and the resulting reaction mixture was stirred at 80°C for 5 hours. The reaction mixture was quenched with water (30 ml) at 0°C and extracted with ethyl acetate (30 ml). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel flash chromatography (eluting with 50% ethyl acetate in hexane) to give 5-(difluoromethyl) -7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (35 mg, 6% yield) as a yellow solid.

[909] Convert 5-(difluoromethyl)-7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole to the final compound, 5-((14-((5-(5- (difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidine -3-yl)isoindolin-1,3-dione, according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[910] Compound 138: ^1H NMR (400 MHz, DMSO-d6): δ 2.01-2.04 (m, 1H), 2.56-2.67 (m, 2H), 2.83-2 .93 (m, 1H), 3.52-3.59 (m, 12H), 3.78 (s, 4H), 4.29 (s, 2H), 4.45 (s, 2H), 5, 11 (d, J=12.8 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.43 ( s, 1H), 7.76-7.83 (m, 3H), 8.14-8.18 (m, 2H), 8.36-8.50 (m, 2H), 8.61-8, 65 (m, 2H), 9.49 (s, 1H), 11.11 (s, 1H). (M+H) ⁺ 788.5.

[911] Scheme for the synthesis of exemplary compound 139

[912] 2-(2,6-Dioxopiperidin-3-yl)-5-((14-((3-fluoro-5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione

[913] Prepared according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[914] Scheme for the synthesis of exemplary compound 140

[915] 2-(2,6-Dioxopiperidin-3-yl)-5-((14-((3-methyl-5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione

[916] Step 1. 2-Fluoro-5-iodo-3-methylpyridine

[917] To a mixture of 6-fluoro-5-methylpyridin-3-amine (300 mg, 2.4 mmol) in N,N-dimethylacetamide (10 ml) was added potassium iodide (395 mg, 2.4 mmol), iodine ( 306 g, 1.2 mmol), copper(1) iodide (137 mg, 0.72 mmol) and tert-butyl nitrite (1.7 g, 14.4 mmol), stirred at 90°C for 2 hours. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (eluting with 10% ethyl acetate in hexane) to give 2-fluoro-5 -iodo-3-methylpyridine (350 mg, 62% yield) as a white solid.

[918] Convert 2-fluoro-5-iodo-3-methylpyridine to the final compound, 2-(2,6-dioxopiperidin-3-yl)-5-((14-((3-methyl-5-(5- methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione, in accordance with diagram below using the procedures described above and conventional procedures known to those skilled in the art.

[919] Scheme for the synthesis of exemplary compound 141

[920] 2-(2,6-Dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrimidin-2-yl)hex-5-yn-1-yl)oxy)isoindolin-1,3-dione

[921] Prepared according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[922] Compound 151 was further prepared from compound 141 using the hydrogenation procedure described previously to convert compound 102 to compound 110.

[923] Scheme for the synthesis of exemplary compound 142

[924] 2-(2,6-Dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)azetidin-3-yl )oxy)isoindoline-1,3-dione

[925] Prepared according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[926] Scheme for the synthesis of exemplary compound 143

[927] 2-(2,6-Dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-6 -(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione

[928] Step 1. 6-Chloro-3-iodo-2-(trifluoromethyl)pyridine

[929] To a solution of lithium diisopropylamide (2 M in THF, 3.03 mmol) in tetrahydrofuran (15 ml) was added a solution of 2-chloro-6-(trifluoromethyl)pyridine (500 mg, 2.75 mmol) in tetrahydrofuran (5 ml ) at -65°C in a nitrogen atmosphere. The dark brown solution was stirred at -65°C for 30 minutes. A solution of iodine (0.7 g, 2.75 mmol) in tetrahydrofuran (5 ml) was added to the reaction mixture at 65°C for 20 minutes. After an additional 20 minutes of stirring at the same temperature, the reaction mixture was quenched with hydrochloric acid (2 M, 6 ml) at 0°C and stirred for 20 minutes. The reaction mixture was extracted with ethyl acetate (30 ml). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel flash chromatography (eluting with 1% ethyl acetate in hexane) to give 6-chloro-3 -iodo-2-(trifluoromethyl)pyridine (316 mg, 37% yield) as a brown oil.

[930] Convert 6-chloro-3-iodo-2-(trifluoromethyl)pyridine to the final compound, 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl -5H-pyrido[4,3-b]indol-7-yl)-6-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3- dione, according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[931] Scheme for the synthesis of exemplary compound 146

[932] 2-(2,6-Dioxopiperidin-3-yl)-5-((6-(6-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol- 7-yl)pyridin-2-yl)oxy)propoxy)pyridin-3-yl)hex-5-in-1-yl)oxy)isoindoline-1,3-dione

[933] Prepared according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[934] Scheme for the synthesis of exemplary compound 152

[935] 2-(2,6-Dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)azetidin-3-yl)oxy)isoindoline-1 ,3-dione

[936] Prepared according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[937] Scheme for the synthesis of exemplary compound 150

[938] Step 1: 2-[5-(3-Benzyloxycyclobutoxy)-2,2-difluoropentoxy]tetrahydropyran

[939] Sodium hydride (581 mg, 14.53 mmol, 60% in mineral oil, 1.10 eq.) at 0°C in a nitrogen atmosphere. The mixture was stirred at 0°C for 0.5 hour and a solution of (4,4-difluoro-5-tetrahydropyran-2-yloxypentyl)-4-methylbenzenesulfonate (5.0 g, 13.21 mmol, 1.00 eq.) [prepared as described for compound 171] in N,N-dimethylformamide (20 ml) at 0°C. The reaction mixture was stirred at 60°C for 6 hours. The mixture was cooled to 25°C and poured into ice water (v/v = 1/1) (30 ml) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (100 ml x 3). The combined organic phase was washed with brine (100 ml x 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/0, 20/1) to give 2-[5-(3-benzyloxycyclobutoxy)-2,2-difluoropentoxy]tetrahydropyran (1.75 g, 4.21 mmol, yield 32%, purity 92%) in the form of a colorless oil.

[940] Step 2: 3-(4,4-Difluoro-5-tetrahydropyran-2-yloxypentoxy)cyclobutanol

[941] A catalyst representing is palladium on activated carbon (1.0 g, purity 10%), in a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under a hydrogen atmosphere (15 psi) at 25°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1 to 1:1) to give 3-(4,4-difluoro-5-tetrahydropyran-2-yloxypentoxy)cyclobutanol (1.2 g, 4 .08 mmol, yield 90%) in the form of a colorless oil.

[942] Step 3: 5-Bromo-2-[3-(4,4-difluoro-5-tetrahydropyran-2-yloxypentoxy)cyclobutoxy]pyridine

[943] In a mixture of 3-(4,4-difluoro-5-tetrahydropyran-2-yloxypentoxy)cyclobutanol (1.2 g, 4.08 mmol, 1.00 eq.) and 5-bromopyridin-2-ol (1 .06 g, 6.12 mmol, 1.50 eq.) in toluene (60 ml) was added in one portion 1,1'-(azodicarbonyl)dipiperidine (1.54 g, 6.12 mmol, 1.50 eq.) and tributylphosphane (1.24 g, 6.12 mmol, 1.50 eq.) at 0°C under nitrogen. The mixture was stirred at 110°C for 16 hours. The mixture was cooled to 25°C and concentrated under reduced pressure at 45°C. The residue was poured into ice water (v/v = 1/1) (30 ml) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (50 ml x 3). The combined organic phase was washed with brine (50 ml x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 100/1, 50/1). 5-Bromo-2-[3-(4,4-difluoro-5-tetrahydropyran-2-yloxypentoxy)cyclobutoxy]pyridine (1.36 g, 3.02 mmol, 74.0% yield) was obtained as a yellow oil.

[944] Step 4: 5-[3-[(5-Bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoropentan-1-ol

[945] To a mixture of 5-bromo-2-[3-(4,4-difluoro-5-tetrahydropyran-2-yloxypentoxy)cyclobutoxy]pyridine (1.1 g, 2.44 mmol, 1.00 eq.) in tetrahydrofuran (25 ml) was added in one portion with hydrogen chloride (4 M, 10 ml, 16.38 eq.) under nitrogen atmosphere. The mixture was then stirred at 25°C for 1 hour. The mixture was poured into saturated sodium hydrogen carbonate solution (20 ml) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (50 ml x 3). The combined organic phase was washed with brine (50 ml x 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1, 5/1) to give 5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoropentane-1 -ol (700 mg, 1.91 mmol, 78% yield) as a colorless oil.

[946] Step 5. [5-[3-[(5-Bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoropentyl]trifluoromethanesulfonate

[947] In a mixture of 5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoropentan-1-ol (400 mg, 1.09 mmol, 1.00 eq.) and triethylamine (552 mg, 5.46 mmol, 5.00 eq.) in dichloromethane (10 ml) trifluoromethanesulfonyl chloride (368 mg, 2.18 mmol, 2.00 eq.) at 0°C under nitrogen atmosphere. After addition was complete, the reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated in vacuo at 40°C. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5/1) to give [5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoropentyl]trifluoromethanesulfonate (465 mg , 0.93 mmol, yield 85%) as a colorless oil.

[948] Step 6. tert-Butyl-6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-5-yl]-2,6-diazaspiro[3.3]heptane-2- carboxylate

[949] In a mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoroisoindoline-1,3-dione (300 mg, 1.09 mmol, 1.00 eq.) and oxalic acid salt and tert. butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (317 mg, 0.65 mmol, 0.60 eq.) in (methylsulfinyl)methane (5 ml) was added in one portion of N,N-diisopropylethylamine (561 mg , 4.34 mmol, 4.00 eq.) under nitrogen. The mixture was heated to 120°C and stirred for 16 hours. The mixture was poured into ice water (w/w = 1/1) (30 ml) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (50 ml x 3). The combined organic phase was washed with brine (50 ml x 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with petroleum ether:ethyl acetate (1:1, 50 ml) to give tert-butyl-6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-5-yl]- 2,6-diazaspiro[3.3]heptane-2-carboxylate (420 mg, 0.92 mmol, 85% yield) as a yellow solid.

[950] Step 7: 5-(2,6-Diazaspiro[3.3]heptan-2-yl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

[951] A mixture of tert-butyl-6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-5-yl]-2,6-diazaspiro was stirred

[952][3.3]heptane-2-carboxylate (420 mg, 0.92 mmol, 1.00 eq.) in trifluoroacetic acid (1 ml) and dichloromethane (10 ml) at 25°C for 1 hour under nitrogen atmosphere . TLC indicated completion of the reaction. The mixture was concentrated under reduced pressure at 45°C. The mixture was purified using semipreparative reverse phase HPLC (column: Phenomenex Synergi Max-RP 250 * 50 mm * 10 μm; mobile phase: [water (0.225% FA) - ACN]; V%: 5% ACN to 30%) ACN, 15 min; 50% min.) to obtain 5-(2,6-diazaspiro[3.3]heptan-2-yl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione formate (260 mg, 0.64 mmol, 70% yield) as a yellow solid.

[953] Step 8: 5-[6-[5-[3-[(5-Bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoropentyl]-2,6-diazaspiro[3.3]heptane-2 -yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

[954] In a mixture of [5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoropentyl]trifluoromethanesulfonate (460 mg, 0.92 mmol, 1.00 eq.) and formate 5-(2,6-diazaspiro[3.3]heptan-2-yl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (443 mg, 1.11 mmol, 1.20 eq.) in acetonitrile (25 ml) and (methylsulfinyl)methane (5 ml) potassium carbonate (255 mg, 1.85 mmol, 2.00 eq.) was added in one portion at 25°C under nitrogen atmosphere. The mixture was stirred at 25°C for 10 hours. LC-MS showed that [5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoropentyl]trifluoromethanesulfonate was completely consumed and one major peak was detected with the required MS. The suspension was filtered and concentrated in vacuo. The residue was diluted with ethyl acetate (100 ml), washed with brine (30 ml x 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/1, 1/3) to give 5-[6-[5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2 ,2-difluoropentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (320 mg, 0.45 mmol, yield 49%) as a yellow solid.

[955] Step 9: 5-[6-[2,2-Difluoro-5-[3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-pyridyl]oxy]cyclobutoxy]pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

[956] Degassed 5-[6-[5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoropentyl]-2,6-diazaspiro[3.3]heptan-2-yl ]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (200 mg, 0.28 mmol, 1.00 eq.), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (86 mg, 0.34 mmol, 1.20 eq.), potassium acetate ( 55 mg, 0.56 mmol, 2.00 eq.) and complex of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride and dichloromethane (23 mg, 0.02 mmol, 0.10 eq.) in dioxane ( 10 ml) and then heated to 90°C for 2 hours under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (dichloromethane:methanol = 20:1) to give 5-[6-[2,2-difluoro-5-[3-[[5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]cyclobutoxy]pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione (200 mg, 0.26 mmol, 94% yield) as a yellow oil.

