JPWO2018102067A5 - - Google Patents

Description

Cross-reference to related applications This disclosure claims priority to US Provisional Application No. 62 / 415,830 filed November 1, 2016, which is incorporated herein by reference in its entirety. Is done.

Built-in by reference
U.S. Patent Application No. 15 / 230,354 filed August 5, 2016. U.S. Patent Application No. 62 / 406,888 filed October 11, 2016. U.S. Patent Application No. 14 / 686,640, filed April 14, 2015 and published as U.S. Patent Application Publication No. 2015/0291562. U.S. Patent Application No. 14 / 792,414, filed July 6, 2015 and published as U.S. Patent Application Publication No. 2016/0058872. U.S. Patent Application No. 14 / 371,956 filed on July 11, 2014 and published as U.S. Patent Application Publication No. 2014/0356322. U.S. Patent Application No. 15 / 074,820, filed March 18, 2016 and published as U.S. Patent Application Publication No. 2016/0272639. These are incorporated herein by reference in their entirety. In addition, all references cited herein are incorporated herein by reference in their entirety.

1. Technical Fields The present specification relates to intracellular ubiquitination and subsequent bifunctional compounds useful for degradation of target polypeptides and proteins, especially Tau protein. The disclosed compounds place the target protein / polypeptide in close proximity to the ubiquitin ligase, causing ubiquitination and degradation (and inhibition) of the tau protein.

2. Background technology
Most small molecule drugs bind closely to enzymes or receptors and in well-defined pockets. On the other hand, it is well known that it is difficult to target protein-protein interactions using small molecule compounds because of the large contact surface of proteins and the shallow grooves involved. This is because it has a shape or a flat interface. E3 ubiquitin ligase, hundreds of which are known in humans, confer substrate specificity on ubiquitination. Therefore, it has specificity for specific protein substrates and is an even more attractive therapeutic target than general-purpose proteasome inhibitors. The development of E3 ligase ligands has proven to be partially difficult due to the fact that they have to disrupt protein-protein interactions. However, recent developments have resulted in specific ligands that bind to these ligases. For example, since the discovery of Natrin, the first small molecule E3 ligase inhibitor, more compounds targeting E3 ligase have been reported, but there are still many undeveloped areas in this area.

One of the attractive therapeutic potential E3 ligases is the von Hippel-Lindau (VHL) tumor suppressor, which is the substrate recognition subunit of the E3 ligase complex VCB and this complex. The body further consists of elongin B and C, Cul2 and Rbx1. The main substrate for VHL is hypoxia-inducible factor 1α (HIF-1α), which upregulates genes such as the angiogenic growth factor VEGF and the erythropoietic cytokine erythropoietin in response to low-level oxygen. It is a transcription factor that rates. The first low molecular weight ligand for von Hippel-Lindou (VHL) for the substrate recognition subunit of E3 ligase was generated and the crystal structure was obtained, and this compound is the transcription factor HIF, which is the main substrate for VHL.
It was confirmed that it mimics the binding mode of -1α.

Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, a clear indication of their physiological importance. Cereblon is a damaged DNA-binding protein 1 (
It forms an E3 ubiquitin ligase complex with DDB1), quince (Cullin) -4A (CUL4A), and quince 1 (Cullins1) regulator (ROC1). This complex ubiquitinates many other proteins. Celebron ubiquitination of the target protein results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10) through a mechanism that has not been fully elucidated. FGF8 then regulates a number of developmental processes, such as the formation of limbs and ear follicles. It is finally concluded that this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2 and functions as a DNA damage binding protein.

Tau protein is an abundant protein in the central nervous system and is predominantly present in neurons, while tau is expressed at low levels in other cells of the central nervous system. In healthy neurons, tau binds to microtubules and regulates microtubule stability. This regulation is important for axonal elongation and neuroplasticity. When pathologically altered, tau molecules are unable to stabilize microtubules and are more likely to form insoluble aggregates. When tau protein forms insoluble aggregates in cells, cell dysfunction occurs, axonal transport is impaired, and nerve cell loss occurs. Accumulation of abnormal tau aggregates in neurons is an important pathological feature of multiple neurodegenerative disorders, including Alzheimer's disease. In certain pathologies, tau aggregation results in paired-helical filaments (PHF), straight filaments (SF) and / or neurofibrillary tangles (NFTs). Accumulation of PHF and NFT in neurons directly correlates with microtubule dysfunction and neurodegeneration. Neurons containing tau PHF, SF, and / or NFT try to activate diverse cellular mechanisms to eliminate abnormal protein aggregates in cells.

More recent studies suggest that soluble tau oligomers, rather than giant insoluble filaments, may play a more important role in the onset and progression of pre-symptomatic disease of PHF-induced or NFT-induced neurotoxicity. ing. Oligomer-type tau can act as a seed for aggregation of native tau, thereby promoting neurotoxic tau aggregation. Accumulating evidence has shown that tau aggregates can be transmitted from one cell to another by propagating in a prion-like manner.

Tau changes and dysfunction, as well as extensive neuronal loss, have long been associated with several neurodegenerative diseases and are now collectively referred to as tauopathy.

The term "tauopathy" as used herein refers to certain neurodegenerative diseases associated with pathological aggregation of tau protein in neurofibrillary tangles or gliofibrillary tangles of the human brain. Examples of tauopathy include AD, Down's syndrome, frontotemporal lobular dementia (FTLD), corticobasal degeneration (CBD), and progressive supranuclear (PSP). palsy), but is not limited to these.

Due to its pathological significance in many neurodegenerative diseases, tau is an important therapeutic target. Prevention of tau aggregation may be a strategy for treating tau-related neurodegenerative disorders. Much efforts have been made to identify the molecular mechanism of tau aggregation and to find a treatment to stop the progression of neurodegeneration.

Tau aggregation inhibitors with promising preclinical data have been shown to be ineffective in recent clinical trials aimed at treating various tauopathy. Therefore, there is a need in the art for effective treatment of diseases and conditions associated with tau aggregation in neurodegenerative disorders such as tauopathy.

The present disclosure describes bifunctional compounds, compositions containing such compounds, and methods of using them, which recruit endogenous proteins to E3 ubiquitin ligase for ubiquitination and subsequent degradation. Works like. In particular, the present disclosure provides bifunctional or proteolytic targeted chimera (PROTAC) compounds, which are found to be useful as modulators of targeted ubiquitination and degradation of tau protein aggregates. Further, the present specification provides a method of using an effective amount of a compound described in the present specification for the treatment or amelioration of a pathological condition due to accumulation or aggregation of tau protein such as tauopathy. These diseases or disorders include, but are not limited to, neurological disorders or neurodegenerative disorders.

Thus, in one embodiment, the disclosure provides compounds that function to recruit endogenous proteins, such as tau, into E3 ubiquitin ligase for ubiquitination and degradation.

In any embodiment, the compound has the following general structure:
PTM-L-ULM.

In certain embodiments, the compound has the following general structure (A):
PTM-L-VLM (A)
In certain embodiments, the compound has the following general structure (B):

PTM-L-CLM (B)
In the formula, PTM represents a protein targeting moiety, ULM represents an E3 ubiquitin ligase targeting moiety such as VLM (VHL ligase binding moiety) and CLM (Celebron ligase binding moiety), and L represents, for example, binding. Or represents a linker such as a chemical linker moiety. As will be appreciated by those of skill in the art, the bifunctional compounds described herein can be synthesized such that the number and position of their respective functional moieties can be varied as desired.

In certain embodiments, the PTM of structure (A) is a ligand that binds to tau as well as VHL E3 ubiquitin ligase.

In certain embodiments, the PTM of structure (B) is a ligand that binds to tau as well as CLM E3 ubiquitin ligase.

In certain embodiments, the compounds described herein include multiple ULMs, multiple PTMs, multiple chemical linkers, or combinations thereof. In an additional aspect, the present specification provides a therapeutic composition comprising an effective amount of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier. Therapeutic compositions can be used in a patient or subject, eg, an animal such as a human, to regulate the degradation of a protein and to treat or ameliorate a medical condition or condition regulated via the degraded protein. In certain embodiments, the therapeutic compositions described herein can be used to cause degradation of a protein of interest for the purpose of treating or ameliorating a disease, eg, a neurological disorder. In yet another embodiment, the present disclosure provides a method of ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described herein, comprising ULM and PTM that can be linked via a linker moiety, as described elsewhere herein. In this case, ULM is bound to PTM, ULM recognizes ubiquitin pathway proteins such as E3 ubiquitin ligase, more preferably ubiquitin ligase such as VLM and CLM, and PTM recognizes target protein (TBM). Causes degradation of the target protein when the target protein (eg, tau) is placed in close proximity to the ubiquitin ligase, which in turn causes degradation of the target protein, impeding its action, and controlling the protein level. Brought to you. In another aspect, the target protein is tau. The present disclosure provides treatment of a pathological condition or condition through regulation of protein levels, i.e., by reducing the level of the protein (eg, tau protein) in a patient cell through degradation.

In particular, PTM is a molecule that binds to tau protein (TBM), and ULM is VHL E3.
A molecule that binds to ubiquitin ligase and / or CLM E3 ubiquitin ligase and has the following general structure:
TBM-L-VLM / CLM
The PTM (Proteolysis Targeting Part) of PROTAC of the present disclosure is represented by the general formulas I, II, III, IV, V, VI, VII, VIII, XI, X, and XI:

During the ceremony:
A, B, C, D, E, and F are independently substituted 5- or 6-membered aryl or heteroaryl rings, optionally substituted 4- to 7-membered cycloalkyl or hetero. Selected from cycloalkyl, the contact portions between the rings show ring fusion; and
The L _PTM is selected from bonds, alkyl, alkenyl or alkynyl and is optionally interrupted by one or more rings (ie cycloalkyl, heterocycloalkyl, aryl or heteroaryl) or one or more functional groups to the functional group. Is -O-, -S-, -NR ¹ _PTM- (in the formula, 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- It may be included, in the formula, the functional group may optionally be located at any end of the linker (ie, directly adjacent to the A, B, C, D, E or F ring).

The above-mentioned aryl rings and heteroaryl rings are independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluomethyl, and cyano, respectively. It can be optionally substituted with 3 substituents and the alkyl and alkenyl groups can be further substituted in the formula.

In any aspect or embodiment described herein, at least one of A, B, C, F, or a combination thereof, is an optionally substituted 5- or 6-membered aryl ring or heteroaryl ring. Is selected from.

In certain embodiments of the present disclosure, the PTM is represented by Formulas I and / or Formula II, where A, B and C are 5- or 6-membered fused aryl or heteroaryl rings, L _PTM . Is selected from bond or alkyl, D is selected from 6-membered aryl, heteroaryl or heterocycloalkyl, where A, B, C and D are optionally alkyl, haloalkyl, halogen, hydroxyl, alkoxy. , Amino, alkylamino, dialkylamino, trifluoromethyl, or cyano.

In other embodiments, the PTM is represented by Formula I and / or Formula II, where A, B and C are 5- or 6-membered fused aryl or heteroaryl rings and the L _PTM is a bonded ring. Or selected from alkyl, D and E are 5- or 6-membered fused aryl or heteroaryl rings, and in the formulas A, B, C, D and E are alkyl, haloalkyl,
It is optionally substituted with halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl, or cyano.

In certain other embodiments of the present disclosure, PTM is represented by Formula I, where A is a phenyl or 6-membered heteroaryl ring, B is a 5-membered heteroaryl ring, and C is phenyl or. A 6-membered heteroaryl ring, an L _PTM is a bond, and D is a 6-membered heteroaryl or a 6-membered heterocycloalkyl ring, each of A, B, C and D being arbitrary in the formula. Are independently substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, trifluoromethyl or cyano, except that the nitrogen atom of any of the A, B, C and D rings , L _PTM is not directly attached to a hetero atom or carbon atom, to which another hetero atom is directly added.

It will be appreciated that the general structure is exemplary and each part can be spatially arranged in any desired order, number or configuration.

In a further embodiment, the present specification describes bifunctional compounds having a structure selected from the group consisting of Examples 1-33 (eg, compounds selected from Tables 1 and 2), salts thereof, polymorphs, and pros. Provide a drug.

In a further embodiment, the present specification comprises bifunctional compounds having a structure selected from Table 1 or Table 2 (eg, a chemical structure selected from Compounds 1-330), salts thereof, polymorphs, and prodrugs. offer.

In another aspect, the present specification provides a composition comprising the compounds described herein and a pharmaceutically acceptable carrier. In certain embodiments, the composition is a therapeutic or pharmaceutical composition comprising an effective amount of a compound described herein and an acceptable carrier. In certain embodiments, the therapeutic or pharmaceutical composition comprises an additional bioactive agent, such as an agent effective in treating a neurological disorder.

In any of the embodiments or embodiments described herein, the therapeutic composition comprising the compounds described herein is in any suitable dosage form, eg solid or liquid, and eg, oral, non-oral. It may be configured to be delivered by any suitable route, such as oral, intravenous, intraperitoneal, subcutaneous, intramuscular, etc.

In another aspect, the specification provides a method of regulating the ubiquitination and degradation of tau protein in a subject such as, for example, a cell, tissue, mammal, or human patient, which method is described herein. Including the administration of an effective amount of a compound described in the document, or a composition containing an effective amount of the compound, to the subject, wherein the compound, or a composition containing the compound, ubiquitinates tau in the subject. And is effective in controlling decomposition.

In yet another aspect, the specification provides a method of treating or ameliorating a symptom of a disease associated with tau activity in a subject such as, for example, a cell, tissue, mammal, or human patient. , The effective amount of a compound described herein, or a composition comprising an effective amount of the compound, comprising administering to the subject in need thereof, wherein the compound, or a composition comprising the compound, comprises administration. It is effective in treating or ameliorating the symptoms of diseases related to tau 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, and the like.

In a preferred embodiment, the subject is a human.
In an additional aspect, the present specification provides a method of identifying the degrading effect of a protein of interest in a biological system using the compounds according to the present disclosure.

Where applicable, or not specifically excluded, any one of the embodiments described herein is in any other embodiment, even if the embodiment is a different embodiment of the present disclosure. It is expected that combinations are possible, even if they were originally described. Therefore, the above-mentioned general statements regarding usefulness are presented for illustrative purposes only and are not intended to limit the scope of the claims of the present disclosure and attachments. Additional objectives and advantages associated with the compositions, methods, and processes of the present disclosure will be apparent to those skilled in the art in light of the claims, detailed description, and examples. For example, the various aspects and embodiments of the present disclosure can be used in many combinations, all of which are expressly expected herein. These additional benefits, objectives and embodiments are expressly included within the scope of this disclosure. The publications and other materials used herein to explain the background of this disclosure and, in certain cases, to provide additional details with respect to practice, are incorporated by reference.

The accompanying drawings that are incorporated into and form part of this specification illustrate some embodiments of the present disclosure and serve to explain the principles of the present disclosure along with the description of the specification. The drawings are for purposes of illustration only of the embodiments of the present disclosure and are not construed as limiting the present disclosure. Further objectives, features and advantages of the present disclosure will become apparent from the following detailed description, along with the accompanying drawings showing exemplary embodiments of the present disclosure.

FIG. 1 shows the total tau level of hippocampal homogenate. The data is displayed as scattered dot blots. Statistical significant difference by one-way ANOVA (One-way ANOVA) between the group treated with the test item (TI) and the vehicle control group, followed by Dunneett's Multiple Comparison Test. Is indicated by the asterisk ** p <0.01, * p <0.05.

The following is a detailed description provided to assist those skilled in the art in the implementation of this disclosure. A person skilled in the art may modify or modify the embodiments described herein without departing from the spirit or scope of the present disclosure. All published documents, patent applications, patents, drawings and other references referred to herein are expressly incorporated by reference in their entirety.