[957] Step 10: 5-[6-[2,2-Difluoro-5-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy ]cyclobutoxy]pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

[958] Degassed 5-[6-[2,2-difluoro-5-[3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 -pyridyl]oxy]cyclobutoxy]pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (200 mg, 0 .26 mmol, 1.00 eq.), 7-bromo-5-methylpyrido[4,3-b]indole (69 mg, 0.26 mmol, 1.00 eq.), sodium carbonate (56 mg, 0.00 eq.), 53 mmol, 2.00 eq.) and complex of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride and dichloromethane (21 mg, 0.02 mmol, 0.10 eq.) in N,N-dimethylformamide (5 ml) and water (0.5 ml) and then heated to 90°C for 2 hours under nitrogen atmosphere. Completion of the reaction was indicated by LCMS. The mixture was cooled to 25°C and filtered. The residue was diluted with ethyl acetate (50 ml), washed with brine (30 ml x 3), dried over anhydrous sodium sulfate, concentrated in vacuo. The mixture was purified by semipreparative reverse phase HPLC (18 to 48% acetonitrile + 0.225% formic acid in water, 10 min). The collected fraction was then concentrated to remove most of the acetonitrile. The solution was lyophilized. 5-[6-[2,2-Difluoro-5-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]pentyl formate was obtained ]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (21.6 mg, 0.02 mmol, yield 9 %, purity 95%) as a yellow solid.

[959] ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ: 10.95 (s, 1H), 9.14 (br s, 1H), 8.15 (s, 1H), 7.52 ( d, J=9.0 Hz, 1H), 7.18-7.04 (m, 5H), 6.83 (d, J=6.7 Hz, 2H), 6.65 (d, J=8 .5 Hz, 1H), 6.61 (s, 1H), 6.54-6.47 (m, 3H), 6.26 (d, J=8.5 Hz, 2H), 5.05 (dd , J=5.0, 13.3 Hz, 1H), 4.38-4.26 (m, 1H), 4.24-4.11 (m, 1H), 3.78 (br t, J= 6.5 Hz, 4H), 3.54-3.31 (m, 3H), 3.03-2.83 (m, 8H), 2.62-2.52 (m, 3H), 2.47 -2.31 (m, 1H), 2.21-2.04 (m, 3H), 2.01-1.87 (m, 3H), 1.71 (br d, J=10.7 Hz, 2H). (M+H) ⁺ 804.5.

[960] Scheme for the synthesis of exemplary compound 153

[961] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(3,3,3-trifluoro-2-((5-((1r,3r)-3-((5- (5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)oxy)propyl)azetidin-1-yl)isoindoline-1,3-dione

[962] Prepared in accordance with the schemes below using the procedures described above and conventional procedures known to those skilled in the art.

[963] Using the procedures for compound 153, the following was obtained: compound 154.

[964] Synthesis scheme for exemplary compound 155

[965] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-((5-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)pyridin-2-yl)oxy)azetidin-1-yl)isoindolin-1,3-dione

[966] Prepared in accordance with the schemes below using the procedures described above and conventional procedures known to those skilled in the art.

[967] Scheme for the synthesis of exemplary compound 156

[968] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindolin-1,3-dione

[969] Prepared in accordance with the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.

[970] Scheme for the synthesis of exemplary compound 157

[971] 2-(2,6-Dioxopiperidin-3-yl)-5-(4-((2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4, 3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutan-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione

[972] Step 1. (1r,3r)-3-((5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanecarboxylic

[973] Into a solution of (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanecarbaldehyde (70 mg , 0.20 mmol) in tetrahydrofuran (1 ml) and water (1 ml), sodium chlorite (62 mg, 0.63 mmol), sodium dihydrogen phosphate dihydrate (168 mg, 1.08 mmol) and 2-methylbut-2- ene (233 mg, 3.33 mmol), then the mixture was stirred at room temperature overnight. TLC indicated completion of the reaction. The reaction mixture was diluted with dichloromethane (20 ml), washed with water (10 ml x 3), brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude (1r,3r)-3-((5- (5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanecarboxylic acid as a yellow solid.

[974] Converted (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanecarboxylic acid to the final compound , 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3- b]indol-7-yl)pyridin-2-yl)oxy)cyclobutan-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione, in accordance with diagram below and using the procedure described above for compound 153.

[975] Scheme for the synthesis of exemplary compound 158

[976] 2-(2,6-Dioxopiperidin-3-yl)-5-(2-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridazin-4-yl)oxy)ethoxy)isoindoline-1,3-dione

[977] Step 1: 5-(2-(Benzyloxy)ethoxy)-3-chloropyridazine

[978] Sodium hydride (60% in oil) (347 mg, 8.68 mmol) at 0°C. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride (15 ml) at 0°C and extracted with ethyl acetate (20 ml x 3). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography (eluting with 15% ethyl acetate in hexane) to give 5- (2-(benzyloxy)ethoxy)-3-chloropyridazine (680 mg, 89% yield) as a light brown oil.

[979] Step 2. (1r,3r)-3-((1-(5-(2-(Benzyloxy)ethoxy)pyridazin-3-yl)piperidin-4-yl)oxy)cyclobutanol

[980] In a mixture of 5-(2-(benzyloxy)ethoxy)-3-chloropyridazine (240 mg, 0.910 mmol) and (1r,3r)-3-(piperidin-4-yloxy)cyclobutanol (155 mg, 0.910 mmol) [prepared by hydrogenation of (1r,3r)-3-((1-benzylpiperidin-4-yl)oxy)cyclobutan-1-ol as described in step 5 for compound 65, but without the presence of di-tert-butyl carbonate] in toluene (5 ml) Pd ₂ (dba) ₃ (83 mg, 0.091 mmol), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (56 mg, 0.091 mmol) and carbonate were added cesium (739 mg, 2.27 mmol) in a nitrogen atmosphere. The mixture was then heated to 90°C overnight. TLC indicated completion of the reaction. The reaction mixture was extracted with ethyl acetate (30 ml x 3). The organic layer was washed with brine (10 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography (eluting with 8% ethyl acetate in hexane) to give ( 1r,3r)-3-((1-(5-(2-(benzyloxy)ethoxy)pyridazin-3-yl)piperidin-4-yl)oxy)cyclobutanol (135 mg, 38% yield) as light yellow oils

[981] Convert (1r,3r)-3-((1-(5-(2-(benzyloxy)ethoxy)pyridazin-3-yl)piperidin-4-yl)oxy)cyclobutanol to the final compound, 2-(2 ,6-dioxopiperidin-3-yl)-5-(2-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridazin-4-yl)oxy)ethoxy)isoindoline-1,3-dione, according to the scheme below and using those described above procedures and routine procedures known to those skilled in the art.

[982] Scheme for the synthesis of exemplary compound 159 and compound 160

[983] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-((3-(5-((1s,3s)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)azetidin-1-yl)isoindolin-1 ,3-dione

[984] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(3-(5-((1s,3s)-3-((5-(5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindolin-1,3-dione

[985] Prepared in accordance with the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.

[986] Scheme for the synthesis of exemplary compound 161

[987] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H -pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione

[988] Prepared in accordance with the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.

[989] Based on the general approach for compound 163 and using routine procedures known to those skilled in the art, additional compounds were prepared: 162, 165, 178, 181 and 182.

[990] Scheme for the synthesis of exemplary compounds 165 and 166

[991] 5-((5-((1-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy )cyclobutan-1-carbonyl)piperidin-4-yl)oxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[992] 5-((5-((1-((1s,3s)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy )cyclobutan-1-carbonyl)piperidin-4-yl)oxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[993] Prepared in accordance with the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.

[994] Scheme for the synthesis of exemplary compounds 167 and 168

[995] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-((3-(5-(3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)prop-2-in-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione

[996] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(3-(5-(3-((5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione

[997] Prepared in accordance with the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.

[998] Scheme for the synthesis of exemplary compound 169

[999] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(3-((3-(((1r,3r)-3-((5-(5-methyl-5H- pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)oxetan-3-yl)methoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione

[1000] Was prepared in accordance with the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.

[1001] Scheme for the synthesis of exemplary compound 174

[1002] 2-(2,6-Dioxopiperidin-3-yl)-5-(4-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4 ,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)butoxy)isoindoline-1,3-dione

[1003] Step 1. Bicyclo[1.1.1]pentane-1,3-diyldimethanol

[1004] To a solution of dimethylbicyclo[1.1.1]pentane-1,3-dicarboxylate (500 mg, 2.72 mmol) in tetrahydrofuran (5 ml) was added lithium aluminum hydride (419 mg, 10.87 mmol) at 0°C and the resulting mixture was stirred at room temperature for 2 hours. TLC indicated completion of the reaction. The reaction mixture was quenched with water (1 ml), sodium hydroxide (2 ml, 10% in water) and water (1 ml). The solid was removed by filtration and the filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give bicyclo[1.1.1]pentane-1,3-diyldimethanol (256 mg, crude, 70% yield) as a light yellow oil .

[1005] Convert bicyclo[1.1.1]pentan-1,3-diyldimethanol to the final compound, 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(((1r,3r )-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentane-1 -yl)methoxy)butoxy)isoindoline-1,3-dione, according to the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.

[1006] Scheme for the synthesis of exemplary compound 175

[1007] 2-(2,6-Dioxopiperidin-3-yl)-5-((5-((3-(3-((5-(5-methyl-5H-pyrido[4,3-b]indole -7-yl)pyridin-2-yl)oxy)azetidin-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pentyl)oxy)isoindoline-1,3-dione

[1008] Step 1: 3-(Hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate

[1009] To a solution of dimethylbicyclo[1.1.1]pentane-1,3-dicarboxylate (1 g, 5.43 mmol) in tetrahydrofuran (10 ml) was added lithium borohydride (120 mg, 5.43 mmol) at 0°C in nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirred at room temperature for 5 hours. The mixture was quenched with an aqueous solution of hydrochloric acid (1 N) to pH 3-4 and extracted with dichloromethane (10 ml x 2). The organic layers were combined, washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 20 to 33% ethyl acetate in hexanes) to give methyl -3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (400 mg, 47%) as a colorless oil.

[1010] Convert 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate to the final compound, 2-(2,6-dioxopiperidin-3-yl)-5-((5-((3-(3 -((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidin-1-carbonyl)bicyclo[1.1.1]pentan-1- yl)methoxy)pentyl)oxy)isoindoline-1,3-dione, in accordance with the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.

[1011] Synthesis scheme for exemplary compound 176

[1012] 5-(3-(3-(3-((1r,3r)-3-((5-(8,9-Difluoro-5-methyl-5H-pyrido[4,3-b]indol- 7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[1013] Prepared according to the schemes below and using the procedures described above for compound 104 (in modified sequence) and conventional procedures known to those skilled in the art.

[1014] Scheme for the synthesis of exemplary compound 177

[1015] 3-(5-(3-(3-(3-((1r,3r)-3-((5-(5-Methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetide in-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione

[1016] Step 1. 5-(3-(3-(3-((1r,3r)-3-((5-(5H-Pyrido[4,3-b]indol-7-yl)-3- (trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[1017] Mixture of 7-(6-((1r,3r)-3-(3-(3-(azetidin-3-yloxy)propoxy)propoxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H- pyrido[4,3-b]indole (crude, 0.390 mmol) [prepared as described for compound 104], N-ethyl-N-isopropylpropan-2-amine (86 mg, 1.17 mmol) and methyl 2-cyano -4-fluorobenzoate (90 mg, 0.468 mmol) in 1-methyl-2-pyrrolidinone (3 ml) was stirred at 90°C for 16 hours. TLC indicated completion of the reaction. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (30 ml). The organic layer was collected, washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography (eluting with 2 to 4% methanol in dichloromethane) with producing 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin- 2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (160 mg, 61% yield) as light - yellow oil.

[1018] Step 2. Methyl-2-formyl-4-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b ]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)benzoate

[1019] Into a mixture of methyl-2-cyano-4-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)benzoate (160 mg, 0.237 mmol) in a mixture of pyridine (3 ml) - water (1.5 ml) - acetic acid (1.5 ml), sodium hypophosphite (125 mg, 1.179 mmol) and Raney nickel (85% in water) (300 mg) were added at room temperature. The resulting mixture was stirred at 50°C for 2 hours. The mixture was diluted with ethyl acetate (30 ml), washed with water (30 ml x 2), dilute hydrochloric acid solution (1N, 30 ml), brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude the residue was purified by flash silica gel chromatography (eluting with 2 to 5% methanol in dichloromethane) to give methyl 2-formyl-4-(3-(3-(3-((1r,3r)-3 -((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)benzoate (90 mg , yield 56%) as a brown oil.

[1020] Step 3. 3-(5-(3-(3-(3-((1r,3r)-3-((5-(5-Methyl-5H-pyrido[4,3-b]indol- 7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione

[1021] A mixture of 3-aminopiperidine-2,6-dione (32 mg, 0.199 mmol), N-ethyl-N-isopropylpropan-2-amine (34 mg, 0.199 mmol), acetic acid (0.5 ml) and methyl-2-formyl-4-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl )pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)benzoate (90 mg, 0.133 mmol) in methanol (5 ml) at room temperature for 15 min. Sodium cyanoborohydride (16 mg, 0.400 mmol) was then added and stirred at room temperature overnight. TLC indicated completion of the reaction. The reaction mixture was partitioned between dichloromethane (30 ml) and water (10 ml), the organic layer was collected, washed with brine (10 ml x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue, which was purified using preparative TLC (8% methanol in ethyl acetate) to give the title compound (50 mg, 50% yield) as a white solid.

[1022] ^1H NMR (400 MHz, DMSO-d6): δ 1.71-1.80 (m, 4H), 1.90-1.93 (m, 1H), 2.28-2.37 ( m, 3H), 2.40-2.44 (m, 2H), 2.56-2.57 (m, 1H), 2.83-2.92 (m, 1H), 3.37 (t, J=6.0 Hz, 2H), 3.43-3.48 (m, 6H), 3.67-3.70 (m, 2H), 3.95 (s, 3H), 4.11-4 .19 (m, 4H), 4.23-4.27 (m, 1H), 4.42-4.44 (m, 1H), 4.99-5.03 (m, 1H), 5.31 -5.34 (m, 1H), 6.46-6.49 (m, 2H), 6.94 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.60-7.63 (m, 2H), 7.97 (s, 1H), 8.17-8.20 (m, 1H), 8.32 (d, J=8, 0 Hz, 1H), 8.50 (d, J=6.0 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H), 9.37 (s, 1H), 10.92 (s, 1H). (M+H) ⁺ 759.6.

[1023] Scheme for the synthesis of exemplary compound 184

[1024] 2-(2,6-Dioxopiperidin-3-yl)-5-((7-(3-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol- 7-yl)pyridin-2-yl)oxy)azetidin-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)heptyl)oxy)isoindoline-1,3-dione

[1025] Step 1. (6-(Benzyloxy)hexyl)triphenylphosphonium bromide

[1026] Stir a mixture of (((6-bromohexyl)oxy)methyl)benzene (2.7 g, 10 mmol) and triphenylphosphine (2.6 g, 10 mmol) in acetonitrile (10 ml) under reflux for 40 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to obtain (6-(benzyloxy)hexyl)triphenylphosphonium bromide (5 g, yield: 94%) as a colorless oil.

[1027] Step 2: Methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate

[1028] To a stirred solution of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (156 mg, 1 mmol) in dichloromethane (10 ml) was added Dess-Martin periodinane (840 mg, 2.0 mmol ) at 0°C. The resulting reaction mixture was allowed to warm to room temperature and stirred at this temperature for an additional 1 hour. The reaction mixture was quenched with aqueous sodium sulfite (10 ml) and extracted with dichloromethane (20 ml × 2), washed with brine (20 ml × 2) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash chromatography on silica gel (eluting with 20% ethyl acetate in hexane) to give methyl-3-formylbicyclo[1.1.1]pentane-1- carboxylate (110 mg, 70% yield) as a colorless oil.

[1029] Step 3: Methyl 3-(7-(benzyloxy)hept-1-en-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

[1030] To a solution of (6-(benzyloxy)hexyl)triphenylphosphonium bromide (373 mg, 0.70 mmol) in anhydrous tetrahydrofuran (6 mL), n-butyllithium (2.5 M in hexane) (0.28 mL) was added dropwise , 0.7 mmol) at -20°C and the resulting mixture was stirred at the same temperature for 30 minutes. Methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (90 mg, 0.58 mmol) in anhydrous tetrahydrofuran (1 ml) was added dropwise. The resulting reaction mixture was slowly warmed to room temperature and stirred at the same temperature for 30 minutes. The reaction mixture was quenched with water (10 ml) at 0°C and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel flash chromatography (eluting with 10% ethyl acetate in hexane) to give methyl-3-( 7-(benzyloxy)hept-1-en-1-yl)bicyclo[1.1.1]pentane-1-carboxylate (56 mg, 29% yield) as a colorless oil.

[1031] Convert methyl 3-(7-(benzyloxy)hept-1-en-1-yl)bicyclo[1.1.1]pentane-1-carboxylate to the final compound, 2-(2,6-dioxopiperidin-3- yl)-5-((7-(3-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidin- 1-carbonyl)bicyclo[1.1.1]pentan-1-yl)heptyl)oxy)isoindoline-1,3-dione, according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.

[1032] Scheme for the synthesis of exemplary compound 185

[1033] (2S,4R)-N-(2-(2-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)-4 -(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide

[1034] Prepared according to the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.

[1035] Using procedures similar to those for compound 185, the following compounds were prepared: compounds 186, 187, 196, 201.

[1036] Scheme for the synthesis of exemplary compound 193

[1037] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(3-(2-(6-((5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-2-oxoethoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione

[1038] Prepared in accordance with the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.

[1039] Scheme for the synthesis of exemplary compound 195

[1040] 5-((14-((5-(4-Chloro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6 ,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1041] Step 1. 3-Bromo-5-chloropyridin-4-amine

[1042] To a solution of 3-chloropyridin-4-amine (10 g, 77.78 mmol) in acetonitrile (100 ml) was added N-bromosuccinimide (14.5 g, 81.67 mmol) at room temperature, and the resulting mixture was stirred at 60°C overnight under nitrogen atmosphere. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated to give a residue, which was purified by silica gel flash chromatography (eluting with 20 to 50% ethyl acetate in hexane) to give 3-bromo -5-chloropyridin-4-amine (8.8 g, 54% yield) as a white solid.

[1043] Step 2: 3-(4-Bromophenyl)-5-chloropyridin-4-amine

[1044] Stir a mixture of 3-bromo-5-chloropyridin-4-amine (5 g, 24.10 mmol), bis(pinacolato)diboron (12 g, 48320 mmol), potassium acetate (4.7 g, 48.20 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (3.5 g, 4.82 mmol) in dioxane (100 ml) at 90°C overnight under nitrogen. TLC indicated completion of the reaction. To this mixture solution was added 1,4-dibromobenzene (11.4 g, 48.20 mmol), potassium carbonate (6.7 g, 48.20 mmol) and water (30 ml). Tetrakis(triphenylphosphine)palladium (1.4 g, 1.21 mmol) was added and the mixture was stirred at 90° C. overnight under nitrogen. The reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (100 ml) and water (100 ml), the organic layer was washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue, which was purified using Flash chromatography on silica gel (eluting with 20 to 50% ethyl acetate in hexane) to give 3-(4-bromophenyl)-5-chloropyridin-4-amine (2.3 g, 34% yield) as a yellow solid.

[1045] Step 3: 4-Azido-3-(4-bromophenyl)-5-chloropyridine

[1046] To a solution of 3-(4-bromophenyl)-5-chloropyridin-4-amine (2.5 g, 8.8 mmol) in 2,2,2-trifluoroacetic acid (10 ml) was added sodium nitrite (1, 5 g, 22.0 mmol) at 0°C for 20 min. and the reaction mixture was stirred at 0°C for 1 hour. Sodium azide (1.43 g, 22.0 mmol) was added to the reaction mixture at 0°C; The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was adjusted to pH 8 with sodium carbonate and partitioned between ethyl acetate (30 mL) and water (50 mL). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 30% ethyl acetate in hexane) as 4-azido-3 -(4-bromophenyl)-5-chloropyridine (850 mg, 31% yield) as a yellow solid.

[1047] Stage 4.

[1048] Stir a mixture of 4-azido-3-(4-bromophenyl)-5-chloropyridine (850 mg, 2.75 mmol) in decalin (10 ml) in a sealed tube at 150°C for 10 hours. After cooling to room temperature, the reaction mixture was triturated with hexane (20 ml). The resulting solid was collected by filtration and dried under vacuum to give 7-bromo-4-chloro-5H-pyrido[4,3-b]indole (600 mg, 77% yield) as a yellow solid, which was directly used in the next step. stage without additional purification.

[1049] Convert 7-bromo-4-chloro-5H-pyrido[4,3-b]indole to the final compound, 5-((14-((5-(4-chloro-5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione, in accordance with the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.

[1050] Scheme for the synthesis of exemplary compound 197

[1051] 5-(6-((2,2-Difluoro-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7- yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)oxy)-2-azaspiro[3.3]heptan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[1052] Prepared in accordance with the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.

[1053] Scheme for the synthesis of exemplary compound 199

[1054] 3-((4-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butoxy)methyl)-N-methyl-N-(( 1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)bicyclo[1.1.1]pentan- 1-carboxamide

[1055] Prepared according to the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.

[1056] Scheme for the synthesis of exemplary compound 202

[1057] 2-((1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methoxy)-N-methyl-N-( 3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)acetamide

[1058] Prepared in accordance with the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.

[1059]

[1060] Synthesis scheme for exemplary compound 203

[1061] 2-((14-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy) -5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile

[1062] Prepared according to the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.

[1063] Scheme for the synthesis of exemplary compound 207

[1064] 5-((14-((5-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)pyridin-2-yl)oxy)-3,6,9,12 -tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1065] Step 1. (E)-1,1,1-Trichloro-4-ethoxy-but-3-en-2-one

[1066] Ethyl vinyl ether (25 g, 346.71 mmol, 33 mL, 2 equiv) was added dropwise to a solution of 2,2,2-trichloroacetyl chloride (31.52 g, 173.36 mmol, 19 mL, 1 eq. .) at 0°C. After addition, the mixture was stirred at this temperature for 5 hours and then the mixture was heated to 25°C for 16 hours. The mixture was stirred at 130°C under reduced pressure to allow the gas (hydrogen chloride) to evaporate to form a deep black solution. To implement the method, it was necessary to wait 1 hour or until gas was no longer released. The residue was concentrated under reduced pressure. The crude product was obtained as (E)-1,1,1-trichloro-4-ethoxy-but-3-en-2-one (39.3 g, crude) as a black oil.

[1067] Step 2: 2-(Trichloromethyl)pyrimido[1,2-a]benzimidazole

[1068] In a mixture of (E)-1,1,1-trichloro-4-ethoxybut-3-en-2-one (39.2 g, 180.25 mmol, 1.09 eq.) and 1H-benzimidazol- 2-amine (22 g, 165.23 mmol, 1 eq.) in toluene (500 ml) was added in one portion with triethylamine (20.06 g, 198.27 mmol, 27 ml, 1.2 eq.) at 25°C in a nitrogen atmosphere. The mixture was stirred at 120°C for 4 hours. The mixture was cooled to 25°C and concentrated under reduced pressure at 55°C. The crude product was obtained as 2-(trichloromethyl)pyrimido[1,2-a]benzimidazole (56.3 g, crude) as a brown solid.

[1069] Step 3. Pyrimido[1,2-a]benzimidazol-2-ol

[1070] To a mixture of 2-(trichloromethyl)pyrimido[1,2-a]benzimidazole (55.2 g, 192.64 mmol, 1 eq.) in acetonitrile (950 ml) was added sodium hydroxide (10.2 g) in one portion , 255.02 mmol, 1.32 eq.) in water (246 ml) at 20°C under nitrogen atmosphere. The mixture was stirred at 100°C for 2 hours. The mixture was cooled to 25°C and concentrated under reduced pressure at 55°C. Ice was added to the resulting residue and the pH of the solution was adjusted to 8 with hydrochloric acid (1 N, 130 ml). The solid was filtered and dried under high vacuum. The filter was cooled to 10° C., some precipitate was formed, the precipitate was collected by filtration and concentrated under reduced pressure to obtain a residue. Pyrimido[1,2-a]benzimidazol-2-ol (9.3 g, 50.22 mmol, 26% yield) was obtained as a yellow solid to give the crude product (ca. 7.3 g) .

[1071] Step 4. 2-Bromopyrimido[1,2-a]benzimidazole

[1072] A solution of pyrimido[1,2-a]benzimidazol-2-ol (0.5 g, 2.70 mmol, 1 eq.) in 1,1-dichloroethane (18 ml) and N,N-dimethylformamide ( 0.18 ml) was added in one portion of phosphoryl tribromide (1.55 g, 5.40 mmol, 2 eq.) at 20°C under nitrogen atmosphere. The mixture was stirred at 100°C for 6 hours. The mixture was cooled to 25°C and concentrated under reduced pressure at 45°C. The residue was poured into ice water (w/w = 1/1, 30 ml) and stirred for 10 min. The aqueous phase was adjusted to pH=8 using saturated aqueous sodium bicarbonate solution. During this period some sediment formed. The precipitate was collected by filtration and dried under high vacuum. The crude product was obtained as 2-bromopyrimido[1,2-a]benzimidazole (0.65 g, crude) as a yellow solid.

[1073] Convert 2-bromopyrimido[1,2-a]benzimidazole to the final compound, 5-((14-((5-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl) pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, in accordance with the scheme below and with using the procedures described above and conventional procedures known to those skilled in the art.

[1074] Scheme for the synthesis of exemplary compound 208

[1075] 2-(2,6-Dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((1-(5-(5-methyl-5H-pyrido[4,3 -b]indol-7-yl)pyridin-2-yl)azetidin-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione

[1076] Prepared according to the schedule below and using the procedures described above and conventional procedures known to those skilled in the art.