The present specification states that the E3 ubiquitin ligase protein can ubiquitinize the target protein when the E3 ubiquitin ligase protein and the target protein are placed in close proximity by the chimeric construct described herein (eg, PROTAC). In connection with a surprising and unexpected discovery, the chimeric construct binds target proteins such as E3 ubiquitin ligase proteins (eg VHL and Celebron) such as tau. Accordingly, the present specification provides compounds for the purpose of ubiquitination and degradation of selected target proteins, compositions containing such compounds, and related uses thereof.

The following terms are used to describe this disclosure. If a term is not specifically defined herein, the term is given a meaning recognized in the art by those skilled in the art applying the term in connection with its use in the description of the present disclosure.

If a range of values is provided, unless explicitly stated otherwise in the context (eg, for groups containing a certain number of carbon atoms, each carbon atom number within that range is provided). And it should be understood that each intervening value up to one tenth of the lower bound unit, between the upper and lower bounds of any other designated range, or the intervening value within that specified range is included within the scope of the invention. The upper and lower bounds of these smaller ranges may be independently included in the smaller range, which is also included within the present disclosure and is any specifically excluded boundary value within the specified range. If the specified range includes one or both of the boundary values, then any of the included boundary values, or a range that excludes both, is also included in the present disclosure.

As used herein, the articles "a" and "an" shall be one or more (ie, at least one) of the grammatical objects of the article, unless the context explicitly suggests otherwise. As used herein to refer to one). As an example, "element" means one element or multiple elements.

As used herein and in the claims, the phrase "and / or" is to be understood to mean "either or both" of the elements so combined. That is, in some examples the elements are combined and in others they are not. Multiple elements listed using "and / or" should be interpreted in the same way. That is, "one or more" of the elements are so combined. Other elements other than those specifically specified by the "and / or" clause may optionally exist, whether or not they are related to those specifically specified elements. Thus, as a non-limiting example, when used in conjunction with a non-limiting wording such as "contains", the reference "A and / or B" refers only to A in one embodiment ( Optionally refers to only B (optionally includes elements other than A) in another embodiment, and in yet another embodiment refers to both A and B (optionally to other). Including elements).

As used herein and in the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, "or" or "and / or" shall be construed as comprehensive when separating items in a list. That is, it contains many elements, or at least one of a list of elements, but also more than one, and optionally additional items not listed. Only terms that clearly suggest the opposite, for example "only one of" or "exactly one of", or "consisting of" when used in the claims. , Many elements, or the inclusion of exactly one element in the list of elements. As used herein in general, the term "or" means, for example, "any", "one of", "only one of", or "exactly of". Only when an exclusive term such as "one" precedes it should be construed as indicating an exclusive option (ie, "one or other, but not both").

In the claims, as well as in the specification described above, "comprising," "including," "carrying," "having," "containing," and "involvement." It should be understood that all transitional phrases such as "involving", "holding", and "composed of" are non-limiting, that is, they are included but not limited. .. Only the transitional phrases "consisting of" and "consisting essentially of" shall be limited or semi-restricted transitional phrases, respectively, which is the US Patent Examination Standard. It is described in Section 2111.03 of.

As used herein, in the specification and claims, with respect to a list of one or more elements, the phrase "at least one" is selected from any one or more of the elements in the element list. It should be understood to mean at least one element that is, but does not necessarily include at least one of all the elements specifically listed in the element list, but any of the elements in the element list. It does not exclude the combination of. In addition, this definition can optionally include elements other than those specifically identified in the element list pointed to by the phrase "at least one", with or without the relevance of those specifically identified elements. Allow it to exist. Thus, as a non-limiting example, "at least one of A and B" (or equally "at least one of A or B", or equally "at least one of A and / or B". ") Refers to at least one A, optionally including a plurality of A's, in one embodiment, where B does not exist (optionally includes elements other than B). In another embodiment, it refers to at least one B that optionally contains more than one B, and A does not exist (optionally includes elements other than A). In yet another embodiment, it refers to at least one A, optionally comprising a plurality of A's, and at least one B, optionally comprising a plurality of B's (including optionally other elements).

In a particular method described herein comprising a plurality of steps or actions, the order of the steps or actions of the method is not necessarily the order in which the steps or actions of the method are listed, unless otherwise indicated by the context. Not limited.

As used herein, unless otherwise indicated, the term "compound" refers to any specific chemical compound disclosed herein, including metamutates, positional isomers, geometry. Isomers, and steric isomers, including optical isomers (enantiomers) and other steric isomers (diasteromers) where appropriate, and pharmaceutically acceptable salts thereof where appropriate in the context. And derivatives (including prodrug type). Within its use in the context, the term compound generally refers to a single compound, such as stereoisomers, positional isomers and / or optical isomers (including racemic mixtures) and specific enantiomers of the disclosed compounds. Other compounds, such as isomers or mixtures enriched with specific enantiomers, may be included. The term also refers in context to a prodrug form of a compound modified to facilitate administration and deliver the compound to the active site. It should be noted that in the description of this compound, many substituents, and in particular the variables associated with them, are mentioned. Those skilled in the art will appreciate that the molecules described herein are stable compounds as outlined below.

Join

When is indicated, both double and single bonds are represented within the context of the indicated compound.

The term "patient" or "subject" is used throughout the specification to describe an animal, preferably a human or livestock, for which treatment is provided, including prophylactic treatment with the compositions according to the present disclosure. With respect to the treatment of an infectious disease, condition or condition specific to a particular animal, for example a human patient, the term patient refers to domestic animals such as dogs or cats, or agricultural animals such as horses, cows, sheep. Refers to a specific animal, including. In general, the term patient in the present disclosure refers to a human patient unless otherwise indicated or implied by the circumstances in which the term is used.

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

The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a particular substrate protein and target that substrate protein for degradation. For example, cereblon is an E3 ubiquitin ligase protein that adds ubiquitin to lysine on a target protein, either in combination with or alone with the E2 ubiquitin conjugating enzyme, and then targets that particular protein substrate for proteasome degradation. Thus, in complex with E2 ubiquitin-binding enzyme, or alone, E3 ubiquitin ligase is involved in the transfer of ubiquitin to the targeted protein. In general, ubiquitin ligase is involved in polyubiquitination, whereby a second ubiquitin is added to the first ubiquitin and a third ubiquitin is added to the second ubiquitin. Polyubiquitination marks the protein against proteasome degradation. However, there are some ubiquitination events that are limited to monoubiquitination, in which case only one ubiquitin is added to the substrate molecule by ubiquitin ligase. Monoubiquitinated proteins are not targets for degradation of the proteasome, but instead alter their intracellular location or function through binding to other proteins that have domains capable of binding ubiquitin, for example. May cause you to. Further complicating the problem is that another lysine on ubiquitin can be targeted by E3 to form a chain. The most common lysine is Lys48 on the ubiquitin chain. It is the lysine used to produce the polyubiquitin recognized by the proteasome.

The term "protein target portion" or "PTM" refers to a protein or polypeptide that binds to the target protein or other protein or polypeptide of interest and allows ubiquitin ligase to degrade the protein or polypeptide. Used to describe small molecules placed / presented in close proximity to ubiquitin ligase. Non-limiting examples of small molecule target protein binding moieties include compounds that target tau protein.

The term "target protein" is used herein in the specification to which the disclosed compounds are bound.
It is used to describe the target protein or polypeptide that is degraded by ubiquitin ligase. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, mirror isomers, solvates, and polymorphs of these compositions, as well as other small molecules capable of targeting the protein of interest. These binding moieties are linked to the ULM group via a linker group.

Tau protein targets may be used in screening to identify a compound moiety that binds to the protein, and incorporation of that moiety within the disclosed compounds alters the activity level of the protein for the end result of treatment. Can be.

The term "pathology or condition" is beneficial to patients who have a protein dysregulation (ie, an increased amount of protein expressed in a patient) and the patient's tau protein degradation is in need. Used to describe any condition or condition that results in treatment or relief of symptoms. In certain cases, the condition or condition can be treated.

Pathologies or conditions that can be treated using the compounds according to the present disclosure include, for example, neurodegeneration, Huntington's disease and muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten's disease, spinal cord and brain damage, paroxysmal disorders, epilepsy, brain tumors, medullary membrane. Flames, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulas, headaches, memory disorders, peripherals These include neuropathy, post-herpes zoster nerve pain, spinal cord tumors, and stroke.

As used herein, the term "neuropathy" refers to any disorder that causes or results from neurological, psychiatric, psychological and / or cerebrovascular signs or origins. Refers to a disease and / or a syndrome. As used herein, the term "neuropathy" also refers to a disorder, disorder or condition of the brain and nervous system, or a mental disorder or condition. Neurological disorders include, but are not limited to: clear septal defect, acquired epileptic aphrodisiac, acute diffuse encephalomyelitis, ADHD, Addy pupil, Addy syndrome, adrenal leukodystrophy, ridge deficiency, deficit, Aicardi Syndrome, AIDS-Neurologic Complications, Alexander's Disease, Alpers Syndrome, Pediatric Alternate Hemiplegia, Alzheimer's Disease, Muscle Atrophic Lateral Sclerosis, Aneurysm, Aneurysm, Angelman Syndrome, Hemangiomatosis, None Oxygenosis, aphagia, asthma, spider membrane cyst, spider inflammation, Arnoldchiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, ataxia, capillary dilatation, ataxia and cerebral degeneration / spinal cord degeneration, attention defect -Hyperactivity disorder, autism, autonomic dysfunction, back pain, Bath syndrome, Batten's disease, Beckermyotny, Bechet's disease, bell paralysis, benign essential eyelid spasm, benign localized muscle atrophy, benign cranial Hyperinternal pressure, Bernhardtrot syndrome, Binswanger's disease, eyelid spasm, Blochsalzberger syndrome, arm plexus delivery trauma, traumatic arm plexus palsy, pure autonomic imbalance, brain and spinal cord tumors, cerebral aneurysms, cerebral trauma, Brown Sekar Syndrome, Ball Spinal Muscle Atrophy, Kanaban Disease, Carpal Canal Syndrome, Kausalgi, Scotchoma, Scotch Hemangioma, Scotch Vascular Malformation, Central Cervical Spinal Syndrome, Central Spinal Syndrome, Central Pain Syndrome , Head disorder, cerebral degeneration, cerebral dysplasia, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral leg qi, cerebral giant disease, cerebral hypoxia, cerebral paralysis, brain-eye-face-skeletal syndrome, Charcoal Marie Tooth's disease, Chiari malformation, butoh's disease, spinous erythroid butoh's disease, chronic inflammatory demyelinating polyneuritis (CIDP), chronic orthostatic hypotension, chronic pain, cocaine syndrome type II, coffin lorry syndrome, COFS, brain Liang defect, coma and persistent vegetative state, complex local pain syndrome, congenital bilateral facial nerve palsy, congenital myasthenia, congenital myopathy, congenital Vascular Cavernous, malformation, cerebral cortical basal nucleus Degeneration, head arteritis, skull fusion, Kreuzfeld-Jakob disease, cumulative trauma disease, Cushing syndrome, giant cell encapsulation, cytomegalovirus infection, Opsocronus myocronus syndrome, Dandy-Walker syndrome, Dawson's disease , Domorcia Syndrome, Deep Brain Stimulation Therapy for Parkinson's Disease, Arm Neural Neuropathy, Dementia, Multiple Infarct Dementia, Semantic Dementia, Subcortical Dementia, Levy Body Type Recognition Intellectual disease, myoclonic cerebral collaborative contractile dysfunction, dentate nucleus erythema atrophy, dermatitis, developmental Dyspraxia, Devic's disease, diabetic neuropathy, diffuse sclerosis, autonomic dysfunction, Writing Disorders, Loss of Reading, Swallowing Disorders, Integrated Motor Disorders, Myocronus Co-motor Disorders, Progressive Cerebral Co-motor Disorders, Gistonia, Early Infant Epilepsy Encephalopathy, Turkish Saddle Cavity Syndrome, Drowsiness Encephalitis, Brain Hernia, Encephalopathy, Cerebral trigeminal hemangiomatosis, epilepsy, superior and inferior paralysis, elve paralysis, Fabry's disease, Farr's disease, fainting, familial autonomic imbalance, familial hemangiomas, familial basal nucleus calcification, familial Periodic paralysis, familial spastic paralysis, febrile spasm, Fisher syndrome, floppy infant syndrome, Friedrich ataxia, frontotemporal dementia, Gaucher disease, Gerstmann syndrome, Gerstmann-Stroisler-Scheinker disease, giant cells Sexual arteritis, giant cell inclusion disease, globoid cell leukodystrophy, lingual neuropathy, Gillan Valley syndrome, Hallerfolden-Spatz disease, head injury, headache, persistent hemilateral headache, unilateral facial spasm, alternating hemiplegia , Hereditary neuropathy, hereditary spastic vs. paralysis, polyneuritis hereditary dysfunction, herpes zoster, ear herpes zoster, Hirayama syndrome, Holmes Addy syndrome, total anterior encephalopathy, HTLV-1-related myelopathy, Huntington's disease, water head Aneurysm, hydrocephalus, normal pressure hydrocephalus, hydromyelopathy, hyperactivity, adrenal cortical hyperactivity, hypersleep, muscle tone hyperactivity, hypotension-infant, hypoxia, immune-mediated encephalomyelitis, inclusion Somaticitis, dyschromia, pediatric muscle tone hypotonia, pediatric neuroaxial dystrophy, pediatric phytanoic acid accumulation, pediatric leftam disease, pediatric spasm, inflammatory myopathy, occipital cerebral prolapse, enteric lipopostrophy, intracranial cyst, Intracranial hypertension, Isaac Syndrome, Jubert Syndrome, Keens-Sair Syndrome, Kennedy's Disease, Opsocronus-Myocronus Syndrome (Kinsbourne syndrome), Kleine-Levin Syndrome, Klipel-File Syndrome, Klippel-Trenone-Weber Syndrome (KTS), Clew Bur-Beaucy Syndrome, Korsakov Oblivion Syndrome, Krabbe's Disease, Kugelberg-Welander's Disease, Cool-, Lambert-Eaton Myasthenia Syndrome, Landow-Klefner Syndrome, Lateral Femoral Skin Nervous Strangler, Lateral Marrow Syndrome, Learning Disorders, Lee's Disease , Lenox-Gastow Syndrome, Le Shu-Naihan Syndrome, Cerebral White Atrophy, Levine-Critchley Syndrome, Levy Body Dementia, Lipid Accumulation, Brain Circulation Deficiency, Confinement Syndrome, Lou Gehrig's Disease, Red spot wolf-nervous, sequelae, Lime's disease- Nervous type, complications, Machad-Joseph's disease, encephalopathy, manic disease, giant encephalomyelopathy, Mercarson-Rosenthal syndrome, meningitis, meningitis and encephalitis, Menquez's disease, dyssensitivity femoral nerve pain, allogeneic type, Cerebral white atrophy, small head disease, migraine, Millerfisher syndrome, mild stroke, mitochondrial myopathy, Mobius syndrome, Hirayama disease, motor neuropathy, moyamoya disease, Mucolipidoses, mucopolysaccharide, polyfocal movement Neuropathy, multiple infarct dementia, multiple sclerosis, multisystem atrophy, multisystem atrophy with orthostatic hypotension, muscular dystrophy, myasthenia-congenital, severe myasthenia, medullary shedding diffuse sclerosis Syndrome, Pediatric Myochrony Encephalopathy, Myocronus, Myopathy, Myopathy-Congenital, Myopathy-Thyroid Addiction, Myotney, Congenital Myotney, Narcolepsy, Neurospinous Erythrocytosis, Neurodegeneration with Intracerebral Iron Accumulation, Neurofibromatosis , Nerve-relaxing drug-induced malignant syndrome, AIDS nervous system complications, Lime disease nervous system complications, Cytomegalovirus infection nervous system effects, Pompe disease nervous system signs, Red spot wolf nervous system Sequel, optic neuromyelitis, neuromuscular tonicity, neuroceroid adipose brown deposits, nerve cell migration disorders, neuropathy-hereditary, neurosarcoidosis, neurotoxicity, spongy vein homozygous (Nevus Cavernosus), Niemann pick Disease, normal pressure hydrocephalus, occipital nerve pain, obesity, split spinal cord, Otawara syndrome, Olive Bridge cerebral atrophy, eyeball myocronus, orthostatic hypotension, O'Sullivan-McLeod Syndrome, overuse syndrome, pain -Chronic, pain, pantothenic kinase-related neurodegeneration, tumor-associated syndrome, sensory impairment, Parkinson's disease, paroxysmal butoh atetose, paroxysmal migraine, hemi-facial atrophy, Peritzus-Merzbacher's disease, Penashocker syndrome type II , Peri-nervous cyst, periodic limb palsy, terminal neuropathy, periventricular leukomalacia, protracted vegetative state, diffuse developmental disorder, phytanoic acid accumulation, Pick's disease, misplacement, pear muscle syndrome, pituitary tumor , Polymyositis, Pompe's disease, encephalopathy, post-herpes neuropathy, post-infection encephalomyelitis, post-porio syndrome, orthostatic hypotension, post-positional Orthostatic tachycardia syndrome, orthostatic tachycardia syndrome, primary Dentatum Atrophy, primary lateral sclerosis, primary progressive ataxia, prion disease, progressive hemilateral atrophy, progression Ataxia with gait, progressive polyfocal leukoencephalopathy, progressive sclerosing polyodystrophy, progressive supranuclear palsy, facial atrophy, pseudobrain tumor, Ramsey Hunt Syndrome I (past name), Ramsey Hunt Syndrome II (past name)
Past names), Rasmussen's encephalitis, reflex sympathetic dystrophy syndrome, Leftham's disease, Leftham's disease-pediatric type, recurrent dyskinesia, repetitive hyperinjury, restless legs syndrome, retrovirus-related myelopathy, Let's syndrome, Rye's syndrome, Relay-Day Syndrome, Sacral Nerve Root Sacosis,
Butoh's disease, salivary gland disease, Sandhoff's disease, Sylder's disease, fissure encephalopathy, Seitelberger's disease, paroxysmal disease, semantic dementia, septal dysplasia, shaken kid syndrome, herpes zoster, Scheidlager's syndrome, Schegren's syndrome , Sleep aspiration syndrome, African sleep disease, Sotos disease, spasm, dichotomous spine, spinal cord infarction, spinal cord injury, spinal tumor, spinal muscle atrophy, spinal cerebral atrophy, spinal cerebral degeneration, Steel-Richardson-Ors Zevsky Syndrome, Stiffperson Syndrome, Striatal melanosis, Stroke, Sturge-Weber Syndrome, Subacute sclerosing panencephalitis, Subcortical arteriosclerotic encephalopathy, SUNCT Headache Swallowing Disorders, Sidenum Butoh Disease, fainting, syphilis spinal sclerosis, spinal water cavities, spinal cavities, systemic erythema, spinal cord epilepsy, late-onset dyskinesia, turlob cysts, Teisax's disease, temporal arteritis, moored spinal cord syndrome, Thomsen Thomsen's Myotonia, thoracic outlet syndrome, thyroid addictive myopathy, trigeminal nerve pain, Todd palsy, Turret syndrome, transient cerebral ischemic attack, transmissible spongy encephalopathy, transverse myelitis, traumatic brain injury, tremors , Triangular nerve pain, tropical spastic deficiency vs. paralysis, nodular sclerosis, vascular erectile tumor, vasculitis-induced temporal arteritis (Vasculitis including Temporal Arteritis), von-echo-nomo disease, von hippel- Lindow's disease (VHL), von Recklinghausen's disease, Wallenberg's syndrome, Weldnig-Hoffmann's disease, Welnicke-Korsakov's syndrome, West syndrome, whiplash, Whipple's disease, William's syndrome, Wilson's disease, X-chain bulbous myelia , Or Zellberger syndrome.