[1077] Scheme for the synthesis of exemplary compound 209

[1078] 2-(2,6-Dioxopiperidin-3-yl)-5-(2-(2-((3-(((1r,3r)-3-((5-(5-methyl-5H- pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)ethoxy)ethoxy)isoindoline-1,3- dione

[1079] Prepared according to the schedule below and using the procedures described above and conventional procedures known to those skilled in the art.

[1080] Synthesis scheme for exemplary compound 210

[1081] 2-(2,6-Dioxopiperidin-3-yl)-5-((15-(4-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperazin-1 -yl)-3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione

[1082] Step 1. tert-Butyl 4-(5-methylpyrido[4,3-b]indol-7-yl)piperazine-1-carboxylate

[1083] In a solution of 7-bromo-5-methylpyrido[4,3-b]indole (1 g, 3.83 mmol, 1 eq.) and tert-butylpiperazine-1-carboxylate (2.14 g, 11.49 mmol, 3 eq.) in dioxane (20 ml) was added (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (71 mg, 0.11 mmol, 0.03 eq.), carbonate cesium (3.74 g, 11.49 mmol, 3 eq.) and palladium(II) acetate (86 mg, 0.38 mmol, 0.1 eq.) under nitrogen, then degassed under vacuum and purged with nitrogen three times . The mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated to remove the solvent and then extracted with ethyl acetate (80 ml x 3). The combined organic layers were washed with 30 ml brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1 to dichloromethane/methanol = 10/1) to give the crude product, the crude product was purified by semipreparative reverse phase HPLC (column: Phenomenex luna C18 250 *50 mm*10 µm; mobile phase: [water (0.225%FA) - ACN]; B%: 27% to 52%, 30; 79% min.). tert-Butyl 4-(5-methylpyrido[4,3-b]indol-7-yl)piperazine-1-carboxylate (700 mg, 1.91 mmol, 49% yield) was obtained as a white solid.

[1084] Step 2: 5-Methyl-7-piperazin-1-ylpyrido[4,3-b]indole

[1085] A solution of tert-butyl-4-(5-methylpyrido[4,3-b]indol-7-yl)piperazine-1-carboxylate (700 mg, 1.91 mmol, 1 eq.) in dichloromethane (4 ml) a mixture of hydrochloric acid/dioxane (4 M, 8 ml, 16.75 eq.) was added, then stirred at 25°C for 1 hour. TLC (dichloromethane/methanol = 10/1) showed that the starting material was completely used up. The reaction mixture was concentrated to obtain a residue. 5-Methyl-7-piperazin-1-ylpyrido[4,3-b]indole (580 mg, crude, HCl) was obtained as a white solid without any purification.

[1086] Stage 3.

[1087] In a solution of 5-methyl-7-piperazin-1-ylpyrido[4,3-b]indole (366 mg, 1.21 mmol, 1 eq., HCl) and dimethyl-4-[2-[2- [2-[2-[3-(p-tolylsulfonyloxy)propoxy]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate (725 mg, 1.21 mmol, 1 eq.) [prepared according to the scheme below and using the procedures described above and conventional procedures known to those skilled in the art] to N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (626 mg, 4.84 mmol, 0.8 mL, 4 eq. .), then stirred at 80°C for 16 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified using semipreparative reverse phase HPLC (column: Phenomenex luna C18 250 * 50 mm * 10 μm; mobile phase: [water (0.225% FA) - ACN]; V%: 10% to 40%, 30 min. , 40% min.). Dimethyl-4-[2-[2-[2-[2-[3-[4-(5-methylpyrido[4,3-b]indol-7-yl)piperazin-1-yl]propoxy]ethoxy] was obtained ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate (131 mg, 0.19 mmol, 15% yield, 100% purity) as a brown oil.

[1088] Step 4: 2-(2,6-Dioxopiperidin-3-yl)-5-((15-(4-(5-methyl-5H-pyrido[4,3-b]indol-7-yl) piperazin-1-yl)-3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione

[1089] Placed dimethyl-4-[2-[2-[2-[2-[3-[4-(5-methylpyrido[4,3-b]indol-7-yl)piperazin-1-yl]propoxy ]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate (120 mg, 0.17 mmol, 1 eq.), 3-aminopiperidine-2,6-dione (142 mg, 0.86 mmol, 5 eq. ., HCl) and lithium iodide (347 mg, 2.60 mmol, 15 eq.) into a microwaving tube into pyridine (4 mL). The hermetically sealed tube was heated at 120°C for 2 hours using microwave radiation. The reaction mixture was concentrated to obtain a residue. The residue was purified by semipreparative reverse phase HPLC (8 to 38% acetonitrile + 0.225% formic acid in water, 10 min), then the collected fraction was concentrated to remove most of the acetonitrile and then lyophilized to give the crude product. The crude product was then purified by preparative TLC (dichloromethane/methanol = 10/1), 10 ml of water and 0.2 ml of 1 M hydrochloric acid were added and then lyophilized to obtain the product. 2-(2,6-dioxopiperidin-3-yl)-5-((15-(4-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperazin-1-yl) was obtained )-3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione dihydrochloride (20 mg, 0.02 mmol, 14% yield) as an off-white solid.

[1090] ^1H NMR: (400 MHz, DMSO-d6) δ: 15.03 (br s, 1H), 11.18-10.95 (m, 2H), 9.55 (s, 1H), 8 .64 (br d, J=6.5 Hz, 1H), 8.30 (br d, J=8.3 Hz, 1H), 8.09 (br d, J=6.9 Hz, 1H), 7.81 (br d, J=8.5 Hz, 1H), 7.48-7.23 (m, 4H), 5.11 (br dd, J=5.0, 12.7 Hz, 1H) , 4.30 (br s, 2H), 4.11 (br d, J=13.1 Hz, 2H), 4.02 (s, 3H), 3.78 (br s, 2H), 3.70 -3.48 (m, 18H), 3.19 (br s, 3H), 2.96-2.82 (m, 1H), 2.62-2.55 (m, 3H), 2.04 ( br s, 3H). (M+H) ⁺ 757.6.

[1091] Scheme for the synthesis of exemplary compound 211

[1092] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(3-(2-(6-((5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)ethoxy)propoxy)azetidin-1-yl)isoindolin-1,3-dione

[1093] Prepared in accordance with the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.

[1094] Scheme for the synthesis of exemplary compound 212

[1095] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(2-((4-((1r,3r)-3-((5-(5-methyl-5H-pyrido [4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)but-2-in-1-yl)oxy)ethoxy)azetidin-1-yl)isoindolin-1,3-dione

[1096] Step 1. tert-Butyl 3-(2-ethoxy-2-oxoethoxy)azetidine-1-carboxylate

[1097] A mixture of tert-butyl-3-hydroxyazetidine-1-carboxylate (3 g, 17.32 mmol, 1 eq.) and diacetoxyrhodium (766 mg, 1.73 mmol, 0.1 eq.) in dichloromethane (50 ml) ethyl 2-diazoacetate (11.86 g, 103.92 mmol, 6 eq.) was added dropwise at 0°C. The reaction mixture was then stirred at 25°C for 4 hours. TLC showed that the starting material had not been consumed. The reaction mixture was then stirred at 25°C for another 16 hours. Acetic acid was added to the reaction solution. The reaction mixture was then extracted with dichloromethane (30 ml x 3) and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30/1 to 8:1) to give the product. tert-Butyl 3-(2-ethoxy-2-oxoethoxy)azetidine-1-carboxylate (2.24 g, 8.64 mmol, 50% yield) was obtained as a light yellow oil.

[1098] Step 2. tert-Butyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate

[1099] To a suspension of lithium aluminum hydride (229.51 mg, 6.05 mmol, 0.7 g) in tetrahydrofuran (30 ml) was added a solution of tert-butyl-3-(2-ethoxy-2-oxoethoxy)azetidine-1 -carboxylate (2.24 g, 8.64 mmol, 1 eq.) in tetrahydrofuran (10 ml) at -20°C. The reaction mixture was stirred at 0°C for 0.5 hours. Water (20 ml) was added to the reaction solution, and the organic layer was extracted with ethyl acetate (40 ml × 3). The combined organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 200/1 to 1:1) to give the product. Tert-butyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate (828 mg, 3.81 mmol, 44% yield) was obtained as a light yellow oil.

[1100] Step 3: 4-[(4-Methoxyphenyl)methoxy]but-2-yn-1-ol

[1101] To a solution of but-2-yne-1,4-diol (5 g, 58.08 mmol, 1 eq.) in N,N-dimethylformamide (50 ml) was added sodium hydride (2.32 g, 58. 08 mmol, 60% in mineral oil, 1 eq.) at 0°C. The mixture was stirred at 0°C for 0.5 hour. Methoxybenzyl chloride (9.55 g, 60.98 mmol, 8.3 mL, 1.05 eq.) was then slowly added to the mixture at 0° C., and the mixture was stirred at 25° C. for 4 hours. Water (40 ml) was added to the reaction mixture. The solution was extracted with ethyl acetate (40 ml x 3). The combined organic phase was then washed with brine (20 ml x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to leave a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30/1 to 3:1) to give the product. 4-[(4-methoxyphenyl)methoxy]but-2-yn-1-ol (2.64 g, 12.80 mmol, 22% yield) was obtained as a light yellow oil.

[1102] Step 4: 1-(4-Bromobut-2-inoxymethyl)-4-methoxybenzene

[1103] In a solution of 4-[(4-methoxyphenyl)methoxy]but-2-yn-1-ol (1 g, 4.85 mmol, 1 eq.) and perbromomethane (1.61 g, 4.85 mmol, 1 eq.) in dichloromethane (10 ml) was added triphenylphosphine (1.40 g, 5.33 mmol, 1.1 eq.) at 0°C. The solution was stirred at 25°C for 16 hours. TLC showed that the starting material was completely consumed. The reaction solution was concentrated under vacuum to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 80:1) to give the product. 1-(4-bromobut-2-inoxymethyl)-4-methoxybenzene (1 g, 3.72 mmol, 77% yield) was obtained as a light yellow oil.

[1104] The final compound was obtained, 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((4-((1r,3r)-3-((5-(5-methyl -5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)but-2-in-1-yl)oxy)ethoxy)azetidin-1-yl)isoindolin-1 ,3-dione, in accordance with the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.

[1105] Synthesis scheme for exemplary compound 213

[1106] 2-(2,6-Dioxopiperidin-3-yl)-5-(6-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[ 4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)-2-azaspiro[3.3]heptan-2-yl)isoindolin-1,3-dione

[1107] Prepared in accordance with the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.

[1108] Additional examples are contemplated in the context of the present invention and are described in detail below. They can be prepared as described in the accompanying diagrams, or by applying procedures similar to those described above (as indicated).

[1109] Scheme for the synthesis of compounds 215 and 217

[1110] Can be prepared in accordance with the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.

[1111] Alternatively, one skilled in the art will appreciate that a different sequence of steps and/or different protecting groups can be used in assembling the linkers from the examples described below. In addition, a different sequence of linker assembly to PTM and ULM may be used for different examples, and sometimes a different sequence of linker assembly and PTM/ULM attachment may be used interchangeably for a given example (i.e., PTM attachment first, ULM second, or ULM attachment first). , then RTM). For example, the linker for compound 216 can be assembled as shown in the diagram below.

[1112] Compound 216 can then be synthesized according to the scheme below.

[1113] Alternatively, compound 216 can be synthesized using different PTM and ULM addition sequences according to the scheme below.

[1114] Scheme for the synthesis of exemplary compound 4

[1115] 4-((14-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)amino )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1116] Prepared according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[1117] ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.30 (s, 1H), 8.90 (br, 1H), 8.52 (d, J=5.6 Hz, 1H), 8 .42 (d, J=2.8 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.49 (dd, J=2.4, 8.8 Hz, 1H) , 7.57 (s, 1H), 7.26-7.46 (m, 3H), 6.97 (d, J=7.2 Hz, 1H), 6.81-6.87 (m, 2H ), 6.35-6.46 (m, 1H), 4.89-4.98 (m, 1H), 4.54 (t, J=4.8 Hz, 2H), 3.90 (t, J=4.8 Hz, 2H), 3.61-3.74 (m, 15H), 3.37-3.81 (m, 2H), 2.65-2.92 (m, 3H), 2 .07-2.15 (m, 1H).

[1118] Using the procedures described for compound 4, the following compounds were prepared: compound 2, compound 3 and compound 48.

[1119] Scheme for the synthesis of exemplary compound 7

[1120] (2S,4R)-1-((S)-14-(4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2 -(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1121] Prepared according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[1122] ¹ H NMR(400 MHz, MeOD): δ 8.85 (s, 1H) 8.71 (d, J=7.6 Hz, 1H), 7.70 (d, J=8.0 Hz , 1H), 7.55 (d, J=8.0 Hz, 1H), 7.34-7.42 (m, 5H), 7.22-7.23 (m, 1H), 6.76 ( d, J=7.6 Hz, 1H), 4.68 (s, 1H), 4.47-4.57 (m, 4H), 4.30-4.39 (m, 1H), 4.05 (s, 3H), 3.56-4.87 (m, 23H), 2.64 (s, 4H), 2.45 (s, 3H), 2.19 (br, 1H), 2.04 ( br, 1H,), 1.03 (s, 9H).

[1123] Using the procedures described for compound 7, the following compounds were prepared: compound 11, compound 12, compound 15, compound 16, compound 19, compound 20, compound 23, compound 25, compound 26.

[1124] Scheme for the synthesis of exemplary compound 10

[1125] (2S,4R)-1-((8)-14-(4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2 -(tert-butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl )phenyl)ethyl)pyrrolidine-2-carboxamide

[1126] Prepared according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[1127] ¹ H NMR (400 MHz, MeOD): δ 8.85 (s, 1H), 8.78 (d, J=7.6 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.35-7.40 (m, 6H), 7.23 (t, J=8.0 Hz, 1H), 4.98-5.00 (m, 1H), 4.67 (s, 1H), 4.55-4.57 (m, 1H), 4.34-4.43 (m, 3H), 3, 83-4.03 (m, 7H), 3.72-3.74 (m, 16H), 2.46 (s, 3H), 2.17-2.21 (m, 1H), 1.95- 2.10 (m, 1H), 1.31 (d, J=8.8 Hz, 3H), 1.03 (s, 9H).

[1128] Additional compounds were prepared using the procedures described for compound 10: 13, 14, 17, 18, 21, 22, 24, 41, 42.

[1129] Scheme for the synthesis of exemplary compound 43

[1130] (2S,4R)-1-((2S)-2-(tert-Butyl)-15-((2-(4-(dimethylamino)phenyl)quinolin-6-yl)oxy)-14-hydroxy -4-oxo-6,9,12-trioxa-3-azapentadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide

[1131] Prepared according to the schemes below using the procedures described above and conventional procedures known to those skilled in the art.

[1132] ¹ H NMR (400 MHz, CD ₃ OD): δ 1.04 (s, 9H), 2.05-2.13 (m, 1H), 2.21-2.23 (m, 1H) , 2.46 (s, 3H), 3.05 (s, 6H), 3.65-3.74 (m, 10H), 3.79-3.90 (m, 2H), 3.98-4 .07 (m, 2H), 4.13-4.22 (m, 3H), 4.33-4.37 (m, 1H), 4.50-4.62 (m, 3H), 4.70 (s, 1H), 6.89 (d, J=8.8 Hz, 2H), 7.25-7.26 (m, 1H), 7.38-7.44 (m, 5H), 7, 83 (d, J=8.8 Hz, 1H), 7.94-7.97 (m, 3H), 8.17 (d, J=8.8 Hz, 1H), 8.85 (s, 1H ).

[1133] Using the procedures described for compound 43, the following compounds were prepared: compound 45, compound 46, compound 47.

[1134] Scheme for the synthesis of exemplary compound 8

[1135] (2S,4R)-1-((S)-2-(tert-Butyl)-15-((2-(4-(dimethylamino)phenyl)quinolin-6-yl)oxy)-4-oxo -6,9,12-trioxa-3-azapentadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1136] Prepared according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[1137] ¹ H NMR (400 MHz, CD ₃ OD): δ 1.01, 1.03 (two singlets, 9H), 2.07-2.25 (m, 4H), 2.45, 2.47 (two singlets, 3H), 3.04 (s, 6H), 3.65-3.71 (m, 10H), 3.78-3.86 (m, 2H), 4.01-4.06 ( m, 2H), 4.18-4.21 (m, 2H), 4.32-4.36 (m, 1H), 4.50-4.60 (m, 3H), 4.68-4, 70 (m, 1H), 6.88 (d, J=9.2 Hz, 2H), 7.23-7.26 (m, 1H), 7.34-7.44 (m, 5H), 7 .82 (d, J=8.4 Hz, 1H), 7.92-7.96 (m, 3H), 8.16 (d, J=8.8 Hz, 1H), 8.85, 8, 86 (two singlets, 1H).

[1138] Using the procedures described for compound 8, the following compounds were prepared: compound 9, compound 27, compound 28, compound 29, compound 30, compound 31, compound 32, compound 33, compound 34, compound 35, compound 36, compound 37, connection 38, connection 39, connection 40, connection 44.

[1139] Synthesis scheme for exemplary compound 49

[1140] 3-(4-((14-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12- tetraoxatetradecyl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione

[1141] Prepared according to the scheme below using the procedures described above and conventional procedures known to those skilled in the art.

[1142] ¹ H NMR (400 MHz, CD ₃ OD): δ 9.36 (s, 1H), 8.39-8.45 (m, 3H), 8.30 (d, J=8.0 Hz , 1H), 8.01 (dd, J=2.4, 6.4 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J=6.0 Hz, 1H), 7 .59 (d, J=8.4 Hz, 1H), 7.26 (t, J=1.6 Hz, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 5.12 (dd, J=5.2, 13.6 Hz, 1H), 4 .47 (t, J=4.4 Hz, 2H), 4.27 (d, J=2.4 Hz, 2H), 3.85 (d, J=4.4 Hz, 2H), 3.62 -3.68 (m, 14H), 3.36 (t, J=5.6 Hz, 2H), 2.75-2.95 (m, 2H), 2.35-2.47 (m, 1H ), 2.10-2.21 (m, 1H).

[1143] Compound 218 can be prepared using procedures similar to those for compound 195.

[1144] Compound 219 can be prepared using procedures similar to those for compounds 73/180/112.

[1145] Compound 220 can be prepared using procedures similar to those for compounds 73/173.

[1146] Compound 221 can be prepared using procedures similar to those for compounds 111/127.

[1147] Compound 222 can be prepared using procedures similar to those for compounds 141/180.

[1148] Compound 223 can be prepared using procedures similar to those for compounds 102/180.

[1149] Compounds 224 and 225 can be prepared in accordance with the schemes below.

[1150] Using the approaches described above (including the general approaches for compounds 73, 173 and 180), compounds 226-234 can be prepared in a similar manner using conventional procedures known to those skilled in the art.

[1151] Additionally, by combining such approaches with the procedures described above for compounds 138, 139, 140 and 203, compounds 235-240 can be prepared.

[1152] Compounds 241-247 can be prepared by using procedures similar to those for compounds 82/198 and 180.

[1153] Compounds 248-251 can be prepared starting from compound 82, followed by additional processing of the linker in a manner similar to the approaches described above and known to those skilled in the art.

[1154] Compounds 252-256 can be prepared based on the approaches for compounds 104, 99 and 198 and combinations thereof.

[1155] Additional examples, compounds 257-330, can be prepared based on the fundamental PTM, ULM and linker approaches described above and combined with applicable functional and protecting group treatments known to those skilled in the art.

[1156] Exemplary PROTACs of the present invention can be prepared from embodiments of the PTMs of the present invention using previously described methods for attaching a linker and an E3 ligase binding moiety.

[1157] Exemplary PROTACs of the present invention are represented by the structures in Tables 1 and 2, while data associated with the exemplary PROTACs is shown in Tables 2 and 3.

*Each compound was tested at 300 nM, 100 nM, 33 nM and 11 nM as described in paragraph [1162]. The highest degree of degradation observed at any dose for each compound is presented in Table 2 as follows. A: ≤50% tau remains after 72 hours of incubation with test compound; B: ≤80% and >50% tau remains after 72 hours of incubation with test compound; C: >80% tau remains after 72 hours of incubation with test compound.

In Vitro Tau Degradation Assay

[1159] To determine the effect of PROTAC on tau protein degradation, SK-N-SH cells were seeded in a 24-well tissue culture plate for at least 18 hours before adding compounds. Tau-targeting PROTACs were assessed for tau degradation by lysing cells in protease inhibitor lysis buffer followed by 72-hour incubation with tau-targeting PROTACs at concentrations of 1000 nM, 300 nM, and 100 nM for compounds from Table 1 and 300 nM, 100 nM, 33 nM and 11 nM for compounds from Table 2. Cell lysates were analyzed on standard SDS-PAGE gels and tau protein levels were determined by Western blotting with using the anti-tau 13 antibody from Abcam (Cambridge, UK), which binds to all forms of human tau. The highest degree of destruction observed at any dose of each compound is shown in Tables 1 and 2 above.

Degradation of tau protein in vivo

[1160] In the study, 21 male wild-type BI6 mice, divided into seven groups of three mice, were treated once with a bilateral intrahippocampal injection of ECP-1 vehicle medium ([5% EtOH and 5% Cremophore RH40 in phosphate buffer pH 7.4 ]; group A; see figure 1) or compound 4, PROTAC, targeting tau protein ([3 μl of 1 mg/ml solution in ECP-1]; groups B-G; see figure 1). All animals were sacrificed at specified time points after injection of test agent or vehicle, as shown in Figure 1, and brain samples were collected. The hippocampus was dissected and total tau protein levels were measured using the Meso Scale Discovery Assay Kit. The results are presented in Figure 1.

Specific Embodiments

[1161] An aspect of the present invention provides a bifunctional compound having the chemical structure:

ULM-L-RTM,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,

Where

ULM is a small molecule E3 ubiquitin ligase binding fragment that binds E3 ubiquitin ligase;

PTM is a fragment that targets tau protein; And

L represents the bond or chemical linker moiety connecting the ULM and PTM.

[1162] In any aspect or embodiment described herein, the E3 ubiquitin ligase binding moiety that targets the E3 ubiquitin ligase is selected from the group consisting of Vippel-Lindau protein targeting (VLM) and cereblon (CLM).

[1163] In any aspect or embodiment described herein, the PTM is represented by formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XI:

Where

A, B, C, D, E and F are independently selected from optionally substituted 5- or 6-membered aryl or heteroaryl ring, optionally substituted 4-7 membered cycloalkyl or heterocycloalkyl, wherein contact between the rings indicates ring condensation; And

L _PTM is selected from a bond, alkyl, alkenyl or alkynyl, optionally interrupted by one or more rings (i.e. cycloalkyl, heterocycloalkyl, aryl or heteroaryl) or one or more functional groups selected from the groups -O-, -S-, - NR ¹ _PTM - (where R ¹ _PTM is selected from H or alkyl), -N=N-, -S(O)-, -SO ₂ -, -C(O)-, -NHC(O)-, -C (O)NH-, -NHSO ₂ -, -NHC(O)NH-, -NHC(O)O- or -OC(O)NH-, wherein said functional group is optionally located at either end of the linker.

[1164] In any aspect or embodiment described herein, at least one of A, B, C, F, or combinations thereof is selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings.

[1165] In any aspect or embodiment described herein, the rings (e.g., aryl and heteroaryl rings) A, B, C, D, and E in PTM are optionally substituted with 1 to 8 substituents, each independently selected from alkyl, alkenyl, alkyl halo, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl and cyano, wherein said alkyl and alkenyl groups are further optionally substituted.

[1166] In any aspect or embodiment described herein, the PTM is represented by Formula I, and

rings A, B and C are independently 5- or 6-membered fused aryl or heteroaryl rings;

L _PTM is selected from a bond or alkyl; And

D is selected from 6-membered aryl, heteroaryl or heterocycloalkyl,

wherein A, B, C and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl or cyano.

[1167] In any aspect or embodiment described herein, the PTM is represented by Formula I, and

A and C represent a phenyl or 6-membered heteroaryl ring;

B is a 5-membered heteroaryl ring;

L _PTM represents the link; And

D represents a 6-membered heteroaryl or 6-membered heterocycloalkyl ring,

wherein each of A, B, C and D is optionally independently substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, trifluoromethyl or cyano, and wherein a nitrogen atom in any of rings A, B, C and D is not directly connected to a heteroatom or a carbon atom to which another heteroatom is directly attached.

[1168] In any aspect or embodiment described herein, the PTM is represented by formula III or IV, and

A, B and C are 5- or 6-membered fused aryl or heteroaryl rings;

L _PTM is selected from a bond or alkyl; And

D and E are 5- or 6-membered fused aryl or heteroaryl rings;

wherein A, B, C, D and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl or cyano.

[1169] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

Where

R ¹ , R ² and R ³ are independently selected from H, methyl, ethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl;

R ⁴ and R ⁵ are independently selected from H, methyl, ethyl and halogen; And

R ⁶ represents 1-2 substituents independently selected from H, methyl, ethyl and halogen.

[1170] In any aspect or embodiment described herein, the PTM is a chemical structure selected from the group consisting of:

Where

R ¹ , R ² and R ³ are independently selected from H, optionally substituted alkyl, methyl, ethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl; And

R ⁷ , R ⁸ , R ⁹ and R ¹⁰ represent 1-8 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino, trifluoromethyl or cyano.