The term "biologically active agent" is used to describe agents other than the compounds of the present disclosure, in order to aid in the therapeutic, inhibitory, and / or control / preventive effects of the intended use of this compound. It is used in combination with the disclosed compounds as an agent having biological activity.

The term "pharmaceutically acceptable salt" is used throughout the specification to describe the salt form of one or more of the compounds described herein where appropriate. , Shows increased solubility of the compound in the gastric juice of the patient's gastrointestinal tract, promoting lysis and bioavailability of the compound. Pharmaceutically acceptable salts include, where appropriate, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, such as alkaline earth metals such as calcium and magnesium, and ammonium salts, among many other acids and bases known, especially in the pharmaceutical arts. Can be mentioned. Salts of sodium and potassium are particularly preferred as neutralizing salts of phosphates according to the present disclosure.

The term "pharmaceutically acceptable derivative" is used throughout the specification to describe any pharmaceutically acceptable prodrug form (eg, esters, amides, other prodrug groups, etc.). When administered to a patient, they give rise to the compound directly or indirectly, or give rise to an active metabolite of the compound.

As used herein, the term "independently" is used to indicate that an independently applied variable changes independently with each application.

The term "hydrocarbyl" shall mean a compound containing carbon and hydrogen, which may be fully saturated, partially unsaturated, or aromatic, with aryl, alkyl, alkenyl and alkynyl groups. include.

The term "alkyl" should, in its context, mean a linear, branched, or cyclic fully saturated hydrocarbon radical or alkyl group, preferably C ₁ -C ₁₀ , more preferably. Are alkyl radicals of C ₁ -C ₆ or C ₁ -C ₃ , which can be optionally substituted. Examples of alkyl groups are especially methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methyl-propyl, cyclopropyl, Cyclo-propyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl.

The term "lower alkyl" means an alkyl group having no more than six carbon atoms.
The term "unsubstituted" shall mean that it has been substituted only with a hydrogen atom. The range of carbon atoms containing C ₀ means that carbon was absent and was replaced by H. Therefore, the range of carbon atoms of C ₀ -C ₆ includes 1, 2, 3, 4, 5 and 6 carbon atoms, and for C ₀ there is H instead of carbon. The term "substituted" or "optionally substituted" refers to one or more substituents (on a moiety in a compound according to the present disclosure) at any carbon (or nitrogen) position on a molecule in the context. Independently up to 5 substituents, preferably up to 3 substituents, often 1 or 2 substituents, which may contain substituents that may be further substituted by themselves). As meant (ie, if there are multiple substituents, each substituent is independent of another), and as substituents, hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (ie). NO ₂ ), halogens (particularly alkyl, preferably 1, 2, or 3 halogens preferably on methyl groups such as trifluoromethyl), alkyl groups (preferably C ₁ -C ₁₀ , more preferably C _{1- 6} ), aryl (especially phenyl and substituted phenyls such as benzyl or benzoyl), alkoxy groups (preferably C ₁ -C ₆ alkyl or aryl, including phenyl and substituted phenyl), thioethers (C ₁ -C ₆ alkyl or aryl). , Acrylic (preferably C ₁ -C ₆ acyl), ester or thioester (preferably C ₁ -C ₆ alkyl or aryl), alkylene ester (its bond is on an alkylene group rather than an ester functional group, preferably on an alkylene group). C ₁ -C ₆ alkyl or aryl group substituted), preferably containing C ₁ -C ₆ alkyl or aryl, halogen (preferably F or Cl), amine (containing 5 or 6 member cyclic alkylene amines) , C ₁ -C ₆ alkylamine or C ₁ -C ₆ dialkylamine, wherein the alkyl group may be substituted with one or two hydroxyl groups), or optionally substituted -N (C ₀ -C ₆ ). Alkyl) C (O) (OC ₁ -C ₆ alkyl) group (which can be optionally substituted with a polyethylene glycol chain, to which an alkyl group containing one halogen, preferably a chlorine substituent is further attached), hydrazine, Amid, preferably one or two C ₁ -C ₆ alkyl groups (including carboxamides optionally substituted with one or two C ₁ -C ₆ alkyl groups), alkanols (preferably C ₁ -C ₆ alkyl). Or aryl), or substituted with alkanoic acid (preferably C ₁ -C ₆ alkyl or aryl) Things, etc. Substituents according to the present disclosure may include, for example, -Si R ₁ R ₂ R ₃ groups, where in the formula each of R ₁ and R ₂ is described elsewhere herein, and R ₃ is H or C ₁ -C ₆ alkyl groups, preferably R ₁ , R ₂ , R ₃ in this context are C ₁ -C ₃ alkyl groups (including isopropyl or t-butyl groups). Each of the above groups may be attached directly to the substituted moiety, or the substituents may be optionally substituted via (CH ₂ ) _m -or optionally substituted-(OCH ₂ ). It may be attached to a substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via an _m -,-(OCH ₂ CH ₂ ) _m -or-(CH ₂ CH ₂ O) _m -group. , They may be substituted with any one or more of the above-mentioned substituents. The-(CH ₂ ) _m -or-(CH ₂ ) _n -group of the alkylene group or other chains, such as the ethylene glycol chains identified above, may be substituted with any of those chains. Preferred substituents on the alkylene group are halogens or C ₁ -C ₆ (preferably C ₁ -C ₃ ).
Alkyl groups can be mentioned, optionally one or two hydroxyl groups, one or two ether groups (OC ₁ -C ₆ groups), up to 3 halo groups (preferably F), or herein. May be substituted with the amino acid side chains described elsewhere, and optionally substituted amides (preferably carboxamides substituted as described above) or urethane groups (often one or two C _0s ). -It has a C ₆ alkyl substituent and this group can be further substituted).
In certain embodiments, the alkylene group (often a single methyl group) is one or two optionally substituted C ₁ -C ₆ alkyl groups, preferably C ₁ -C ₄ alkyl groups, most of which. In some cases, it is replaced with a methyl or O-methyl group, or an amino acid side chain described elsewhere herein. In the present disclosure, the moiety in the molecule may be optionally substituted with up to 5 substituents, preferably up to 3 substituents. In most cases, the moieties substituted in this disclosure are substituted with one or two substituents.

The term "substituted" (each substituent is independent of any other substituent) is used in the context of its use as C _{1-C 6 alkyl, C 1 -C 6 alkoxy} , halogen. , Amides, Carboxamides, Sulfons Containing Sulfonamides, Keto, Carboxy, C ₁ -C ₆ Esters (Oxyesters or carbonyl Esters), C ₁ -C ₆ Ketos, Urethanes-OC (O) -NR ₁ R ₂ or -N (R ₁ )-C (O) -OR ₁ , nitro, cyano, and amines (especially C ₁ -C ₆ alkylene-NR ₁ R ₂ , mono or di-C ₁ -C ₆ alkyl substituted amines. It also means (including those which can be optionally substituted with one or two hydroxyl groups). Each of these groups contains 1 to 6 carbon atoms in context, unless otherwise indicated. In certain embodiments, depending on the context in which the substituent is used, preferred substituents are, for example, -NH-, -NHC (O)-, -O-, = O,-(CH ₂ ) _m- (book). In the specification, m and n are 1, 2, 3, 4, 5 or 6 in the context), -S-, -S (O)-, SO _2- or -NH-C (O) -NH. -,-(CH ₂ ) _n OH,-(CH ₂ ) _n SH,-(CH ₂ ) _n COOH, C ₁ -C ₆ alkyl,-(CH ₂ ) _n O- (C ₁ -C ₆ alkyl), -(CH ₂ ) _n C (O)-(C ₁ -C ₆ alkyl),-(CH ₂ ) _n OC (O)-(C ₁ -C ₆ alkyl),-(CH ₂ ) _n C (O) O- (C ₁ -C ₆ alkyl),-(CH ₂ ) _n NHC (O) -R ₁ ,-(CH ₂ ) _n C (O) -NR ₁ R ₂ ,-(OCH ₂ ) _n OH,- (CH ₂ O) _n COOH, C ₁ -C ₆ alkyl,-(OCH ₂ ) _n O- (C ₁ -C ₆ alkyl),-(CH ₂ O) _n C (O)-(C ₁ -C ₆ ) Alkyl),-(OCH ₂ ) _n NHC (O) -R ₁ ,-(CH ₂ O) _n C (O) -NR ₁ R ₂ , -S (O) _{2 -RS} , -S (O)- R _S (R _S )
Is C ₁ -C ₆ alkyl or-(CH ₂ ) _m -NR ₁ R ₂ groups), NO ₂ , CN or halogen (F, Cl, Br)
, I, preferably F or Cl). R ₁ and R ₂ are each in context an H or C ₁ -C ₆ alkyl group (one or two hydroxyl groups, or up to three halogen groups, preferably optionally substituted with fluorine). The term "substituted" is also optionally substituted aryl or heteroaryl group within the chemical background of the specified compound and the substituent used or optionally as described elsewhere herein. It shall mean the heterocyclic group to be substituted. The alkylene group may also be substituted as otherwise disclosed herein, preferably optionally substituted C ₁ -C ₆ alkyl groups (preferably methyl, ethyl or hydroxymethyl or hydroxyethyl). A chiral center is provided), the side chains of the amino acid groups described elsewhere herein, the above-mentioned amide groups, or urethane groups, OC (O) -NR ₁ R ₂ groups, in the formula, R ₁ and R ₂ may be substituted with groups as described elsewhere herein, but many other groups may also be used as substituents. Various optionally substituted moieties may be substituted with 3 or more substituents, preferably 3 or less substituents, and preferably 1 or 2 substituents. In a compound, a substitution is required at a particular position in the molecule (mainly because of the valence), but if no substitution is indicated, the substituent is H unless otherwise suggested in the context of the substitution. Note that it is considered or understood.

The term "aryl" or "aromatic" has been substituted in the context with a single ring (eg, benzene, phenyl, benzyl) or a fused ring (eg, naphthyl, anthrasenylphenyl, phenanthrenyl, etc.). Refers to an unsubstituted monovalent aromatic radical described herein) or unsubstituted, as specified otherwise in accordance with the present disclosure, at any available stable position on the ring or in the presented chemical structure. Can be attached to the compound as such. Other examples of aryl groups include, in context, in heterocyclic aromatic ring systems such as imidazole, furyl, pyrrole, furanyl, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole and the like. Examples include "heteroaryl" groups having one or more nitrogen, oxygen or sulfur atoms, or fused ring systems such as, for example, indole, quinoline, indolidin, azindridin, benzoflazan, etc., as described above. Can be optionally replaced with. Among the heteroaryl groups that can be mentioned, among others, nitrogen-containing heteroaryl groups such as pyrrol, pyridine, pyridone, pyridazine, pyrimidine, pyrimidine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indridin, azine. Lysine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinolin, quinolysin, phthalazine, naphthylidine, quinoxalin, quinazoline, cinnoline, pteridine, imidazolepyridine, imidazolidin, pyrazinopyrimidine, acridin, phenant Sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles; Aromatic heterocycles containing two or more heteroatoms selected from, for example, furan, pyrimidine, cyclopentapirane, benzofuran, and isobenzofuran; and nitrogen, sulfur, and oxygen, such as thiazole, thiazole, isothiazole, etc. Includes benzoxazole, benzothiazole, benzothiasiazol, phenothiazine, isoxazole, frazane, phenoxazine, pyrazoloxazole, imidazolethazole, thienofuran, flopirol, pyridoxazine, flopyridine, flopyrimidine, thienopyrimidine, and oxazol, all of which. Can be optionally replaced.

The term "heterocycle" refers to a cyclic group containing at least one heteroatom, i.e. O, N or S, which may be aromatic (heteroaryl) or non-aromatic. Therefore, the heteroaryl moiety is included under the definition of a heterocycle, depending on the circumstances of its use. Exemplary heteroaryl groups are described above herein. Exemplary non-aromatic heterocyclic groups used in the present disclosure include, for example, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, pyrazoridinyl, imidazolidinone, morpholinyl, as described herein in particular. , Tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl, pyridone, 2-pyrrolidone, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, phthalimide and succinimide.

The term "co-administration" or "combination therapy" refers to a patient in which at least two compounds or compositions are administered simultaneously to the patient, whereby the effective amount or concentration of each of the two or more compounds is given to the patient for a given period of time. It shall mean that it can exist in. The compounds according to the present disclosure may be co-administered to a patient at the same time, but the term refers to two or more agents as long as the effective concentration of all co-administered compounds or compositions is present in the patient for a given time. It also includes administration at the same time or at different times. In certain preferred embodiments of the present disclosure, one or more of the compounds described above are co-administered in combination with at least one additional bioactive agent, particularly including an anti-cancer agent. In the individual embodiments of the present disclosure, co-administration of compounds results in synergistic treatment, including anti-cancer treatment.

The present disclosure describes bifunctional compounds and their use, which function to recruit and degrade endogenous proteins into E3 ubiquitin ligase. In particular, the present disclosure provides bifunctional or proteolytic targeted chimera (PROTAC) compounds, which are found to be useful as modulators of targeted ubiquitination of tau protein. The advantage of the compounds provided herein is the potential for a wide range of pharmacological activities, consistent with the degradation / inhibition of tau protein.

Accordingly, the present disclosure provides the compounds and compositions comprising an E3 ubiquitin ligase targeting moiety (ULM) bound to a tau protein targeting moiety (PTM), which results in ubiquitination of the tau protein. This results in degradation (and / or inhibition) of tau protein. The present disclosure also provides a library of compositions and their use.

The present description provides compounds containing a ligand, eg, a low molecular weight ligand (ie, having a molecular weight of less than 2000 daltons, 1,000 daltons, 500 daltons, or 200 daltons), wherein the compound is a ubiquitin ligase such as VHL or cereblon. Can be combined. The protein also includes a moiety capable of placing the target protein in close proximity to the ubiquitin ligase and binding to the target protein so as to cause degradation (and / or inhibition) of the protein. In addition to the above, a small molecule means that the molecule is non-peptidyl, i.e., it is often not considered a peptide, for example containing less than 4, 3, or 2 amino acids. According to the present specification, the PTM, ULM, or PROTAC molecule may be a small molecule.

In one embodiment, the present specification provides a composition useful for controlling protein activity. The composition comprises a ubiquitin pathway protein binding moiety (preferably for VHL or celebrone) according to the defined chemical structure, and preferably a tau protein targeting moiety linked together via a linker, in which case the ubiquitin pathway. The protein binding moiety recognizes the ubiquitin pathway protein, the targeting moiety recognizes the tau target protein, and in this case the ubiquitin pathway protein binding moiety is bound to the tau targeting moiety.

In another embodiment, the disclosure provides a library of compounds. The library comprises multiple compounds, in which case each compound has a ubiquitin pathway protein binding moiety (preferably VHL or celebrone) and a tau protein binding moiety, in which case ULM is (preferably via a linker moiety). It is bound to tau, and in this case the ubiquitin pathway protein binding moiety recognizes ubiquitin pathway proteins, especially E3 ubiquitin ligase.

In another aspect, the present disclosure provides a method of ubiquitinating / degrading a target protein (eg, tau) in a cell. The method comprises administering a bifunctional compound comprising a ubiquitin pathway protein binding moiety and a targeting moiety, preferably linked via a linker moiety, as described elsewhere herein, in which case ubiquitin. The pathway protein binding moiety recognizes the ubiquitin pathway protein (eg VHL, Celebron) and the targeting moiety recognizes the target protein (eg tau) so that the target protein is placed in close proximity to the ubiquitin ligase. Degradation occurs, which results in a reduction / inhibition of the action of the target protein and control of the protein level. The regulation of protein levels provided by the present disclosure provides treatment for a pathological condition or condition, which is regulated via a target protein by lowering the level of that protein in patient cells.

In yet another embodiment, the present disclosure is directed to a method of treating a patient in need of a condition or condition regulated via a protein (eg, tau), wherein degradation of the protein is treated in the patient. The method is effective and comprises administering an effective amount of the disclosed compound to a patient in need, optionally in combination with another bioactive agent. The condition or condition may be a disease caused by a microbial organism or an exogenous subject such as a virus, bacterium, fungal agent, protozoan or other microorganism, or overexpression of protein, i.e. the cause of the condition and / or condition. It may be a pathological condition caused by the accumulation or aggregation of the tau protein.

In one embodiment, the present disclosure provides compounds useful for controlling protein activity. The composition comprises an E3 ubiquitin ligase, a ubiquitin pathway protein binding moiety, and a protein targeting moiety, which are preferably linked or bound together via a linker, where the ubiquitin pathway protein binding moiety is the ubiquitin pathway protein. The targeting portion recognizes the target protein (eg, tau). Such compounds, or pharmaceutically acceptable salts thereof, mirror isomers, stereoisomers, solvates, polymorphs or prodrugs, are herein PROTAC compounds or PROTACs having the following general chemical structure: Sometimes referred to as:
ULM-L-PTM,
In the formula, ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to E3 ubiquitin ligase;
PTM is a small molecule containing a tau protein targeting moiety that degrades tau protein;
L is the bond or chemical link that connects ULM and PTM.

In certain embodiments, the E3 ubiquitin ligase binding moiety is of the group consisting of Von Hippel-Lindau (VLM), Cereblon (CLM), mouse double-minute homolog2 (MLM), and IAP (ILM). Target one.

In one aspect, the present specification provides a tau protein binding moiety (PTM). In certain embodiments, the PTM is Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X.
, Or expressed by the expression XI:

, During the ceremony:
A, B, C, D, E, and F are independently substituted 5- or 6-membered aryl or heteroaryl rings, optionally substituted 4- to 7-membered cycloalkyl or heterocyclo. Selected from alkyl, the contact moieties between the rings indicate ring fusion; and the _LPTM is selected from bond, alkyl, alkenyl or alkynyl, optionally one or more rings (ie cycloalkyl, heterocycloalkyl, Interrupted by an aryl or heteroaryl) or one or more functional groups, the functional group being -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) Selected from NH-, -NHC (O) O-, or -OC (O) NH-, the functional group is optionally located at either end of the linker in the formula.

In certain embodiments, the A, B, C, D, E and F aryl rings and heteroaryl rings of PTM are alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino. , Acylamino, trifluomethyl, and cyano are optionally substituted with 1 to 3 substituents, each independently selected, and the alkyl and alkenyl groups are further optionally substituted in the formula.

In certain embodiments, the ring of at least one of A, B, C, F, or a combination thereof, is selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings;
In certain embodiments, the PTM has the chemical structure of formula I and in the formula:
Rings A, B and C are independently 5- or 6-membered fused aryl or heteroaryl rings;
L _PTM is selected from bonded or alkyl, and
D is selected from 6-membered aryl, heteroaryl or heterocycloalkyl,
In the formula, A, B, C and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino or cyano.

In certain additional embodiments, the PTM has the chemical structure of formula I and in the formula:
A and C are phenyl or 6-membered heteroaryl rings;
B is a 5-membered heteroaryl ring;
L _PTM is a bond; and
D is a 6-membered heteroaryl or a 6-membered heterocycloalkyl ring;
In the formula, each of A, B, C and D is optional and is independently substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino or cyano, where the A, B, C and D rings One of the nitrogen atoms is not directly attached to the heteroatom or carbon atom, to which another heteroatom is directly added.

In other embodiments, the PTM has the chemical structure of formula III or formula IV, where A, B and C are 5- or 6-membered fused aryl or heteroaryl rings, and the L _PTM is. Selected from bonded or alkyl, D and E are 5- or 6-membered fused aryl or heteroaryl rings, where A, B, C, D and E are alkyl, haloalkyl, halogen, hydroxyl, It is optionally substituted with alkoxy, amino, alkylamino, dialkylamino, or cyano.

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

During the ceremony:
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 is one or two substituents independently selected from H, methyl, ethyl and halogen, and PTM is attached to ULM via L.

In any of the embodiments or embodiments described herein, the PTM is covalently attached to one or more ULM (VLM or CLM) groups, or one or more as described herein. Covalently attached to a linker attached to the ULM (VLM or CLM) group of.

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

During the ceremony:
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 are selected independently of H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino, trifluoromethyl, or cyano. 1 to 8 substituents, PTM is ULM via L
Combined to (VLM or CLM).

In certain additional embodiments, the PTM is represented by the following chemical structure:

In certain embodiments, the linker binding points to the PTM are as indicated by the dotted lines:

Illustrative VLM:
In one embodiment, ULM is VHL.

In certain embodiments of the compounds described herein, ULM is VLM, the ULM-a below.
Includes chemical structures selected from the group of:

During the ceremony:
Dashed lines indicate the binding of at least one PTM, another ULM or VLM or CLM (ie ULM'or VLM' or CLM'), or a chemical linker moiety, at least one PTM, ULM.
'Or VLM' or CLM' is attached to the other end of the linker;
X ¹ and X ² are independently selected from the group of binding, O, NR ^Y3 , CR ^Y3 R ^Y4 , C = O, C = S, SO, and SO ₂ ;
R ^Y3 and R ^Y4 are independently selected from the group of H, straight or branched C _1-6 alkyl, which are optionally substituted with one or more halos, C _1-6 alkoxyls;
R ^P are 1, 2 or 3 groups, each independently selected from the group of H, halo, -OH, C _1-3 alkyl;
W ³ is optionally substituted-TN (R ^1a R ^1b ), optionally substituted-TN (R ^1a R ^1b ) X ³ , -T-aryl, optionally substituted-T-heteroaryl, Arbitrarily substituted -T-heterocycle, optionally substituted-NR ¹ -T-aryl, optionally substituted -NR ^{1 -T-heteroaryl, or optionally substituted -NR 1 -T-} Selected from a group of heterocycles;
X ³ is C = O, R ¹ , R ^1a , R ^1b ,
R ¹ , R ^1a , and R ^1b are independent, H, linear or branched C ₁ -C ₆ alkyl groups, R ^{Y 3} C = optionally substituted by one or more halo or -OH groups. 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 ) Selected from the group consisting of SO ₂ ;
Where T is covalently attached to X ¹ ; W ⁴ is optionally substituted-NR ¹ -T-aryl, optionally substituted-NR ¹ -T-heteroaryl group, or optionally substituted. -NR ¹ -T-Heterocycle, preferably -NR ¹ is covalently bonded to X ² and R ¹ is H or CH ₃ .

In any of the embodiments described herein, T is selected from the group of optionally substituted alkyl,-(CH ₂ ) _n -groups, in which each one of the methylene groups is a halogen. , Methyl, a linear or branched C ₁ -C ₆ alkyl group optionally substituted with one or more halogens or -OH, or one selected from the group of amino acid side chains optionally substituted. Arbitrarily substituted with two substituents; and
n is 0-6, often 0, 1, 2, or 3, preferably 0 or 1.

In certain embodiments, W ⁴

And in the equation, R _14a, R _14b, respectively, are independently selected from the group of H, haloalkyl, or optionally substituted alkyl;
In any of the embodiments or embodiments described herein, W ⁵ is selected from the group of phenyls or 5- to 10-membered heteroaryls.
R ₁₅ can be replaced with 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 . Alkyl to be substituted, haloalkyl optionally substituted, haloalkoxy optionally substituted; selected from the group of aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl;
In an additional embodiment, the W ⁴ substituent for use in the present disclosure further specifically comprises a W ⁴ substituent present in a particular compound disclosed herein (in the particular disclosed compound). Not limited). Each of these W ⁴ substituents may be used in conjunction with any number of W ³ substituents, which are also disclosed herein.

In certain additional embodiments, ULM-a is optionally substituted with 1-3 ^RP groups at the pyrrolidine moiety. Each R ^P is independently H, halo, -OH, C _1-3 alkyl.

In any of the embodiments described herein, W ³ and W ⁴ may be independently covalently attached to a linker to which one or more PTM groups are attached.
And in the formula, the dashed line indicates the binding site of the chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM' to ULM.

In certain embodiments, ULM is VHL and is represented by the following structure:

During the ceremony:
W ³ is optionally substituted aryl, optionally substituted heteroaryl, or

Selected from the group of;
R ₉ and R ₁₀ are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R ₉ , R ₁₀ , and the carbon atoms they bond to form cycloalkyls that are optionally substituted;
R ₁₁ is optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

Selected from the group of;
R ₁₂ is selected from the group of H or optionally substituted alkyl;
R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optional Selected from a group of (heterocyclyl) carbonyls substituted with, or optionally substituted aralkyl;
R _{14a and} R _14b are independently selected from the group of H, haloalkyl, or optionally substituted alkyl;
W ⁵ is selected from the group of phenyl or 5-10 membered heteroaryls,
R ₁₅ can be replaced with 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 . Alkyl to be substituted, haloalkyl optionally substituted, haloalkoxy optionally substituted; selected from the group of aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl (each independently and optionally substituted);
R ₁₆ is independently selected from the group of H, halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;
o is 0, 1, 2, 3, or 4;
R ₁₈ is independently selected from the group of halos, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or linkers; and
p is 0, 1, 2, 3, or 4, and in the equation, the dashed line indicates at least one PTM, another ULM (ULM'), and at least one PTM and / or ULM'to ULM. The binding site of the chemical linker moiety to be bound is shown.

In certain embodiments, the R ₁₅ is

In the formula, R ₁₇ is H, halo, optionally substituted C _3-6 cycloalkyl, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkenyl, and C. It is _1-6 haloalkyl; and Xa is S or O.

In certain embodiments, R ₁₇ is selected from methyl, ethyl, isopropyl and cyclopropyl.

In certain additional embodiments, R ₁₅ is selected from the group consisting of:

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

In certain embodiments, ULM has a chemical structure selected from the following groups:

During the ceremony:
R ₁ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl. , Or haloalkyl;
R _14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;
R ₁₅ is H, halogen, CN, OH, NO _2, optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted halo. Selected from the group consisting of alkoxy, cycloalkyl, or cycloheteroalkyl; X is C, CH ₂ , or C = O.
R ₃ is a 5- or 6-membered heteroaryl bound or optionally substituted; and in the formula, the dashed line is at least one PTM, another ULM (ULM'), or at least one PTM or ULM'. The binding site of the chemical linker moiety that binds or both to ULM (ULM-a) is shown.

In certain embodiments, ULM comprises groups according to the following chemical structure:

During the ceremony:
R _14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;
R ₉ is H;
R ₁₀ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
R ₁₁ is

Or it is a heteroaryl optionally substituted;
p is 0, 1, 2, 3, or 4;
Each R ₁₈ is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or linker;
R ₁₂ is H, C = O;
R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optional A (heterocyclyl) carbonyl substituted with, or an 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;

Selected from the group consisting of; and in the formula, the dashed line indicates the binding site of the chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM' to ULM. show.

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

In the formula, n is 0 or 1.
In certain embodiments, ULM is selected from the following structures:

Here, the phenyl rings of ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9 are optionally fluorine, lower alkyl, and alkoxy groups. Substituted with, where the dashed line indicates the binding site of the chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM' to ULM-a.

In one embodiment, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15,
And the phenyl rings of ULM-d1 to ULM-d9 are functionalized as esters, which can be part of the prodrug.

In certain embodiments, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15,
And the hydroxyl groups on the pyrrolidine rings of ULM-d1 to ULM-d9 each contain an ester-bonded prodrug moiety.