[1171] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[1172] In any aspect or embodiment described herein, the ULM is a Vippel-Lindau (VHL) ligase complex (VLM) binding moiety, which is represented by the structure:

Where

each of X ¹ , X ² is independently selected from the group consisting of bond, O, NR ^Y3 , CR ^Y3 R ^Y4 , C=O, C=S, SO and SO ₂ ;

each of R ^Y3 , R ^Y4 is independently selected from the group consisting of H, straight or branched C _1-6 alkyl, optionally substituted with 1 or more halogen atoms, C _1-6 alkoxy);

R ^P represents 1, 2 or 3 groups, each independently selected from the group consisting of H, halogen, -OH, C _1-3 alkyl;

W ³ is selected from the group consisting of optionally substituted -TN(R ^1a R ^1b ), optionally substituted -TN(R ^1a R ^1b )X ³ , T-aryl, optionally substituted T-heteroaryl, optionally substituted -T-heterocycle, optional substituted -NR ¹ -T-aryl, optionally substituted -NR ¹ -T-heteroaryl or optionally substituted -NR ¹ -T-heterocycle;

X ³ represents C=O, R ¹ , R ^1a , R ^1b ;

each of R ¹ , R ^1a , R ^1b is independently selected from the group consisting of an H, straight or branched C ₁ -C ₆ alkyl group, optionally substituted with 1 or more halogen atoms or -OH groups, R ^Y3 C=O, R ^Y3 C=S, R ^Y3 SO, R ^Y3 SO ₂ , N(R ^Y3 R ^Y4 )C=O, N(R ^Y3 R ^Y4 )C=S, N(R ^Y3 R ^Y4 )SO and N(R ^Y3 R ^Y4 )SO ₂ ;

T is selected from the group consisting of an optionally substituted alkyl, the -(CH ₂ ) _n - group, wherein each of the methylene groups is optionally substituted with one or two substituents selected from the group consisting of halogen, methyl, linear or branched C ₁ -C ₆ an alkyl group optionally substituted with 1 or more halogen atoms or -OH groups, or an optionally substituted amino acid side chain;

n equals 0-6;

W ⁴ represents or

each of R _14a , R _14b is independently selected from the group consisting of H, haloalkyl or optionally substituted alkyl;

W ⁵ is selected from the group consisting of phenyl or 5-10 membered heteroaryl; And

R ₁₅ is selected from the group consisting of H, halogen, CN, OH, NO ₂ , NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a COR _14b , SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl or cycloheteroalkyl,

wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to the ULM.

[1173] In any aspect or embodiment described herein, the ULM is a Vippel-Lindau (VHL) ligase complex (VLM) binding moiety, which is represented by the structure:

Where

W ³ is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, or

R ₉ and R ₁₀ independently represent hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, 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 selected from the group consisting of optionally substituted heterocyclic group, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

R ₁₂ is selected from the group consisting of H or optionally substituted alkyl;

R ₁₃ is selected from the group consisting of 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;

each of R _14a , R _14b is independently selected from the group consisting of H, haloalkyl or optionally substituted alkyl;

W ⁵ is selected from the group consisting of phenyl or 5-10 membered heteroaryl;

R ₁₅ is selected from the group consisting of H, halogen, CN, OH, NO ₂ , NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a COR _14b , SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl or cycloheteroalkyl (each independently optionally substituted);

R ₁₆ is independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy or optionally substituted haloalkoxy;

o equals 0, 1, 2, 3 or 4;

R ₁₈ is independently selected from the group consisting of halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker; And

p is 0, 1, 2, 3 or 4, and where the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety binding at least one PTM or ULM', or both of them, to ULM.

[1174] In any aspect or embodiment described herein, the ULM provides a chemical structure selected from the group:

Where

R ₁ is H, ethyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl;

R _14a represents H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

R ₁₅ is selected from the group consisting of H, halogen, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl or cycloheteroalkyl;

X represents C, CH ₂ or C=O; And

R ₃ represents a bond or optionally substituted 5- or 6-membered heteroaryl,

wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to the ULM.

[1175] In any aspect or embodiment described herein, the ULM provides a group in accordance with the chemical structure:

Where

R _14a represents H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

R ₉ represents H;

R ₁₀ is H, ethyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R ₁₁ represents

or optionally substituted heteroaryl;

p equals 0, 1, 2, 3 or 4;

each R ₁₈ independently represents halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker;

R ₁₂ represents H, C=O;

R ₁₃ represents 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; And

R ₁₅ is selected from the group consisting of H, halogen, Cl, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl;

wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to the ULM.

[1176] In any aspect or embodiment described herein, the ULM provides a group selected from the structure consisting of:

wherein the phenyl ring in ULM-a1 - ULM-a15, ULM-b1 - ULM-b12, ULM-c1 - ULM-c15 and ULM-d1 - ULM-d9 is optionally substituted with fluorine, lower alkyl and alkoxy groups, and wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM-a.

[1177] In any aspect or embodiment described herein, the ULM is a moiety that binds to the cereblon ligase complex (CLM), which is thalidomide, lenalidomide, pomalidomide, analogs, isosteres, or derivatives thereof.

[1178] In any aspect or embodiment described herein, CLM has the chemical structure represented by:

Where

W is selected from the group consisting of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

each X is independently selected from the group consisting of O, S and H ₂ ;

Y is selected from the group consisting of CH ₂ , -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Z is selected from the group consisting of O, S and H ₂ ;

G and G' are independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted with R'), OH, R'OCOOR, R'OCONRR'', CH ₂ -heterocyclyl, optionally substituted with R', and benzyl, optionally substituted R';

Q ₁ , Q ₂ , Q ₃ and Q ₄ represent a C carbon atom substituted by a group independently selected from R', N or N-oxide;

A is independently selected from a group; consisting of H, alkyl, cycloalkyl, Cl and F;

R provides -CONR'R'', -OR', -NR'R'', -SR', -SO ₂ R', -SO ₂ NR'R'', -CR'R''-, -CR'NR'R''-, -aryl, -heteroaryl, -alkyl (linear, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -P(O)(OR')R'', -P(O)R'R'',-OP(O)(OR')R'',-OP(O)R'R'', -Cl, -F, -Br, -I, -CF ₃ , -CN, -NR' SO ₂ NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'',-NR'C(=N-CN)R'',-NR'C(=C-NO ₂ )NR'R'', -SO ₂ NR'COR'', -NO ₂ , -CO ₂ R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'' , -SF ₅ or -OCF ₃ ;

R' and R'' are independently selected from the group consisting of a bond, H, N, N-oxide, alkyl (straight, branched), cycloalkyl, aryl, heteroaryl, heterocyclic group, -C(=O)R or heterocyclyl, each of which is optionally substituted;

is a bond that may or may not provide a stereospecific configuration ((R) or (S)); And

_Rn provides a functional group or atom,

where n is an integer from 1 to 4, and where

if n is 1, then R _n is modified to covalently bind to the linker group (L), and

if n is 2, 3 or 4, then one R _n is modified to covalently bind to a linker group (L), and any other R _n is optionally modified to covalently bind to a PTM, a CLM, a second CLM having the same chemical a structure such as CLM, CLM', a second linker, or any plurality or combination thereof.

[1179] In any aspect or embodiment described herein, CLM has the chemical structure represented by:

Where

W is independently selected from the group consisting of CH2, C=O, NH and N-alkyl;

R is independently selected from H, methyl, alkyl;

is a bond that may or may not provide a stereospecific configuration ((R) or (S)); And

Rn provides 1 to 4 independently selected functional groups or atoms, and optionally one of them is modified to covalently bind to a PTM, a chemical linker group (L), a CLM (or CLM'), or a combination thereof.

[1180] In any aspect or embodiment described herein, CLM has the chemical structure represented by:

where the dotted lines indicate the linker attachment points.

[1181] In any aspect or embodiment described herein, the linker (L) provides a chemical entity represented by the formula:

Where

A represents a group that is connected to a ULM or PTM moiety; And

q represents an integer that is greater than or equal to 1,

where A is selected from the group consisting of communication, 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 , OS, 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 groups ^RL1 and/or ^RL2 , C _3-11 heterocyclyl, optionally substituted with 0-6 groups ^RL1 and/or ^RL2 , aryl, optionally substituted with 0-6 groups ^RL1 and/or ^RL2 , heteroaryl, optionally substituted with 0-6 groups ^RL1 and/or ^RL2 , where each of ^RL1 or ^RL2 is independently optionally combined with other groups to form a cycloalkyl and/or heterocyclyl fragment, optionally substituted with 0-4 R ^L5 groups;

R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are each independently H, halogen, 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, OS _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 , NHSO ₂ NH(C _1-8 alkyl), NHSO ₂ N(C _1-8 alkyl) ₂ , NHSO ₂ NH ₂ .

[1182] In any aspect or embodiment described herein, the linker (L) includes a group represented by a general structure selected from the group consisting of:

-N(R)-(CH2) _m -O(CH2) _n -O(CH ₂ ) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-,

-O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-,

-O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-;

where each of m, n, o, p, q and r is independently equal to 0, 1, 2, 3, 4, 5, 6, provided that if the number is zero, then there is no NO or O-O bond; R is selected from the group consisting of H, methyl or ethyl, and X is selected from the group consisting of H or F;

[1183] In any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

[1184] In any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

where each of n and m is independently equal to 0, 1, 2, 3, 4, 5 or 6.

[1185] In any aspect or embodiment described herein, L provides the following chemical structure:

W ^L1 and W ^L2 are each independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with RQ, wherein each RQ is independently H, halogen, OH, CN, CF3, C1-C6 alkyl (linear , branched, optionally substituted), C1-C6 alkoxy (linear, branched, optionally substituted), or 2 RQ groups, taken together with the atom to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms ;

each Y ^L1 independently represents a bond, C1-C6 alkyl (linear, branched, optionally substituted), and optionally one or more C atoms are replaced by O; or C1-C6 alkoxy (linear, branched, optionally substituted); And

the dotted line indicates the point of attachment to the PTM or ULM fragments.

[1186] In any aspect or embodiment described herein, L provides the following chemical structure:

Where

each of W ^L1 and W ^L2 is independently aryl, heteroaryl, cyclic group, heterocyclic group, C _1-6 alkyl, bicyclic group, biaryl, biheteroaryl or biheterocyclic group, each optionally substituted with R ^Q , with each R ^Q independently represents H, halogen, OH, CN, CF ₃ , hydroxyl, nitro, C≡CH, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ -C ₆ alkyl (linear, branched, optionally substituted), C ₁ -C ₆ alkoxy (linear, branched, optionally substituted), OC _1-3 alkyl (optionally substituted with 1 or more -F), OH, NH ₂ , NR ^Y1 R ^Y2 , CN, or 2 R ^Q groups taken together with an atom , to which they are attached, form a 4-8-membered ring system containing 0-4 heteroatoms;

each Y ^L1 independently represents a bond, NR ^YL1 , O, S, NR ^YL2 , CR ^YL1 R ^YL2 , C=O, C=S, SO, SO ₂ , C ₁ -C ₆ alkyl (linear, branched, optionally substituted) , and optionally one or more C atoms are replaced by O; C ₁ -C ₆ alkoxy (linear, branched, optionally substituted);

^QL is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally containing a bridged bond, optionally substituted with 0-6 ^RQ , each ^RQ independently representing H, C _1-6 alkyl (linear, branched , optionally substituted with 1 or more halogen atoms, C _1-6 alkoxy), or 2 R ^Q groups, taken together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms);

each of R ^YL1 , R ^YL2 independently represents H, OH, C _1-6 alkyl (linear, branched, optionally substituted with 1 or more halogen atoms, C _1-6 alkoxyl), or R ¹ , R ² together with an atom, k to which they are attached form a 3-8-membered ring system containing 0-2 heteroatoms);

n equals 0-10; And

the dotted line indicates the point of attachment to the PTM or ULM fragments.

[1187] In any aspect or embodiment described herein, L represents a polyethyleneoxy group, optionally substituted with aryl or phenyl, containing from 1 to 10 ethylene glycol units.

[1188] In any aspect or embodiment described herein, the compound contains multiple ULMs, multiple PTMs, multiple linkers, or any combination thereof.

[1189] In any aspect or embodiment described herein, the compound is selected from the group consisting of compounds 1-330 (Table 1 or Table 2).

[1190] In any aspect or embodiment described herein, the compound is selected from Table 1 or Table 2 (ie, Compounds 1-330).

[1191] In any aspect or embodiment described herein, the compound has a chemical structure selected from the formulas CI - CV:

Where

R ¹⁰¹ represents 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;

R ¹⁰² is selected from H, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl;

R ¹⁰³ represents 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;

R ¹⁰⁴ represents 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;

R ¹⁰⁵ represents 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;

each of R ¹⁰⁶ , R ^{107 ,} R ¹⁰⁹ , R ¹¹⁰ , R ¹¹¹ , R 112, R ¹¹³ , R ¹¹⁴ , R ¹¹⁶ , R ¹¹⁷ , R ¹²⁰ , R ¹²¹ , R ¹²⁶ , R ¹²⁷ , R ¹²² and R ¹²³ independently selected from H, alkyl, halogen or haloalkyl;

R ¹⁰⁸ represents 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl, cyano or methoxy;

R ¹¹⁵ is selected from H, alkyl and haloalkyl;

R ¹¹⁸ and R ¹¹⁹ are independently selected from H, alkyl, halogen or haloalkyl, or R ¹¹⁸ and R ¹¹⁹ , taken together with the carbon atom to which they are attached, represent a 3-6 membered cycloalkyl or heterocycloalkyl ring such as cyclopropane or oxetane;

R ¹²⁴ and R ¹²⁵ are independently selected from H, alkyl, halogen or haloalkyl, or R ¹²⁴ and R ¹²⁵ , taken together with the carbon atom to which they are attached, represent a 3-6 membered cycloalkyl or heterocycloalkyl ring such as cyclopropane or oxetane;

G represents a phenyl or a 5- or 6-membered heteroaryl ring; And

Z represents CH ₂ or C=O.