In any of the embodiments or embodiments described herein, ULM, and ULM'if present, or pharmaceutically acceptable salts, stereoisomers, solvates or polymorphs thereof, respectively. Independently, it is a group that follows the following chemical structure:

During the ceremony:
ULM-g R ^1'is 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- (C ₁ -C ₆ ) Alkyl group, optionally substituted (CH ₂ ) _n -WCOCW- (C ₀ -C ₆ ) Alkyl group containing epoxidized moiety WCOCW There, during the ceremony,
Each W is an independently H or 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 Is-(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 ), Arbitrarily substituted-(CH ₂ ) _n C (O) -O- (C ₁ -C ₆ alkyl), Arbitrarily substituted-(CH ₂ O) _n COOH, Arbitrarily 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 replaced-(CH ₂ O) _n C (O) -NR ₁ R ₂ ,-(CH ₂ CH ₂ O) _n H, optionally substituted-(CH 2 O) CH ₂ CH ₂ O) _n COOH, optionally substituted-(O CH 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 S (O) R _S , NO ₂ , CN or halogen (F, Cl, Br, I, preferably F or Cl) And;
R ₁ and R ₂ of ULM-g can be independently substituted with H, or a C ₁ -C ₆ alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine). And;
The R _S of ULM-g is a C ₁ -C ₆ alkyl group, an optionally substituted aryl, heteroaryl group or heterocyclic group, or-(CH ₂ ) _m NR ₁ R ₂ groups;
The X and X'of ULM-g are independently C = O, C = S, -S (O), S (O) ₂ (preferably both X and X'are C = O). );
ULM-g R ^2'is optionally substituted-(CH ₂ ) _n- (C = O) _u (NR ₁ ) _v (SO ₂ ) _w alkyl group, optionally substituted-(CH ₂ ) _n- (C = O) _u (NR ₁ ) _v (SO ₂ ) _w NR _1N R _2N groups, 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-(CH ₂ ) _n- ( C = O) _v NR ₁ (SO ₂ ) _w -heterocycle, optionally substituted-NR ^1- (CH ₂ ) _n -C (O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optional Replaced by -NR ^1- (CH ₂ ) _n -C (O) _u (NR ₁ ) _v (SO ₂ ) _w --NR _1N R _2N , optionally replaced by -NR ^1- (CH ₂ ) _n- C (O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C (O) R _1N , optionally replaced -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; optionally substituted -X ^R2' -aryl Group; optionally substituted-X ^R2' --heteroaryl group; optionally substituted-X ^R2' --heterocyclic group; optionally substituted;
ULM-g R ^3'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 replaced-(CH ₂ ) _n -C (O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C (O) R _1N , optionally replaced- (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 replaced-NR ^1- (CH ₂ ) _n -C (O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C (O) R _1N , optionally replaced-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 ) _n -C (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 replaced -O- (CH ₂ ) _n- (C = O) _u (NR ₁ ) _v (SO) ₂ ) _w -NR ₁ C (O) R _1N , optionally replaced -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, optional Substituted with-(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' --Alkyl group; optionally substituted-X ^R3' --aryl group; optionally substituted-X ^R3' --Herocyclic group; optionally substituted -X ^R3' --heterocyclic group; optionally substituted;
ULM-g's R _1N and R _2N are independently H, C ₁ -C ₆ alkyl optionally substituted with one or two hydroxyl groups or up to three halogen groups, or optionally substituted-( CH ₂ ) _n -aryl,-(CH ₂ ) _n -heteroaryl, or-(CH ₂ ) _n -heterocyclic group;
The V of ULM-g is O, S or NR ₁ ;
R ₁ of ULM-g is the same as above;
R ¹ and R _1'of ULM-g are independently H or C ₁ -C ₃ alkyl groups;
ULM-g's X ^R2'and X ^R3' are independent and optionally replaced- ( CH ₂ ) _n -,- ( CH ₂ ) _n -CH (X _v ) = CH (X _v )-( Sis or trans),- ( CH ₂ ) _n -CH≡CH-,-(CH ₂ CH ₂ O) _n- , or C ₃ -C ₆ cycloalkyl group, where X _v is H, halo, Or an optionally substituted C ₁ -C ₃ alkyl group;
Each m of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;
Each m'of ULM-g is independently 0 or 1;
Each n of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;
Each n'in ULM-g is independently 0 or 1;
Each u of ULM-g is independently 0 or 1;
Each v in ULM-g is independently 0 or 1;
Each w of ULM-g is independently 0 or 1; and
If any one or more of ULM-g's R ^1' , R ^2' , R ^3' , X and X'is optionally modified and the PTM is not ULM', then a PTM group via a linker group. If the PTM is ULM', any one or more of R ^1' , R ^2' , R ^3' , X and X', respectively, of ULM and ULM'are optionally modified. And are covalently attached to each other either directly or via a linker group.

In any of the embodiments or embodiments described herein, ULM, and ULM', if present, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, solvate or poly. Each form is an independent group that follows the following chemical structure:

During the ceremony:
Each of ULM-h's R ^{1' ,} R ^2'and R 3'is the same as above, where X is C = O, C = S, -S (O) or ₂ S (O). Yes, more preferably the C = O group, and
If any one or more of ULM-h's R ^1' , R ^{2' ,} and R 3'is optionally modified and the PTM is not ULM', then a linker group that is further covalently attached to the PTM group. , Or if the PTM is ULM', any one or more of each of ULM and ULM', R ^1' , R ^2' , R ^3' , is optionally modified, either directly or Covalently bonded to each other via a linker group.

In any of the embodiments or embodiments described herein, ULM, and ULM', if present, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, solvate or poly. Each form independently follows the following chemical structure:

In the formula: If any one or more of R ^1' , R ^{2' ,} and R 3'of ULM-I is optionally modified and the PTM is not ULM', it is further covalently attached to the PTM group. If the PTM is ULM', one or more of each of ULM and ULM', R ^1' , R ^2' , R ^3' , is optionally modified. Covalently attached to each other either directly or via a linker group.

In a more preferred embodiment of the invention, R ^1'of ULM-g to ULM-i is preferably a hydroxyl group, or a group that can be metabolized to a hydroxyl group or a carboxylic acid group, whereby the compound is a pro of the active compound. It becomes a drag type. Examples of preferred R ^1'groups are-(CH ₂ ) _n OH, (CH ₂ ) _n -O- (C ₁ -C ₆ ) alkyl groups,-(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. In the formula, R ^1'is a carboxylic acid group, a hydroxyl group or an amine group, or contains it, and the hydroxyl group, a carboxylic acid group or an amine (each of which can be optionally substituted) is further chemically modified. Can provide a covalent bond to a linker group that is attached to a PTM group, including a ULM'group;
The X and X'of ULM-g and ULM-h, if present, are preferably C = O, C = S, -S (O) or _two S (O) groups, more preferably C = O. Is the basis;
R ^2'of ULM-g to ULM-i is preferably optionally substituted-NR ¹ -T-aryl, optionally substituted -NR ¹ -T-heteroaryl group, or optionally substituted- NR ¹ -T- is a heterocycle, in which R ¹ is H or CH ₃ , preferably H, and T is optionally substituted-(CH ₂ ) _n -group, in the formula. Each one of the middle and methylene groups is preferably a halogen, one or two substituents selected from the amino acid side chains or C ₁ -C ₃ alkyl groups described elsewhere herein, preferably optionally. It may be optionally substituted with one or two methyl groups which can be substituted, and n is 0-6, often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T can be-(CH ₂ O) _n -group,-(OCH ₂ ) _n -group,-(CH ₂ CH ₂ O) _n -group,-(OCH ₂ CH ₂ ) _n -group. Well, all of those groups are optionally replaced.

Preferred aryl groups for R ^2'of ULM-g to ULM-i include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, where the phenyl or naphthyl groups are PTM groups (ULM' groups. Includes), linker groups, halogens (preferably F or Cl), amines, monoalkylamines or dialkylamines (preferably dimethylamines), F, Cl, OH, COOH, C ₁ -C ₆ alkyls, preferably CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN group (each of which may be substituted at the ortho-, meta-, and / or para-position, preferably para-position of the phenyl ring), optionally substituted. A phenyl group (the phenyl group itself is optionally attached to a PTM group (including ULM'group) via a linker group) and / or F, Cl, OH, COOH, CH ₃ , CF ₃ , OMe, At least one of OCF ₃ , NO ₂ , or CN groups (at the ortho-, meta-, and / or para-position, preferably para-position of the phenyl ring), optionally substituted naphthyl group, any Heteroaryl substituted with, preferably optionally substituted isoxazole containing methyl substituted isoxazole, optionally substituted oxazole containing methyl substituted oxazole, optionally substituted thiazole containing methyl substituted thiazole. , Arbitrarily substituted isothiazole containing methyl-substituted isothiazole, optionally substituted pyrol containing methyl-substituted pyrrole, optionally substituted imidazole containing methylimidazole, optionally substituted benzimidazole orメトキシベンジルイミダゾール、任意で置換されるオキシイミダゾールまたはメチルオキシイミダゾール、メチルジアゾール基を含む任意で置換されるジアゾール基、メチル置換されたトリアゾール基を含む任意で置換されるトリアゾール基、ハロ-（好ましくIs an optionally substituted pyridine group containing F) or a methyl substituted pyridine group or an oxapyridine group (the pyridine group is attached to a phenyl group by oxygen), an optionally substituted furan, an optionally substituted benzofuran. , Arbitrarily substituted dihydrobenzofuran, optionally substituted indol, indolidine or azaindridin (2, 3 or 4-azindridin), optionally substituted quinoline, optionally according to chemical structure It is optionally attached via a group to be substituted.

During the ceremony:
The Sc of ULM-g to ULM- ⁱ is CHR ^SS , NR ^URE or O;
The R ^HETs of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C ₁ -C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups (Substituted with) or optionally substituted acetylene group -C≡CR _a , in which R _a is an H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). It is an acetylene group;
The R ^SS of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C ₁ -C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
The R ^UREs of ULM-g to ULM-i are H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or -C (O) (C ₁ -C ₆ alkyl). Each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or optionally substituted phenyl group, optionally substituted heteroaryl group, or optionally. Substituted heterocycles such as piperidine, morpholine, pyrrolidine, tetrahydrofuran;
ULM-g to ULM-i R ^PROs are groups of H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocycle, and they. The groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazin, morpholin, quinoline ( Each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halo group, preferably F or Cl), selected from the group consisting of benzofurans, indoles, indolidines, azindridinins;
ULM-g to ULM-i R ^PRO1 and R ^PRO2 are independently H, optionally substituted C ₁ -C ₃ alkyl groups, or both form keto groups; and
Each n of ULM-g to ULM-i is a heterocycle, preferably 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1) or optionally substituted. Tetrahydrofuran, tetrahydrothien, piperazine, piperazine or morpholine (each of these groups is preferably substituted with methyl or halo (F, Br, Cl) when substituted, each of which is via a linker group. Can optionally be attached to a PTM group (including a ULM'group).

In certain preferred embodiments, ULM-g to ULM-i

And
In the formula, the R ^PRO of ULM-g to ULM-i is the same as above.

Preferred heteroaryl groups for R ^2'of ULM-g to ULM-i are optionally substituted quinoline (which can be attached to a pharmacophore or substituted on any carbon atom within the quinoline ring). , Arbitrarily substituted indole, optionally substituted indolidine, optionally substituted azaindidine, optionally substituted benzofuran including optionally substituted benzofuran, optionally substituted isoxazole, optionally substituted Thiazole to be optionally substituted isothiazole, optionally substituted thiophene, optionally substituted pyridine (2-, 3- or 4-pyridine), optionally substituted imidazole, optionally substituted pyrol , Optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted oxyimidazole, or groups according to the following chemical structure:

During the ceremony:
The Sc of ULM-g to ULM- ⁱ is CHR ^SS , NR ^URE or O;
The R ^HETs of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C ₁ -C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups , Or optionally substituted acetylene group -C≡CR _a , in which the R _a of ULM-g to ULM-i is H or C ₁ -C ₆
An acetylene group that is an alkyl group (preferably C ₁ -C ₃ alkyl);
The R ^SS of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C ₁ -C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
The R ^UREs of ULM-g to ULM-i are H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or -C (O) (C ₁ -C ₆ alkyl). Each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or optionally substituted heterocycles such as piperazine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydro. Thiophene, piperidine, piperazine, etc., each of which is optionally substituted, and
The Y ^C of ULM-g to ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C. ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (eg CF ₃ )), optionally substituted O (C ₁ -C ₆ alkyl) (preferably) Is substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR _a , where R _a is H or C _1- It is an acetylene group which is a C ₆ alkyl group (preferably C ₁ -C ₃ alkyl), and each of each group can optionally be attached to a PTM group (including a ULM'group) via a linker group.

Preferred heterocyclic groups for R ^2'of ULM-g to ULM-i include tetrahydrofuran, tetrahydrothien, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane or thiane, each of which contains It may be optionally substituted or may be a group according to the following chemical structure:

During the ceremony:
The R ^PROs of ULM-g to ULM-i are groups of H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted aryl, heteroaryl or heterocycle;
ULM-g to ULM-i R ^PRO1 and R ^PRO2 are independently H, optionally substituted C ₁ -C ₃ alkyl groups, or both form keto groups, and
Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1), and each of each group is via a linker group. Can optionally be attached to PTM groups (including ULM'groups).

Preferred R ^{2'substituents} for ULM-g to ULM-i are found in the specific compounds disclosed herein, including the specific compounds disclosed herein and the drawings accompanying the specification. Specific examples include R ^{2'substituted} groups (but not limited to the specified compounds disclosed). Each of these R ^{2'substituents} may be used in conjunction with any number of R ^{3'substituents} , which are also disclosed herein.

R ^3'of ULM-g to ULM-i is preferably optionally substituted-T-aryl, optionally substituted-T-heteroaryl, optionally substituted-T-heterocycle, optionally substituted. Is -NR ¹ -T-aryl, optionally substituted-NR ^{1 -T-heteroaryl, or optionally substituted -NR 1 -T-} heterocycle, where R ¹ is H or C. ₁ -C ₃ alkyl group, preferably H or CH ₃ , where T is optionally substituted-(CH ₂ ) _n -group, where each one of the methylene groups is preferably halogen, It may be optionally substituted with a C ₁ -C ₃ alkyl group, or one or two substituents selected from the side chains of the amino acids described elsewhere herein, preferably methyl, which can be optionally substituted. ; And n is 0-6, often 0, 1, 2, or 3, preferably 0 or 1. Alternatively, T can be-(CH ₂ O) _n -group,-(OCH ₂ ) _n -group,-(CH ₂ CH ₂ O) _n -group,-(OCH ₂ CH ₂ ) _n -group. Often, each of those groups is optionally substituted.

Preferred aryl groups for R ^3'of ULM-g to ULM-i include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, in which case the phenyl or naphthyl group is a linker group. And / or halogen (preferably F or Cl
), Amine, monoalkylamine or dialkylamine (preferably dimethylamine), amide group (preferably-(CH ₂ ) _m -NR ₁ C (O) R ₂ , m, R ₁ and R in the formula. ₂ is the same as above), halo (often F or Cl), OH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ , CN or S (O) ₂ R _S group ( _RS is , C ₁ -C ₆ alkyl groups, optionally substituted aryls, heteroaryls or heterocyclic groups, or (CH ₂ ) _m NR ₁ R ₂ groups), each of which is an ortho, meta of a phenyl ring. , And / or those that can be substituted at the para-position (preferably the para-position), or optionally attached to a PTM group (including the ULM'group) via an aryl (preferably phenyl), heteroaryl, or heterocycle. .. The phenyl group of the preferred substituent is an optionally substituted phenyl group (ie, the phenyl group of the substituent itself is preferably F, Cl, OH, SH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ ). , NO ₂ , CN, or at least one of the linker groups, and those groups are attached to PTM groups (including ULM'groups), in which case the substitution is ortho, meta, and / of the phenyl ring. Or para-positions, preferably occurring at the para-position), optionally substituted naphthyl groups including the above, optionally substituted heteroaryls (preferably optionally substituted isoxazoles, including methyl substituted isoxazoles, methyl substituteds). Arbitrarily substituted oxazole containing a substituted oxazole, optionally substituted thiazole containing a methyl-substituted thiazole, optionally substituted pyrol containing a methyl-substituted pyrrole, methyl imidazole, benzyl imidazole or methoxybenzyl imidazole. Includes optionally substituted imidazole, oxyimidazole or methyloxyimidazole, optionally substituted diazole group including methyldiazol group, optionally substituted triazole group including methyl substituted triazole group, halo (preferably F). ) Or a pyridine group containing a methyl-substituted pyridine group or an oxapyridine group (the pyridine group is bonded to a phenyl group with oxygen), or an optionally substituted heterocycle (tetrahydrothiophene, pyrrolidine, piperidine). , Morphorin, piperazine, tetrahydroquinoline, oxane, or thian). The aryl, heteroaryl or heterocyclic groups can optionally be attached to a PTM group (including the ULM'group) via a linker group.

Preferred heteroaryl groups for R ^3'of ULM-g to ULM-i are optionally substituted quinoline (which can be attached to a pharmacophore or substituted on any carbon atom in the quinoline ring), Optionally substituted indols (including dihydroindols), optionally substituted indolidines, optionally substituted azindolidines (2, 3, or 4-azindolidins), optionally substituted benzimidazoles, Benzodiazol, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole , Tetrazol, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or thiol substituted), optionally substituted isothiazole, optionally substituted Triazole (preferably a methyl group, a triisopropylsilyl group, optionally substituted (CH ₂ ) _m -OC ₁ -C ₆ alkyl group, or optionally substituted (CH ₂ ) _m -C (O) -OC ₁ -C ₆ Alkyl group substituted 1,2,3-triazole), optionally substituted pyridine (2,3, or 4-pyridine), or groups with the following chemical structure:

During the ceremony:
The Sc of ULM-g to ULM- ⁱ is CHR ^SS , NR ^URE or O;
The R ^HETs of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C ₁ -C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups (Substituted with) or optionally substituted acetylene group -C≡CR _a , in which R _a is an H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). It is an acetylene group;
The R ^SS of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C ₁ -C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
The R ^UREs of ULM-g to ULM-i are H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or -C (O) (C ₁ -C ₆ alkyl). Each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or optionally substituted heterocycles such as piperazine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydro. Thiophene, piperidine, piperazine, etc., each of which is optionally substituted, and
The Y ^C of ULM-g to ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C. ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (eg CF ₃ )), optionally substituted O (C ₁ -C ₆ alkyl) (preferably) Is substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR _a , where R _a is H or C _1- It is an acetylene group which is a C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). Each of the heteroaryl groups can optionally be attached to a PTM group, including a ULM'group, via a linker group.

Preferred heterocyclic groups for R ^3'of ULM-g to ULM-i include tetrahydroquinoline, piperazine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane or thiane, each of which contains It may be optionally substituted or may be a group according to the following chemical structure:

During the ceremony:
ULM-g to ULM-i R ^PROs are groups of H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocycle, and they. The groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazin, morpholin, quinoline ( Each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halo group, preferably F or Cl), selected from the group consisting of benzofurans, indoles, indolidines, azindridinins;
ULM-g to ^ULM -i R PRO 1 and R ^{PRO 2} are H, optionally substituted C ₁ -C ₃ alkyl groups, or both form a keto group, and ULM-g ~ Each n of ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), and each of the heterocyclic groups is a PTM group (preferably 0 or 1) via a linker group. Can optionally be attached to (including ULM'groups).

Preferred R ^{3'substituents} for ULM-g to ULM-i are found in the specific compounds disclosed herein, including the specific compounds disclosed herein and the drawings accompanying the specification. Specific examples include R ^{3'substituted} groups (but not limited to the specified compounds disclosed). Each of these R ^{3'substituents} may be used in conjunction with any number of R ^{2'substituents} , which are also disclosed herein.

In certain other preferred embodiments, the R ^2'of ULM-g to ULM-i is optionally substituted -NR ₁ -X ^R2' -alkyl group, -NR ₁ -X ^R2' -aryl group; optional. Substituted with -NR ₁ --X R2'-HET, optionally substituted -NR ₁ -X ^{R2 '} -aryl-HET, or optionally substituted -NR ₁ --X R2 ^' -HET-aryl ,
During the ceremony:
R ₁ of ULM-g to ULM-i is an H or C ₁ -C ₃ alkyl group (preferably H);
X ^R2'in ULM-g to ULM-i is optionally replaced- ( CH ₂ ) _n -,- ( CH ₂ ) _n -CH (X _v ) = CH (X _v )-(cis or trance) ,-(CH ₂ ) _n -CH≡CH-,-(CH ₂ CH ₂ O) _n- , or C ₃ -C ₆ cycloalkyl group; and
ULM-g to ULM-i X _v are H, halos, or C ₁ -C ₃ alkyl groups optionally substituted with one or two hydroxyl groups or up to three halogen groups;
The alkyl of ULM-g to ULM-i is an optionally substituted C ₁ -C ₁₀ alkyl (preferably C ₁ -C ₆ alkyl) group (in certain preferred embodiments, the alkyl group is a halo group, Often closed with Cl or Br);
The aryls of ULM-g to ULM-i are optionally substituted phenyl or naphthyl groups (preferably phenyl groups); and
ULM-g to ULM-i HETs are optionally substituted with oxazole, isoxazole, thiazole,
Isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperazine, piperazine, morpholine, benzofuran, indole, indolizine, azindridin, A quinoline (when substituted, each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl or halo group, preferably F or Cl), or a group according to the following structure:

The Sc of ULM-g to ULM- ⁱ is CHR ^SS , NR ^URE or O;
The R ^HETs of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C ₁ -C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups (Substituted with) or optionally substituted acetylene group -C≡CR _a , in which R _a is an H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). It is an acetylene group;
The R ^SS of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C ₁ -C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
The R ^UREs of ULM-g to ULM-i are H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or -C (O) (C ₁ -C ₆ alkyl). Each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or optionally substituted heterocycles such as piperazine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydro. Thiophene, piperidine, piperazine, etc., each of which is optionally substituted;
The Y ^C of ULM-g to ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C. ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (eg CF ₃ )), optionally substituted O (C ₁ -C ₆ alkyl) (preferably) Is substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR _a , where R _a is H or C _1- It is an acetylene group that is a C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);
ULM-g to ULM-i R ^PROs are groups of H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocycle, and they. The groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazin, morpholin, quinoline ( Each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halo group, preferably F or Cl), selected from the group consisting of benzofurans, indoles, indolidines, azindridinins;
ULM-g to ULM-i R ^PRO1 and R ^PRO2 are independently H, optionally substituted C ₁ -C ₃ alkyl groups, or both form keto groups, and
Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).

Each of the above groups can optionally be attached to a PTM group, including a ULM'group, via a linker group.

In certain other preferred embodiments of the invention, R ^3'of ULM-g to ULM-i is optionally substituted-(CH ₂ ) _n- (V) _n' -(CH ₂ ) _n- (CH 2) n-( V) _n' -R ^S3'group , optionally substituted-(CH ₂ ) _n -N (R _1' ) (C = O) _m' -(V) _n' -R ^S3'group , optionally substituted -X ^R3' -alkyl group, optionally substituted -X ^R3' -aryl group; optionally substituted -X ^R3' -HET group, optionally substituted -X ^R3' -aryl-HET group , Or optionally substituted -X ^R3' -HET-aryl group,
During the ceremony:
R ^S3'is an optionally substituted alkyl group (C ₁ -C ₁₀ , preferably C ₁ -C ₆ alkyl), an optionally substituted aryl or HET group;
R _1'is an H or C ₁ -C ₃ alkyl group (preferably H);
V is O, S or NR _1' ;
X ^R3'is- (CH ₂ ) _n -,-(CH ₂ CH ₂ O) _n -,- ( CH ₂ ) _n -CH (X _v ) = CH (X _v )-(cis or trance),- ( CH ₂ ) _n -CH≡CH-, or C ₃ -C ₆ cycloalkyl groups, all of which are optionally substituted;
X _v is an H, halo, or C ₁ -C ₃ alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups;
The alkyl is an optionally substituted C ₁ -C ₁₀ alkyl (preferably C ₁ -C ₆ alkyl) group (preferably a C 1-C 6 alkyl).
In certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br);
Aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); and
HET can be optionally substituted with oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperazine, piperazine. , Morphorin, benzofuran, indole, indolidine, azindolidine, quinoline (preferably C ₁ -C ₃ alkyl groups, respectively, if substituted).
It is preferably substituted with a methyl or halo group, preferably F or Cl), or a group according to the following structure:

The Sc of ULM-g to ULM- ⁱ is CHR ^SS , NR ^URE or O;
The R ^HETs of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C ₁ -C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups (Substituted with) or optionally substituted acetylene group -C≡CR _a , in which R _a is an H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). It is an acetylene group;
The R ^SS of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C ₁ -C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
The R ^UREs of ULM-g to ULM-i are H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or -C (O) (C ₀ -C ₆ alkyl). Each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or optionally substituted heterocycles such as piperazine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydro. Thiophene, piperidine, piperazine, etc., each of which is optionally substituted;
The Y ^C of ULM-g to ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C. ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (eg CF ₃ )), optionally substituted O (C ₁ -C ₆ alkyl) (preferably) Is substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR _a , where R _a is H or C _1- It is an acetylene group that is a C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);
ULM-g to ULM-i R ^PROs are groups of H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocycle, and they. The groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazin, morpholin, quinoline ( Each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halo group, preferably F or Cl), selected from the group consisting of benzofurans, indoles, indolidines, azindridinins;
R PRO 1 and R ^{PRO 2} of ^ULM -g to ULM-i are H, optionally substituted C ₁ -C ₃ alkyl groups, or both form keto groups;
Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1);
Each m'of ULM-g to ULM-i is 0 or 1; and
Each n'of ULM-g to ULM-i is 0 or 1;
In the formula, each of the above compounds, preferably an alkyl group, an aryl group or a Het group, is optionally attached to a PTM group (including a ULM'group) via a linker group.

In another embodiment, R ^3'of ULM-g to ULM-i is-(CH ₂ ) _n -aryl,-(CH ₂ CH ₂ O) _n -aryl,-(CH ₂ ) _n -HET or-. (CH ₂ CH ₂ O) _n -HET,
During the ceremony:
The aryl of ULM-g to ULM-i is a phenyl optionally substituted with one or two substituents, where the substituent is preferably-(CH ₂ ) _n OH, itself. CN, halo (up to 3 halo groups), OH,-(CH ₂ ) _n O (C ₁ -C ₆ ) alkyl, amine, mono- or di- (C ₁ -C ₆ alkyl) amine and more optionally Selected from the substituted C ₁ -C ₆ alkyl, in this case the alkyl group of the amine is optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, or
The aryl groups of ULM-g to ULM-i are-(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) substituted with the alkyl group of the amine in this case Is one or two hydroxyl groups, or up to three halo (preferably F, Cl) groups, CN, NO ₂ , optionally substituted-(CH ₂ ) _n- (V) _m' -CH ₂ ) _n- (V) _m' -(C ₁ -C ₆ ) Alkyl group,-(V) _m' -(CH ₂ CH ₂ O) _n -R Arbitrarily substituted with ^PEG group, where V is O , S or NR _{1' ,} R 1'is an H or C ₁ -C ₃ alkyl group (preferably H), and R ^PEG is an H or optionally substituted C ₁ -C ₆ alkyl group (carboxyl). (Including those optionally substituted with a group), or
The aryl groups of ULM-g to ULM-i include oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, Piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indole, azindridin (if substituted, each preferably preferably a C ₁ -C ₃ alkyl group, preferably a methyl or halo group, preferably F or Cl. (Substituted with), or optionally substituted with a heterocyclic ring containing a heteroaryl selected from the group consisting of groups according to the following structure:

The Sc of ULM-g to ULM- ⁱ is CHR ^SS , NR ^URE or O;
The R ^HETs of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C ₁ -C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups (Substituted with) or optionally substituted acetylene group -C≡CR _a , in which R _a is an H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). It is an acetylene group;
The R ^SS of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C ₁ -C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
The R ^UREs of ULM-g to ULM-i are H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or -C (O) (C ₀ -C ₆ alkyl). Each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or optionally substituted heterocycles such as piperazine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydro. Thiophene, piperidine, piperazine, etc., each of which is optionally substituted;
The Y ^C of ULM-g to ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C. ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (eg CF ₃ )), optionally substituted O (C ₁ -C ₆ alkyl) (preferably) Is substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR _a , where R _a is H or C _1- It is an acetylene group that is a C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);
ULM-g to ULM-i R ^PROs are groups of H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocycle, and they. The groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazin, morpholin, quinoline ( Each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halo group, preferably F or Cl), selected from the group consisting of benzofurans, indoles, indolidines, azindridinins;
R PRO 1 and R ^{PRO 2} of ^ULM -g to ULM-i are H, optionally substituted C ₁ -C ₃ alkyl groups, or both form keto groups;
The ULM-g to ULM-i HETs are preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine. , Piperidine, piperazine, morpholine, quinoline (preferably substituted with C ₁ -C ₃ alkyl group, preferably methyl or halo group, preferably F or Cl), benzofuran, indole, indolein, azind. A lysine, or a group that follows the structure below:

The Sc of ULM-g to ULM- ⁱ is CHR ^SS , NR ^URE or O;
The R ^HETs of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C ₁ -C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups (Substituted with) or optionally substituted acetylene group -C≡CR _a , in which R _a is an H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). It is an acetylene group;
The R ^SS of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C ₁ -C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
The R ^UREs of ULM-g to ULM-i are H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or -C (O) (C ₀ -C ₆ alkyl). Each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or optionally substituted heterocycles such as piperazine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydro. Thiophene, piperidine, piperazine, etc., each of which is optionally substituted;
The Y ^C of ULM-g to ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C. ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (eg CF ₃ )), optionally substituted O (C ₁ -C ₆ alkyl) (preferably) Is substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR _a , where R _a is H or C _1- It is an acetylene group that is a C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);
The R ^PROs of ULM-g to ULM-i are groups of H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted aryl, heteroaryl or heterocycle;
R PRO 1 and R ^{PRO 2} of ^ULM -g to ULM-i are H, optionally substituted C ₁ -C ₃ alkyl groups, or both form keto groups;
Each m'of ULM-g to ULM-i is independently 0 or 1; and
Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).
In the formula, each of the above compounds, preferably the aryl group or the HET group, is optionally attached to a PTM group (including a ULM'group) via a linker group.

In a further additional embodiment, preferred compounds follow the following chemical structure or include pharmaceutically acceptable salts thereof, stereoisomers, solvates or polymorphs:

During the ceremony:
ULM-i's R ^1'is OH, or a group that is metabolized to OH in a patient or subject;
ULM-i's R ^2'is -NH-CH ₂ -aryl-HET- (preferably phenyl directly attached to methyl-substituted thiazole);
ULM-i's R ^3'is -CHR ^CR3' -NH-C (O) -R ^{3P 1} or -CHR ^{CR 3'} -R 3P 2;
ULM-i's R ^CR3'is a C ₁ -C ₄ alkyl group, preferably methyl, isopropyl, or tert-butyl;
ULM-i's R ^{3P 1} is C ₁ -C ₃ alkyl (preferably methyl), an optionally substituted oxetane group (preferably methyl substituted-(CH ₂ ) _n OCH ₃ groups, where n is in the formula. 1 or 2 (preferably 2)), or

(The ethyl ether group is preferably meta-substituted with the phenyl moiety), a morpholino group (bonded to the carbonyl at the 2- or 3-position);
ULM-i's R ^3P2

And;
The aryl of ULM-i is phenyl;
The ULM-i HET is an optionally substituted thiazole, or isothiazole; and
The R ^HET of ULM-i is an H or halo group (preferably H);
In this case, each of the above compounds is optionally attached to a PTM group (including a ULM'group) via a linker group.