[1192] A further aspect of the present invention provides a composition comprising an effective amount of a bifunctional compound of the present invention and a pharmaceutically acceptable carrier.

[1193] In any aspect or embodiment described herein, the composition further comprises at least one of an additional bioactive agent, another bifunctional compound according to any of paragraphs 1-29, or a combination thereof.

[1194] In any aspect or embodiment described herein, the additional biologically active agent is an anti-neurodegenerative agent.

[1195] In any aspect or embodiment described herein, the additional biologically active agent is a P-gp inhibitor.

[1196] In any aspect or embodiment described herein, the P-gp inhibitor is amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tariquidar, elacridar, or verapamil.

[1197] Another aspect of the invention provides a composition containing a pharmaceutically acceptable carrier and an effective amount of at least one compound of the present invention for treating a disease or disorder in a subject, the method comprising administering the composition to a subject in need thereof, wherein the compound is effective in treating or alleviating at least one symptom of a disease or disorder.

[1198] In any aspect or embodiment described herein, the disease or disorder is associated with the accumulation and aggregation of tau protein.

[1199] In any aspect or embodiment described herein, the disease or disorder is a neurodegenerative disease associated with the accumulation and aggregation of tau protein.

[1200] In any aspect or embodiment described herein, the disease or disorder is acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, Ady-Holmes syndrome, Eydie syndrome, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Ecardi syndrome, neurological complications of AIDS, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, ataxia, telangiectasia, forms of ataxia and cerebellar/spinocerebellar degeneration, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Barth syndrome, Batten disease, Becker myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal amyotrophy, benign intracranial hypertension, Bernhardt-Roth syndrome, Binswanger's disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus injury during childbirth, brachial plexus injury, Bradbury-Eggleston syndrome, brain and spinal cord tumors, cerebral aneurysm, brain injury , Brown-Séquard syndrome, bulbospinal muscular atrophy, Canavan disease, carpal tunnel syndrome, causalgia, cavernomas, cavernous angioma, cavernous malformation, central paralysis syndrome, pyramidal palsy, central pain syndrome, cephalic disorders, cerebellar degeneration, cerebellar hypoplasia, cerebral vascular aneurysm brain, cerebral arteriosclerosis, cerebral atrophy, cerebral beriberi, cerebral gigantism, cerebral hypoxia, cerebral palsy, cerebro-oculofacioskeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chorea-acanthocytosis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic orthostatic intolerance, chronic pain caused by Cockayne syndrome type II, Coffin-Lowry syndrome, COFS, colpocephaly, coma and persistent vegetative state, complex regional pain syndrome, congenital facial diplegia, congenital myasthenia, congenital myopathy, congenital cavernous vascular malformations, corticobasal degeneration , temporal arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative traumatic disorders, Cushing's syndrome, inclusion cytomegaly, cytomegalovirus infection, opso-myoclonal syndrome, Dandy-Walker syndrome, Dawson's disease, de Morsier syndrome, deep brain stimulation in Parkinson's disease, paralysis Dejerine-Klumpke, dementia, multi-infarct dementia, semantic dementia, subcortical dementia, dementia with Lewy bodies, progressive cerebellar ataxia, dentorubral atrophy, dermatomyositis, developmental dyspraxia, Devic's syndrome, diabetic neuropathy, diffuse sclerosis, autonomic dystonia, dysgraphia, dyslexia, dysphagia yu, dyspraxia, cerebellar myoclonic dyssynergia of Hunt, progressive cerebellar dyssynergia, forms of dystonia, epileptic encephalopathy of early childhood, empty sella syndrome, lethargic encephalitis, cranial hernia, encephalopathy, encephalotrigeminal angiomatosis, epilepsy, Duchenne-Er palsy ba and Dejerine-Klumpke, spinal Erb's palsy, Fabry's disease, Fahr's syndrome, syncope, familial dysautonomia, familial hemangioma, familial idiopathic basal ganglia calcification, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher's syndrome, floppy baby syndrome, Friedreich's hereditary ataxia, frontotemporal dementia, Gaucher disease, Gerstmann syndrome, Gerstmann-Straussler-Scheinker syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, glossopharyngeal neuralgia, Guillain-Barré syndrome, Hallervorden-Spatz disease, traumatic brain injury, headache, prolonged hemicrania , hemifacial spasm, alternating hemiplegia, hereditary neuropathies, hereditary spastic paraplegia, polyneuritis-like hemeralopic heredoataxia, herpes zoster, ganglion neuralgia, Hirayama syndrome, Eydie-Holmes syndrome, holoprosencephaly, HTLV-1-associated myelopathy, Huntington's disease , hydroanencephaly, hydrocephalus, normotensive hydrocephalus, hydromyelia, hyperfunction, hypercortisolism, hypersomnia, hypertension, infantile hypotension, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, pigmentary dermatosis, infantile hypotonia, infantile neuroaxonal dystrophy, infantile phytanic acid storage disease, infantile Refsum's disease, infantile spasms , inflammatory myopathy, inencephaly, intestinal lipodystrophy, intracranial cysts, intracranial hypertension, Isaac syndrome, Joubert syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsborne syndrome, Kleine-Levin syndrome, Klippel-Feil syndrome, Klippel-Trenaunay syndrome (KTS), syndrome Klüver-Bucy, Korsakoff amnestic syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lambert-Eaton myasthenic syndrome, Landau-Klefner syndrome, neuropathy of the lateral cutaneous nerve of the thigh, Wallenberg syndrome, learning disabilities, Leigh disease, Lennox-Gastaut syndrome , Lesch-Nyhan syndrome, leukodystrophy, Levine-Critchley syndrome, dementia with Lewy bodies, lipid storage diseases, lissencephaly, locked-in syndrome, Lou Gehrig's disease, neurological complications of lupus, complication of the disease, neurological complications of Lyme disease, Machado-Joseph disease , macroencephaly, manic syndrome, macroencephaly, Melkersson-Rosenthal syndrome, meningitis, meningitis and encephalitis, Menkes disease, mebius syndrome, mebius syndrome, monomelic amia otrophy, motor diseases neuron, Moya-Moya disease, mucolipidoses, mucopolysaccharidoses, multifocal motor neuropathy, multi-infarct dementia, multiple sclerosis, multiple system atrophy, multiple system atrophy with orthostatic hypotension, muscular dystrophy, congenital myasthenia, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic encephalopathy yu in babies, myoclonus, myopathy, congenital myopathy, thyrotoxic myopathy, myotonia, congenital myotonia, narcolepsy, neuroacanthocytosis, neurodegeneration with iron accumulation in the brain, neurofibromatosis, neuroleptic malignant syndrome, neurological complications of AIDS, neurological complications of Lyme disease, neurological consequences of cytomegalovirus infection, neurological manifestations of the disease Pompe, neurological complication of lupus, neuromyelitis optica, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorders, hereditary neuropathy, neurosarcoidosis, neurotoxicity, carvenous angioma, Niemann-Pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, latent spinal cord dysraphism, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus, orthostatic hypotension, O'Sullivan-MacLeod syndrome, overload syndrome, chronic pain, pain, pantothenate kinase-associated neurodegeneration, paraneoplastic syndromes, paresthesia, Parkinson's disease, paroxysmal choreoathetosis, paroxysmal hemicrania, Paris-Romberg syndrome, Peliceus disease -Merzbacher, Pen-Chockair II syndrome, perineural cysts, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent vegetative state, pervasive developmental disorders, phytanic acid storage disease, Pick's disease, pinched nerve, piriformis syndrome, pituitary tumors, polymyositis, disease Pompe, porencephaly, postherpetic neuralgia, post-infectious encephalomyelitis, post-polio syndrome, postural hypotension, postural orthostatic tachycardia syndrome, postural tachycardia syndrome, progressive cerebellar dyssynergia, primary lateral sclerosis, primary progressive aphasia, prion diseases, progressive hemifacial atrophy, progress progressive motor ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing polydystrophy, progressive supranuclear palsy, prosopagnosia, benign intracranial hypertension, Ramsay-Hunt syndrome I (formerly known as), Ramsay-Hunt syndrome II (formerly known as), Rasmussen's encephalitis, sympathetic reflex dystrophy, Refsum's disease, infantile form Refsum's disease, repetitive motion disorder, tunnel syndrome, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye syndrome, Riley-Day syndrome, perihilar cysts of the sacral nerve, St. Vitus's dance, salivary gland disease, disease Sandhoff's disease, Schilder's disease, schizencephaly, Seitelberger's disease, seizure disorder, semantic dementia, septo-optic dysplasia, shaken baby syndrome, herpes zoster, Shy-Drager syndrome, Sjögren's syndrome, sleep apnea, sleeping sickness, Sotos syndrome, spasticity, spina bifida , spinal cord infarction, spinal cord injury, spinal cord tumors, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Steele-Richardson-Olszewski syndrome, muscle stiffness syndrome, striatonigral degeneration, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, short-term attacks of unilateral neuralgic headache with conjunctival injection and lacrimation, swallowing dysfunction, Sydenham's chorea, syncope, syphilitic spinal sclerosis, syringohydromyelia, syringomyelia, systemic erythematous lupus, tabes spinal cord, tardive dyskinesia, Tarlov cysts, Tay-Sachs disease, temporal arteritis, tethered spinal cord syndrome, Thomsen's myotonia, scalene muscle syndrome, thyrotoxic myopathy, trigeminal neuralgia, Todd's palsy, Tourette's syndrome, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, tuberous sclerosis, cavernous angioma, vasculitis, including temporal arteritis, Economo disease, VHL disease, Recklinghausen disease, Wallenberg syndrome, Werdnig-Hoffmann disease, Wernicke-Korsakoff syndrome, West syndrome, whiplash injury, disease Whipple syndrome, Williams syndrome, Wilson disease, X-linked spinobulbar muscular atrophy or Zellweger syndrome.

[1201] In any aspect or embodiment described herein, the disease or disorder is a neurological disorder of at least one of Huntington's disease, muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten disease, spinal cord injury, and brain injury, seizure disorders, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformation, cerebral aneurysm, dural arteriovenous fistulas, headache, memory disorders, peripheral neuropathy, postherpetic neuralgia, spinal cord tumors and stroke.

[1202] In any aspect or embodiment described herein, the disease or disorder is Alzheimer's disease.

Claims (137)