In certain embodiments, a bifunctional compound comprising a ubiquitin E3 ligase binding moiety (ULM),
Or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, wherein the ULM is a group according to the following chemical structure:

During the ceremony:
Each R ₅ and R ₆ of ULM-j is an independently substituted OH, SH, or optionally substituted alkyl,
Or R ₅ , R ₆ and the carbon atoms to which they bond form a carbonyl;
R ₇ of ULM-j is H or an optionally substituted alkyl;
E in ULM-j is binding, C = O, or C = S;
G in ULM-j is a bond, optionally substituted alkyl, -COOH, or C = J;
J of ULM-j is O or NR ₈ ;
R ₈ of ULM-j is H, CN, optionally substituted alkyl, or optionally substituted alkoxy;
ULM-j's M is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclic compound, or

And;
ULM-j R ₉ and R ₁₀ are independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide bonded ULM. , Arbitrarily substituted heteroaryl or haloalkyl, or R ₉ , R ₁₀ , and the carbon atoms to which they are attached form an optionally substituted cycloalkyl;
ULM-j's R ₁₁ can be optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

Is; R ₁₂ of ULM-j is H or an optionally substituted alkyl;
ULM-j's R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl,
Arbitrarily substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl, or optionally substituted aralkyl, optionally substituted (Oxoalkyl) carbamate,
Each R ₁₄ of ULM-j is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl;
ULM-j R ₁₅ is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl;
Each R ₁₆ of ULM-j is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy;
Each R ₂₅ of ULM-j can be independently H or an optionally substituted alkyl, or both R ₂₅ groups can be combined together to form an oxo or optionally substituted cycloalkyl group. Often;
R ₂₃ of ULM-j is H or OH;
ULM-j's Z ₁ , Z ₂ , Z ₃ and Z ₄ are independently C or N; and
The o of ULM-j is 0, 1, 2, 3 or 4.

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

In certain embodiments, G in ULM-j is C = J, J is O, R ₇ is H, each R ₁₄ is H, and R ₁₅ is an optionally substituted heteroaryl. And o is 0. In another example, E is C = O and M is

Is.
In certain embodiments, E in ULM-j is C = O and R ₁₁ is an optionally substituted heterocyclic or

And M is

Is.
In certain embodiments, E in ULM-j is C = O and M is

And R ₁₁ is

or

Each R ₁₈ is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy, and p is 0, 1, 2, 3 or 4. ..

In certain embodiments, ULM, and ULM'if present, are independent groups that follow the following chemical structures:

During the ceremony:
G in ULM-k is C = J and J is O;
R ₇ of ULM-k is H; each R ₁₄ of ULM-k is H;
ULM-k o is 0;
ULM-k R ₁₅

And;
R ₁₇ of ULM-k is H, halo, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, and haloalkyl.

In another example, R ₁₇ of ULM-k is alkyl (eg, methyl) or cycloalkyl (eg, cyclopropyl).

In other embodiments, ULM, and ULM'if present, are independent groups that follow the following chemical structures:

During the ceremony:
G in ULM-k is C = J and J is O;
ULM-k's R ₇ is H;
Each R ₁₄ of ULM-k is H;
ULM-k o is 0; and
ULM-k's R ₁₅ is selected from the following group:

In other embodiments, ULM, and ULM'if present, are independent groups that follow the following chemical structures:

During the ceremony:
E in ULM-k is C = O;
ULM-k M is

And;
ULM-k R ₁₁ is selected from the following group:

In yet another embodiment, a compound having the following chemical structure,

During the ceremony:
E in ULM-k is C = O;
ULM-k R ₁₁

And;
ULM-k M is

And;
The q of ULM-k is 1 or 2;
ULM-k's R ₂₀ is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or

And;
R ₂₁ of ULM-k is H or an optionally substituted alkyl; and
R ₂₂ of ULM-k is H, optionally substituted alkyl, optionally substituted alkoxy, or haloalkyl.

In any of the embodiments described herein, R ₁₁ of ULM-j or ULM-k is selected from the group consisting of:

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

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

During the ceremony:
ULM-l's X is O or S;
Y of ULM-l is H, methyl or ethyl;
R ₁₇ of ULM-l is H, methyl, ethyl, hydroxymethyl, or cyclopropyl; M of ULM-l is optionally substituted aryl, optionally substituted heteroaryl, or

And;
ULM-l's R ₉ is H;
ULM-l R ₁₀ is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted. Is thioalkyl, or cycloalkyl;
ULM-l R ₁₁ can be optionally substituted heteroaromatic, optionally substituted heterocyclic, optionally substituted aryl, or

And;
R ₁₂ of ULM-l is H or an optionally substituted alkyl; and
ULM-l R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl,
Arbitrarily substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl, or optionally substituted aralkyl, optionally substituted (Oxoalkyl) carbamate.

In some embodiments, ULM, and ULM'if present, are independent groups that follow the following chemical structures:

During the ceremony:
Y of ULM-m is H, methyol or ethyl
ULM-m's R ₉ is H;
R ₁₀ is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl;
ULM-m R ₁₁ is an optionally substituted amide, an optionally substituted isoindolenone, an optionally substituted isooxazole, an optionally substituted heterocycle.

In another preferred embodiment of the invention, ULM, and ULM'if present, are independent groups that follow the following chemical structures:

During the ceremony:
ULM-n R ₁₇ is methyl, ethyl, or cyclopropyl; and
ULM-n's R ₉ , R ₁₀ , and R ₁₁ are as defined above. In another example, R ₉ is H; and
R ₁₀ of ULM-n is H, alkyl, or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

In any of the embodiments or embodiments described herein, the ULMs (or ULMs, if any) described herein are pharmaceutically acceptable salts, enantiomers, diastereomers thereof. It may be a mar, a solvate, or a polymorph. Further, in any of the embodiments or embodiments described herein, the ULM described herein (or ULM'if present) is attached to the PTM either directly via binding or by a chemical linker. It may be combined.

In a particular aspect of the invention, the ULM moiety is selected from the group consisting of:

In this case, at any suitable location, including eg aryl, heteroaryl, phenyl, or phenyl of indol groups, optionally via any suitable functional group such as amine, ester, ether, alkyl, or alkoxy. , VLM may be attached to PTM via a linker as described herein.

Illustrative CLM:
In any embodiment or embodiment described herein, the present specification provides compounds useful for binding and / or inhibiting cereblon (eg, ULM is CLM, PTM is CLM, or Both ULM and PTM are CLM).

In some embodiments, ULM is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostar thereof, or a derivative thereof, CLM.

Neo-imide compounds In certain embodiments, the CLM is selected from the group consisting of the following chemical structures:

During the ceremony:
W is selected from the group consisting of CH ₂ , CHR, C = O, SO ₂ , NH and N-alkyl;
Each X is selected independently 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-hetaryl, 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 H, alkyl (linear, branched chain optionally substituted with R'), OH, R'OCOOR, R'OCONRR ", optionally substituted with R'CH ₂ -Selected from the group consisting of heterocyclyl and benzyl optionally substituted with R';
Q ₁ , Q ₂ , Q ₃ and Q ₄ represent carbon C substituted with a group independently selected from R', N or N-oxides;
A is independently selected from the group of H, alkyl, cycloalkyl, Cl and F;
R is -CONR'R ", -OR', -NR'R", -SR', -SO ₂ R', -SO ₂ NR'R ", -CR'R"-, -CR'NR'R "-, -aryl, -hetalyl, -alkyl (optionally substituted linear, branched chain), -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) Includes -OR') R ”, -CR'= CR'R”, -CCR', -S (C = O) (C = N-R') R ”, -SF ₅ , or -OCF ₃ Not limited to;
R'and R'are independent, bonded, H, N, N-oxide, alkyl (straight chain, branched chain), cycloalkyl, aryl, heteroaryl, heterocyclic, -C (= O) R, Or selected from the group consisting of heterocyclyls, each of which is optionally substituted;

Represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and R _n comprises a functional group or atom.
In the formula, n is an integer from 1 to 4, and in the formula,
If n is 1, R _n is modified to be covalently attached to the linker group (L), and
If n is 2, 3, or 4, one R _n is modified to be covalently attached to the linker group (L), and any other R _n is optional with PTM, CLM, CLM. It is modified to be covalently attached to a second CLM, CLM', a second linker, or any plurality or combination thereof having the same chemical structure.

Illustrative CLM
In any of the compounds described herein, CLM comprises a chemical structure selected from the following group:

During the ceremony:
W is independently selected from the group consisting of CH ₂ , CHR, C = O, SO ₂ , NH and N-alkyl;
X is selected independently of the O, S and H ₂ groups;
Y is independently selected from the group CH ₂ , -C = CR', NH, N-alkyl, N-aryl, N-hetalyl, N-cycloalkyl, N-heterocyclyl, O and S;
Z is independently selected from the group O and S or H ₂ , but both X and Z must not be H 2;
G and G'are independently H, alkyl (linear, branched chain optionally substituted with R'), OH, R'OCOOR, R'OCONRR ", optionally substituted with R'CH ₂ -Selected from the group of heterocyclyls, and benzyls optionally substituted with R';
Q ₁ to Q ₄ represent carbon C substituted with a group independently selected from R', N or N-oxide;
A is independently selected from the group of H, alkyl, cycloalkyl, Cl and F;
R includes, but is not limited to: -CONR'R ", -OR', -NR'R", -SR', -SO ₂ R', -SO ₂ NR'R ", -CR' R "-, -CR'NR'R"-,-aryl, -hetalyl, -alkyl (optionally substituted straight chain, branched chain), -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 independent, bonded, H, N, N-oxide, alkyl (straight chain, branched chain), cycloalkyl, aryl, heteroaryl, heterocyclic, -C (= O) R, Or selected from the group consisting of heterocyclyls, each of which is optionally substituted;
n is an integer from 1 to 4;

Represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and Rn comprises 1 to 4 independent functional groups or atoms, and optionally within. One is modified to be covalently attached to ABM, chemical linker group (L), ULM, CLM (or CLM') or a combination thereof.

In certain embodiments described herein, CLM or ULM comprises a chemical structure selected from the following group:

During the ceremony:
W is selected independently from the group of CH ₂ , C = O, NH and N-alkyl;
R is independently selected from H, methyl, alkyl;

Represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific; and
Rn contains 1 to 4 independently selected functional groups or atoms, and optionally one of which is modified to PTM, chemical linker group (L), CLM (or CLM') or them. Covalently combined to the combination of.

In some embodiments, the CLM is represented by the following structure, where the dashed line indicates the linker binding point:

More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules resulting from one or more combinations of different properties shown in the following molecules.

In any of the compounds described herein, CLM comprises a chemical structure selected from the following group:

During the ceremony:
W in equations (h) to (ab) is independently selected from CH ₂ , CHR, C = O, SO ₂ , NH and N-alkyl;
_Q1 , _Q2 , _Q3 , _Q4 , and Q5 of formulas (h) to ₍ ab) are independently substituted with a group selected independently from R', N or N-oxide. Represents C;
R ¹ of equations (h) to (ab) is selected from H, CN, C ₁ to C ₃ alkyl;
R ² of equations (h) to (ab) is selected from the group H, CN, C ₁ to C ₃ alkyl, CHF ₂ , CF ₃ , CHO; R ³ of equations (h) to (ab). Is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;
R ⁴ of equations (h) to (ab) is selected from H, alkyl, substituted alkyl;
R ⁵ in equations (h) to (ab) is H or a lower alkyl;
X in equations (h)-(ab) is C, CH or N;
R'in formula (h)-formula (ab) is selected from H, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy;
R in formulas (h)-(ab) is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy, or halogenated lower alkyl.
Equations (h) to (ab)

Is a single or double bond; and the CLM is covalently attached to a PTM, a chemical linker group (L), ULM, CLM (or CLM') or a combination thereof.

In any embodiment or embodiment described herein, CLM or CLM'is represented by the formula (h).
)-R group of equation (ab) (eg R, R ¹ , R ² , R ³ , R ⁴ or R'), W, X, or Q group (eg Q ₁ , Q ₂ , Q ₃ , Q 3) Covalently attached to PTM, chemical linker group (L), _ULM , CLM, CLM', or a combination thereof via ₄ , or Q5).

In any of the embodiments described herein, CLM or CLM'is expressed in formula (h).
) ~ 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 in equation (ab), Covalently attached to PTM, chemical linker group (L), ULM, CLM, CLM', or a combination thereof.

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

More specifically, non-limiting examples of CLMs include those listed below, as well as "hybrid" molecules or compounds resulting from a combination of one or more properties of the following compounds:

During the ceremony:
W of formula (ac)-formula (an) is independently selected from the group of CH ₂ , CHR, C = O, SO ₂ , NH and N-alkyl;
R ¹ of formula (ac) to formula (an) is selected from the group of H, CN, C ₁ to C ₃ alkyl; R ³ of formula (ac) to formula (an) is H, alkyl, substituted alkyl. , Alkoxy, substituted alkoxy;
R of equations (ac) to equations (an) is H;

Is a single bond or a double bond; and Rn of formulas (ac) to formula (an) comprises a functional group or an atom.

In any of the embodiments described herein, W, R ¹ , R ² of equations (ac) to (an).
, Q ₁ , Q ₂ , Q ₃ , Q ₄ , and Rn may be independent and covalently attached to the linker, and /
Alternatively, it may be covalently attached to a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

In any of the embodiments described herein, R ¹ , R ² , Q ₁ of the formulas (ac) to (an).
, Q ₂ , Q ₃ , Q ₄ , and Rn may be independently covalently attached to the linker and / or a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups. May be covalently bonded to.

In any of the embodiments described herein, _Q1 , _Q2 , _Q3 , _Q4 , and Rn of formulas (ac) to formula (an) may be independently covalently attached to the linker. Well and / or may be covalently attached to a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

In any of the embodiments or embodiments described herein, R _n of formula (ac)-formula (an) has been modified to have the same chemical structure as the linker group (L), PTM, ULM, CLM. Covalently attached to a second CLM, CLM', a second linker, or any plurality or combination thereof.

In any embodiment or embodiment described herein, the CLM is selected from:

In the formula, R'is a halogen, and R ¹ is as described above for formulas (h) to formula (ab) or formulas (ac) to formula (an).

In certain examples, the CLM may be an imide that binds to cereblon E3 ligase.
These imide and linker binding points may have, but are not limited to, the following structures:

In the formula, R'is a halogen.
Illustrative linker:
In either embodiment or embodiment comprising the structure of ULM-L-PTM, the linker (L) comprises a chemical structural unit represented by the following formula:
-(A) _q- ,
During the ceremony:
A is the group linked to the ULM or PTM moiety; and
q is an integer greater than or equal to 1
In the equation, A is the bond, CR ^L1 R ^L2 , O, S, SO, SO ₂ , NR ^L3 , SO ₂ NR ^L3 , SONR ^L3 , CONR ^L3 , NR ^L3 CONR ^L4 , NR ^L3 SO ₂ NR ^L4 , CO, CR ^L1 = CR ^L2 , C≡C, SiR ^L1 R ^L2 , P (O) R ^L1 , P (O) OR ^L1 , NR ^L3 C (= NCN) NR ^L4 , NR ^L3 C (= NCN), NR ^L3 C (= CNO ₂ ) NR ^L4 , C _3-11 cycloalkyl optionally substituted with 0-6 R ^L1 and / or R ^L2 , with 0-6 R ^L1 and / or R ^L2 Optionally substituted C _3-11 heterocyclyl, optionally substituted with 0-6 R ^L1 and / or R ^L2 , optionally with 0-6 R ^L1 and / or R ^L2 Selected from the group consisting of the heteroaryls to be substituted, in the formula, R ^L1 or R ^L2 are independently and arbitrarily attached to each other, and are optionally substituted with 0 to 4 R ^L5 groups and / or a cycloalkyl moiety. Or form a heterocyclyl moiety;
R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are independently H, halo, C _1-8 alkyl, OC _1-8 alkyl, SC _1-8 alkyl, NHC _1-8 alkyl, N ( C _1-8 alkyl) ₂ , C _3-11 cycloalkyl, aryl, heteroaryl, C _3-11 heterocyclyl, OC _1-8 cycloalkyl, SC _1-8 cycloalkyl, NHC _1-8 cycloalkyl, N (C) _1-8 cycloalkyl) ₂ , N (C _1-8 cycloalkyl) (C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P (O) (OC _1-8 alkyl) ) (C _1-8 alkyl), P (O) (OC _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH = CH (C _1-8 alkyl), C (C _1-8 alkyl) ) = CH (C _1-8 alkyl), C (C _1-8 alkyl) = C (C _1-8 alkyl) ₂ , Si (OH) ₃ , Si (C _1-8 alkyl) ₃ , Si (OH) (C _1-8 alkyl) ₂ , COC _1-8 alkyl, CO ₂ H, halogen, CN, CF ₃ , CHF ₂ , CH ₂ F, NO ₂ , SF ₅ , SO ₂ NHC _1-8 alkyl, SO ₂ N (C _1-8 alkyl) ₂ , SONHC _1-8 alkyl, SON (C _1-8 alkyl) ₂ , CONHC _1-8 alkyl, CON (C _1-8 alkyl) ₂ , N (C _1-8 alkyl) CONH (C _1-8 alkyl), N (C _1-8 alkyl) CON (C _1-8 alkyl) ₂ , NHCONH (C _1-8 alkyl), NHCON (C _1-8 alkyl) ₂ , NHCONH ₂ , N ( C _1-8 alkyl) SO ₂ NH (C _1-8 alkyl), N (C _1-8 alkyl) SO ₂ N (C _1-8 alkyl) ₂ , NH SO ₂ NH (C _1-8 alkyl), NH SO ₂ N (C _1-8 alkyl) ₂ , NHSO ₂ NH ₂ .