1. A compound having a chemical structure or a pharmaceutically acceptable salt thereof, where ULM has the chemical structure represented by: where R _14a represents H or C _1-6 alkyl; R ₉ represents H; R ₁₀ is H, ethyl, isopropyl, t-butyl or sec-butyl; R ₁₁ represents R ₁₂ represents H; R ₁₃ represents C _1-6 alkyl or C _1-6 alkylcarbonyl; R ₁₅ selected from H, dotted line indicates the attachment site L; or ULM has a chemical structure represented by: wherein W represents CH ₂ or C=O; each X represents an O; Z represents O; G represents H; Q ₁ , Q ₂ , Q ₃ and Q ₄ represent a C carbon atom substituted by an R'group; A represents H; R selected from -CONR'R'', -OR', -NR'R'', -CR'R''-, -CR'NR'R''-, -Cl, -F, -Br, -I , -CF ₃ , -CN, -NR'CONR'R'', -CONR'COR'', -CO ₂ R', -C(C=N-OR')R'', -CR'=CR'R'',-CCR' or -OCF ₃ ; R' and R'' represent H; is a bond that may or may not provide a stereospecific configuration; n is 1, 2, 3 or 4; PTM is represented by a chemical structure selected from the group consisting of: where R ¹ , R ² and R ³ independently represent H or optionally substituted 1-3 halogens C _1-6 alkyl; And R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each represent 1 or 2 substituents independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, halogen or cyano; And L is represented by the formula: where A represents a group that is connected to a ULM or PTM moiety; And q is an integer between 1 and 19, where A is selected from CR ^L1 R ^L2 , O, NR ^L3 , CO, CR ^L1 =CR ^L2 , C≡C, cyclopropyl, cyclobutyl, bicyclopentyl, oxetanyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, wherein cyclopropyl, cyclobutyl, bicyclopentyl, oxetanyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl are optionally substituted with 1 or 2 R ^L1 ; each of R ^L1 , R ^L2 and R ^L3 is independently selected from H, halogen, C _1-8 alkyl, OH, CN, CF ₃ , CHF ₂ and CH ₂ F. 2. The compound according to claim 1, where RTM is represented by a chemical structure selected from: 3. Connection according to claim 1 or 2, where the ULM provides a group selected from: Where indicates the site of attachment of the chemical linker moiety. 4. A compound according to claim 1 or 2, where CLM has the chemical structure represented by: where W represents CH ₂ or C=O; each R is independently selected from H and C _1-6 alkyl; is a bond that may or may not provide a stereospecific configuration; And one Rn represents the attachment point to L. 5. Connection according to any one of paragraphs. 1, 2 or 4, where CLM has the chemical structure represented by: Where indicate linker attachment points. 6. Connection according to any one of paragraphs. 1-5, where the linker (L) provides a group represented by a general structure selected from: -N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH ₂ -, -O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-, -O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-; -N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-; -(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-; -(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-; where m, n, o, p, q and r are each independently equal to 0, 1, 2, 3, 4, 5 and 6, with the proviso that if the number is zero, then there is no N-O or O-O bond; R is selected from H, methyl and ethyl and X is H or F; 7. Connection according to any one of paragraphs. 1-5, where L is selected from: 8. Connection according to any one of paragraphs. 1-5, where L is selected from: where each of n and m is independently equal to 0, 1, 2, 3, 4, 5 or 6. 9. Connection according to any one of paragraphs. 1-5, where L represents a polyethyleneoxy group containing from 1 to 10 ethylene glycol units. 10. Connection according to any one of paragraphs. 1-9, where the connection is selected from: 11. Connection according to any one of paragraphs. 1-9, where the connection is selected from: 12. Connection according to any one of paragraphs. 1-9, where the connection is selected from: 13. Connection according to any one of paragraphs. 1-12, where the compound has a chemical structure selected from: where R ¹⁰¹ represents 1-2 substituents independently selected from H, C _1-6 alkyl, halogen, C _1-6 haloalkyl and cyano; R ¹⁰² represents H or C _1-6 haloalkyl; R ¹⁰³ represents 1-2 substituents independently selected from H, C _1-6 alkyl, halogen, C _1-6 haloalkyl and cyano; R ¹⁰⁴ represents 1-2 substituents independently selected from H, C _1-6 alkyl, halogen, C _1-6 haloalkyl and cyano; R ¹⁰⁵ represents 1-2 substituents independently selected from H, C _1-6 alkyl, halogen and cyano; each of R ¹⁰⁶ , R ^{107 ,} R ¹⁰⁹ , R ¹¹⁰ , R ¹¹¹ , R 112, R ¹¹³ , R ¹¹⁴ , R ¹¹⁶ , R ¹¹⁷ , R ¹²⁰ , R ¹²¹ , R ¹²⁶ , R ¹²⁷ , R ¹²² and R ¹²³ independently selected from H, C _1-6 alkyl and halogen; R ¹⁰⁸ represents 1-2 substituents independently selected from H, halogen and cyano; R ¹¹⁵ represents H; R ¹¹⁸ and R ¹¹⁹ are independently selected from H and halogen, or R ¹¹⁸ and R ¹¹⁹ , taken together with the carbon atom to which they are attached, are cyclopropyl or oxetanyl; R ¹²⁴ and R ¹²⁵ are independently selected from H and halogen, or R ¹²⁴ and R ¹²⁵ , taken together with the carbon atom to which they are attached, are cyclopropyl or oxetanyl; G is phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; And Z represents CH ₂ or C=O. 14. A pharmaceutical composition containing an effective amount of a compound according to any one of paragraphs. 1-13 and a pharmaceutically acceptable carrier for use in the treatment of a disease or disorder associated with tau protein. 15. A pharmaceutical composition containing a pharmaceutically acceptable carrier and an effective amount of a compound according to any one of paragraphs. 1-13, for use in the treatment of a disease or disorder associated with tau protein, wherein the disease or disorder is associated with the accumulation and aggregation of tau protein and the compound causes destruction of tau. 16. The pharmaceutical composition according to claim 15, wherein the disease or disorder associated with the accumulation and aggregation of tau protein is a neurodegenerative disease. 17. The pharmaceutical composition according to claim 16, where the disease or disorder is acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, Eydie-Holmes syndrome, Eydie syndrome, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Ecardi syndrome, neurological complications of AIDS, Alexander disease , Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, ataxia-telangiecta zyu , forms of ataxia and cerebellar/spinocerebellar degeneration, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Barth syndrome, Batten disease, Becker myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal amyotrophy, benign intracranial hypertension , Bernhardt-Roth syndrome, Binswanger disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus injury during childbirth, brachial plexus injury, Bradbury-Eggleston syndrome, brain and spinal cord tumors, cerebral aneurysm, brain injury, Brown-Séquard syndrome , bulbospinal muscular atrophy, Canavan disease, carpal tunnel syndrome, causalgia, cavernomas, cavernous angioma, cavernous malformation, central palsy syndrome, pyramidal palsy, central pain syndrome, cephalic disorders, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysm, cerebral arterioscler oz, cerebral atrophy, cerebral beriberi, cerebral gigantism, cerebral hypoxia, cerebral palsy, cerebrooculofacioskeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chorea-acanthocytosis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic orthostatic nephropathy wearability, chronic pain, Cockayne syndrome type II, Coffin-Lowry syndrome, COFS, colpocephaly, coma and persistent vegetative state, complex regional pain syndrome, congenital facial diplegia, congenital myasthenia gravis, congenital myopathy, congenital cavernous vascular malformations, corticobasal degeneration, temporal arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative traumatic disorders, Cushing's syndrome, inclusion cytomegaly, cytomegalovirus infection, opso-myoclonal syndrome, Dandy-Walker syndrome, Dawson's disease, de Morsier syndrome, deep brain stimulation in Parkinson's disease, Dejerine-Klumpke palsy, dementia, multi-infarct dementia, semantic dementia, subcortical dementia, dementia with Lewy bodies, progressive cerebellar ataxia, dentorubral atrophy, dermatomyositis, developmental dyspraxia, Devic's syndrome, diabetic neuropathy, diffuse sclerosis, autonomic dystonia, dysgraphia, dyslexia, dysphagia, dyspraxia, cerebellar Hunt's myoclonic dyssynergia , progressive cerebellar dyssynergia, forms of dystonia, epileptic encephalopathy of early childhood, encephalopathy, empty sella syndrome, lethargic encephalitis, cranial hernias, encephalopathy, encephalotrigeminal angiomatosis, epilepsy, Duchenne-Erb and Dejerine-Klumpke palsies, spinal Erb's palsy, disease Fabry, Fahr syndrome, syncope, familial dysautonomia, familial hemangioma, familial idiopathic basal ganglia calcification, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher syndrome, floppy child syndrome, Friedreich's hereditary ataxia, frontotemporal dementia, Gaucher disease , Gerstmann syndrome, Gerstmann-Straussler-Scheinker syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, glossopharyngeal neuralgia, Guillain-Barré syndrome, Hallervorden-Spatz disease, traumatic brain injury, headache, prolonged hemicrania, hemifacial spasm, alternating hemiplegia, hereditary neuropathies, hereditary spastic paraplegia, polyneuritis-like hemeralopic heredoataxia, herpes zoster, ganglion neuralgia, Hirayama syndrome, Eydie-Holmes syndrome, holoprosencephaly, HTLV-1-associated myelopathy, Huntington's disease, hydroanencephaly, hydrocephalus leia, normal pressure hydrocephalus, hydromyelia, hyperfunction, hypercortisolism, hypersomnia, hypertension, infantile hypotension, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, pigmentary dermatosis, infantile hypotonia, infantile neuroaxonal dystrophy, infantile phytanic acid storage disease, infantile Refsum's disease, infantile spasms, inflammatory myopathy, in encephaly , intestinal lipodystrophy, intracranial cysts, intracranial hypertension, Isaac syndrome, Joubert syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Kleine-Levin syndrome, Klippel-Feil syndrome, Klippel-Trenaunay syndrome (KTS), Kluver-Bucy syndrome, Korsakoff amnestic syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lambert-Eaton myasthenic syndrome, Landau-Klefner syndrome, neuropathy of the lateral cutaneous nerve of the thigh, Wallenberg syndrome, learning disabilities, Leigh disease, Lennox-Gastaut syndrome, Lesch syndrome Nyhan, leukodystrophy, Levine-Critchley syndrome, dementia with Lewy bodies, lipid storage diseases, lissencephaly, locked-in syndrome, Lou Gehrig's disease, neurological complications of lupus, neurological complications of Lyme disease, Machado-Joseph disease, macroencephaly, manic syndrome, macroencephaly , Melkersson-Rosenthal syndrome, meningitis, meningitis and encephalitis, Menkes disease, meralgia paresthetica, metachromatic leukodystrophy, microcephaly, migraine, Miller-Fisher syndrome, microstrokes, mitochondrial myopathies, Mobius syndrome, monomelic amyotrophy, motor neuron diseases, Moya-Moya disease, mucolipidoses, mucopolysaccharidoses, multifocal motor neuropathy, multi-infarct dementia, multiple sclerosis, multiple system atrophy, multiple system atrophy with orthostatic hypotension, muscular dystrophy, congenital myasthenia gravis, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic encephalopathy in infants, myoclonus, myopathy, congenital myopathy, thyrotoxic myopathy, myotonia, myotonia congenita, narcolepsy, neuroacanthocytosis, neurodegeneration with iron accumulation in the brain, neurofibromatosis, neuroleptic malignant syndrome, neurological complications of AIDS, neurological complications of Lyme disease, neurological consequences of cytomegalovirus infection, neurological manifestations of Pompe disease, neurological complications of lupus, neuromyelitis optica , neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorders, hereditary neuropathy, neurosarcoidosis, neurotoxicity, carvenous hemangioma, Niemann-Pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, latent spinal cord dysraphism, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus oclonus, orthostatic hypotension, O'Sullivan-MacLeod syndrome, overload syndrome, chronic pain, pain, pantothenate kinase-associated neurodegeneration, paraneoplastic syndromes, paresthesia, Parkinson's disease, paroxysmal choreoathetosis, paroxysmal hemicrania, Paris-Romberg syndrome, Pelizaeus-Merzbacher disease, Pena-Chockair syndrome II, perineural cysts, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent vegetative state, pervasive developmental disorders, phytanic acid storage disease, Pick's disease, pinched nerve, piriformis syndrome, pituitary tumors, polymyositis, Pompe disease, porencephaly, postherpetic neuralgia, post-infectious encephalomyelitis, post-polio syndrome, postural hypotension, postural orthostatic tachycardia syndrome, postural tachycardia syndrome, progressive cerebellar dyssynergia, primary lateral sclerosis, primary progressive aphasia, prion diseases, progressive hemifacial atrophy, progressive motor ataxia, progressive multifocal leukoencepha lopatia, progressive sclerosing polydystrophy, progressive supranuclear palsy, prosopagnosia, benign intracranial hypertension, Ramsay-Hunt syndrome I, Ramsay-Hunt syndrome II, Rasmussen's encephalitis, sympathetic reflex dystrophy, Refsum's disease, infantile form of Refsum's disease, repetitive motion disorders, tunnel syndrome, fatigue syndrome legs, retrovirus-associated myelopathy, Rett syndrome, Reye syndrome, Riley-Day syndrome, perihilar cysts of the sacral nerve, St. Vitus' dance, salivary gland disease, Sandhoff disease, Schilder disease, schizencephaly, Seitelberger disease, seizure disorder, semantic dementia, septo -optical dysplasia, shaken baby syndrome, herpes zoster, Shy-Drager syndrome, Sjogren's syndrome, sleep apnea, sleeping sickness, Sotos syndrome, spasticity, spina bifida, spinal cord infarction, spinal cord injury, spinal cord tumors, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Steele-Richardson-Olypevsky syndrome, muscle stiffness syndrome, striatonigral degeneration, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, short-term attacks of unilateral neuralgic headache with conjunctival injection tion and lacrimation, swallowing dysfunction , Sydenham's chorea, syncope, syphilitic spinal sclerosis, syringohydromyelia, syringomyelia, systemic erythematous lupus, tabes spinal cord, tardive dyskinesia, Tarlov cysts, Tay-Sachs disease, temporal arteritis, tethered spinal cord syndrome, Thomsen's myotonia, scalene syndrome, thyrotoxic mi apathy , trigeminal neuralgia, Todd's palsy, Tourette's syndrome, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, tuberous sclerosis, cavernous angioma, vasculitis, including temporal arteritis, disease Economo, Hippel-Lindau disease (VHL), Recklinghausen disease, Wallenberg syndrome, Werdnig-Hoffmann disease, Wernicke-Korsakoff syndrome, West syndrome, whiplash injury, Whipple disease, Williams syndrome, Wilson disease, X-linked spinobulbar muscle atrophy or Zellweger syndrome. 18. The pharmaceutical composition according to claim 15, where the disease or disorder is selected from Huntington's disease, muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten disease, spinal cord and brain injuries, seizure disorders, epilepsy, brain tumors, meningitis, autoimmune diseases , such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformation, cerebral aneurysm, dural arteriovenous fistula, headache, memory disorders, peripheral neuropathy, postherpetic neuralgia, spinal cord tumor and stroke. 19. The pharmaceutical composition according to claim 16, wherein the disease or disorder is Alzheimer's disease.