In any of the embodiments or embodiments described herein, the linker (L) comprises the following chemical structure:

During the ceremony:
W ^L1 and W ^L2 are independently, optionally substituted, 4- to 8-membered rings with ^{0-4 heteroatoms, and each R Q is} independently H, halo, OH, CN, CF ₃ , C ₁ -C ₆ alkyl (optionally substituted straight chain, branched chain), C ₁ -C ₆ alkoxy (optionally substituted linear, branched chain),
Or two Race ^Queen groups, together with the atoms to which they bind, form a 4- to 8-membered ring system containing 0-4 heteroatoms;
Y ^L1 are independently bonded, C ₁ -C ₆ alkyl (optionally substituted straight chain, branched chain), and optionally one or more C atoms are O, or C ₁ -C. ₆ Substituted with alkoxy (optionally substituted straight chain, branched chain); and dashed lines indicate the point of attachment to the PTM or ULM moiety.

In any of the embodiments or embodiments described herein, the linker (L) comprises the following chemical structure:

During the ceremony:
W ^L1 and W ^L2 are independently aryl, heteroaryl, cyclic, heterocyclic, C _1-6 alkyl, bicyclic, biaryl, biheteroaryl, or dihypocyclic, and each is optionally R. Substituted with ^Q , each R ^Q is independently H, halo, OH, CN, CF ₃ , hydroxyl, nitro, _C≡CH , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl (Optionally substituted linear, branched chain), C ₁ -C ₆ alkoxy (optionally substituted linear, branched chain), OC _1-3 alkyl (optionally substituted by one or more -Fs) ), OH, NH ₂ , NR ^Y1 R ^Y2 , CN, or 4-8 members in which 2 R ^Q groups contain 0-4 heteroatoms, along with the atoms to which they are attached. Form a ring system;
Y ^L1 is independently coupled, NR ^YL1 , O, S, NR ^YL2 , CR ^YL1 R ^YL2 , C = O, C = S, SO, SO ₂ , C ₁ -C ₆ alkyl (optionally substituted) Straight chain, branched chain), and optionally one or more C atoms are substituted with O, C ₁ -C ₆ alkoxy (optionally substituted straight chain, branched chain);
Q ^L is a 3- to 6-membered alicyclic or aromatic ring with 0 to 4 heteroatoms, optionally crosslinked, optionally replaced by 0 to 6 R ^Q , and each R ^Q. Are independently H, C _1-6 alkyl (straight, branched, optionally substituted with one or more halos, C _1-6 alkoxyls), or two R ^Q groups Form a 3- to 8-membered ring system containing 0 to 2 heteroatoms with the atoms to which they bond); R ^YL1 and R ^YL2 are independently H, OH, and C _1-6 alkyl. (Linear, branched, optionally substituted with one or more halos, C _1-6 alkoxyls), or R ¹ , R ² are 0 to 2 with the atom to which they are attached. Forming a 3- to 8-membered ring system containing heteroatoms of);
n is 0-10; and
The dashed line indicates the point of connection to the PTM or ULM moiety.

In some embodiments, the linker (L) comprises a group represented by a general structure selected from the group consisting of:
-N (R)-(CH ₂ ) _m -O (CH ₂ ) _n -O (CH ₂ ) _o -O (CH ₂ ) _p -O (CH ₂ ) _q -O (CH ₂ ) _r -OCH _2- ,
-O- (CH ₂ ) _m -O (CH ₂ ) _n -O (CH ₂ ) _o -O (CH ₂ ) _p -O (CH ₂ ) _q -O (CH ₂ ) _r -OCH _2- ,
-O- (CH ₂ ) _m -O (CH ₂ ) _n -O (CH ₂ ) _o -O (CH ₂ ) _p -O (CH ₂ ) _q -O (CH ₂ ) _r -O- ；
-N (R)-(CH ₂ ) _m -O (CH ₂ ) _n -O (CH ₂ ) _o -O (CH ₂ ) _p -O (CH ₂ ) _q -O (CH ₂ ) _r -O-;
-(CH ₂ ) _m -O (CH ₂ ) _n -O (CH ₂ ) _o -O (CH ₂ ) _p -O (CH ₂ ) _q -O (CH ₂ ) _r -O-;
-(CH ₂ ) _m -O (CH ₂ ) _n -O (CH ₂ ) _o -O (CH ₂ ) _p -O (CH ₂ ) _q -O (CH ₂ ) _r -OCH _2- ;

In the equation, each m, n, o, p, q, and r are 0, 1, 2, 3, 4, 5, and 6, respectively, respectively.
However, if the number is zero and there are no NO or OO bonds, then R is selected from the group H, methyl or ethyl, and X is selected from the group H or F;

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

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

In the equation, each n and m are independently 0, 1, 2, 3, 4, 5, or 6.
In some embodiments, L is an optionally substituted polyethyleneoxy group containing 1-10 units.

In some additional embodiments, L is a polyethylene group optionally substituted with aryl or phenyl, containing 1-10 ethylene glycol units.

In any embodiment, the compound comprises a plurality of ULMs, a plurality of PTMs, a plurality of linkers, or any combination thereof.

Exemplary Tau-PROTAC Compounds In certain embodiments as described above, the present specification is the at least one PTM described herein.
Provided is a bifunctional PROTAC compound containing a group, a linker, and at least one ULM (VLM or CLM) group.

In certain embodiments, the compound is selected from the group consisting of compounds 1-330 (eg, compounds selected from Tables 1 or 2) as well as salts and polymorphs thereof.

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

In any of the embodiments or embodiments described herein, the compound is selected from the following formulas CI-CV:

During the ceremony:
R ¹⁰¹ is one or two substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;
R ¹⁰² is selected from H, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl;
R ¹⁰³ is one or two substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;
R ¹⁰⁴ is one or two substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;
R ¹⁰⁵ is one or two substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;
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 are independent of each other. And choose from H, alkyl, halogen or haloalkyl;
R ¹⁰⁸ is one or two 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 are together with the carbon atom to which they are attached, for example 3 to such as cyclopropane or oxetane. Represents a 6-membered cycloalkyl or heterocycloalkyl ring;
R ¹²⁴ and R ¹²⁵ are independently selected from H, alkyl, halogen or haloalkyl, or R ¹²⁴ and R ¹²⁵ , together with the carbon atom to which they are attached, such as cyclopropane or oxetane 3 ~ Represents a 6-membered cycloalkyl or heterocycloalkyl ring;
G is a phenyl, or 5- or 6-membered heteroaryl ring; and
Z is CH ₂ or C = O.

In any aspect or embodiment described herein, at least one of the following:
R ¹⁰¹ is H, F, or Cl;
R ¹⁰² is H, CH ₃ , or CF ₂ H;
R ¹⁰³ is H or F;
R ¹⁰⁴ is H, CH ₃ , F or CN;
R ¹⁰⁵ is H, CN, CH ₃ , or CF ₃ ;
R ¹⁰⁶ and R ¹⁰⁷ are independently H, F or CH ₃ ;
R ¹⁰⁸ is H, F, or CH ₃ O;
R ¹⁰⁹ and R ¹¹⁰ are independently H or CH ₃ ;
R ¹¹¹ and R ¹¹² are independently H, F or CH ₃ ;
R ¹¹³ and R ¹¹⁴ are independently H or CH ₃ ;
R ¹¹⁵ is H or CH ₃ ;
R ¹¹⁶ and R ¹¹⁷ are independently H or CH ₃ ;
R ¹¹⁸ and R ¹¹⁹ are independently H, CH ₃ , F, respectively, or R ¹¹⁸ and R ¹¹⁹ represent a ring of cyclopropane or oxetane with the carbon atom to which they are attached;
R ¹²⁰ and R ¹²¹ are independently H or CH ₃ ;
R ¹²² and R ¹²³ are independently H or CH ₃ ;
R ¹²⁴ and R ¹²⁵ are independently H, CH ₃ , F, respectively, or R ¹²⁴ and R ¹²⁵ represent a ring of cyclopropane or oxetane with the carbon atom to which they bind;
R ¹²⁶ and R ¹²⁷ are independently H or CH ₃ ;
A is pyridine or pyrimidine;
Z is CH ₂ or C = O; or a combination thereof.

In any of the embodiments or embodiments described herein, the compound is selected from the group consisting of: (2S, 4R) -1-((S) -14-(5- (5H-pyridin]. 4,3-b] Indol-7-yl) Pyridine-2-yloxy) -2-tert-butyl-4-oxo-6,9,12-Trioxa-3-azatetradecane) -4-Hydroxy-N-( 4- (4-Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (1); 4- (2- (2- (2- (2- (5- (5H-pyrido] 4,3-b) ] Indol-7-yl) Pyridine-2-yloxy) ethoxy) ethoxy) ethoxy) ethylamino) -2- (2,6-dioxopiperidine-3-yl) isoindrin-1,3-dione (2); 4- (2- (2- (2- (5- (5- (5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yloxy) ethoxy) ethoxy) ethylamino) -2- (2, 6-Dioxopiperidin-3-yl) Isoindrin-1,3-dione (3); 4-(14-(5-(5H-pyrido [4,3-b] indol-7-yl) pyridin-2 -Iloxy) -3,6,9,12-Tetraoxatetradecylamino) -2- (2,6-dioxopiperidin-3-yl) Isoindrin-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) Acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (5); (2S, 4R) -1- ((S) -17-(5- (5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yloxy) -2-tert-butyl-4-oxo-6,9,12, 15-Tetraoxa-3-azaheptanedecane) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (6); (2S, 4R) -1- ( (S) -14-(4- (Benzo [4,5] imidazole [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-methylthia) Zol-5-yl) benzyl) pyrrolidine-2-carboxamide (7); (2S, 4R) -1-((S) -2-tert-butyl-15- (2- (4- (dimethylamino) phenyl)) Kinolin-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) quinoline-6-yloxy) -4-oxo-6 , 9,12,15-Tetraoxa-3-azaoctadecane) -4-Hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) Pyrrolidine-2-carboxamide (9); (2S, 4R) -1-((S) -14-(4- (benzo [4,5] imidazo [1,2-a] pyrimidine-2-yl) piperazine-1-yl) -2- (tert-butyl) -4 , 14-Dioxo-6,9,12-trioxa-3-azatetradecanoyl) -4-hydroxy-N-(4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (10) (2S, 4R) -1-((S) -14-(4- (benzo [4,5] imidazo [1,2-a] pyrimidine-2-yl) piperazin-1-yl) -2- ( tert-butyl) -4-oxo-6,9,12-trioxa-3-azatetradecanoyl) -4-hydroxy-N-(4-(4-methyloxazole-5-yl) benzyl) pyrrolidine-2- Carboxamide (11); (2S, 4R) -1-((S) -17- (4- (benzo [4,5] imidazo [1,2-a] pyrimidine-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) Pyrrolidine-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-methyl) Oxazole-5-yl) benzyl) pyrrolidine- 2-Carboxamide (13); (2S, 4R) -1-((S) -17- (4- (benzo [4,5] imidazo [1,2-a] pyrimidine-2-yl) piperazine-1- Il) -2- (tert-butyl) -4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl) -4-hydroxy-N- (4- (4-methyloxazole-) 5-yl) benzyl) pyrrolidine-2-carboxamide (14); (2S, 4R) -1-((S) -14-(4- (benzo [4,5] imidazo [1,2-a] pyrimidin- 2-Il) Piperazine-1-yl) -2- (tert-butyl) -4-oxo-6,9,12-trioxa-3-azatetradecanoyl) -4-hydroxy-N-((S)- 1-(4- (4-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (15); (2S, 4R) -1-((S) -17- (4- (benzo [4) , 5] Imidazo [1,2-a]
Pyrimidine-2-yl) Piperazine-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) piperazine-2-carboxamide (16); (2S, 4R) -1-((S) -14- (4-) (Benzo [4,5] imidazo [1,2-a] pyrimidin-2-yl) piperazine-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) piperazine-2-carboxamide (17); (2S, 4R) -1-((S) -17-(4- (benzo [4,5] imidazo [1,2-a] piperazine-2-yl) piperazine-1-yl) -2- (tert-butyl) -4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazole-5-yl) ) Phenyl) ethyl) pyrrolidine-2-carboxamide (18); (2S, 4R) -1-((S) -14- (4- (benzo [4,5] imidazo [1,2-a] piperazine-2) -Il) Piperazine-1-yl) -2- (tert-butyl) -4-oxo-6,9,12-trioxa-3-azatetradecanoyl) -4-hydroxy-N-((S) -1 -(4- (4-Methyloxazole-5-yl) phenyl) ethyl) piperazine-2-carboxamide (19); (2S, 4R) -1-((S) -17- (4- (benzo [4,,, benzo] 5] Imidazo [1,2-a] pyrimidin-2-yl) piperazine-1-yl) -2- (tert-butyl) -4-oxo-6,9,12,15-tetraoxa-3-azaheptadeca Noyl) -4-hydroxy-N-((S) -1- (4- (4-methyloxazol-5-yl) phenyl) ethyl) piperazine-2-carboxamide (20); (2S, 4R) -1- ((S) -14-(4- (benzo [4,5] imidazo [1,2-a] piperazine-2-yl) piperazine-1-yl) -2- (tert-butyl) -4,14- Dioxo-6,9,12-trioxa-3-azatetradecanoyl) -4-hydroxy-N-((S) -1- (4-) (4-Methyloxazole-5-yl) phenyl) ethyl) piperazine-2-carboxamide (21); (2S, 4R) -1-((S) -17- (4- (benzo [4,5] imidazo] 1,2-a] pyrimidin-2-yl) piperazine-1-yl) -2- (tert-butyl) -4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl) -4-Hydroxy-N-((S) -1-(4- (4-methyloxazole-5-yl) phenyl) ethyl) piperazine-2-carboxamide (22); (2S, 4R) -1-(( S) -17-(4- (benzo [4,5] imidazo [1,2-a] pyrimidin-2-yl) piperazine-1-yl) -2- (tert-butyl) -4-oxo-6, 9,12,15-Tetraoxa-3-azaheptadecanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) piperazine-2-carboxamide (23); (2S, 4R) )-1-((S) -17-(4- (Benzo [4,5] imidazo [1,2-a] piperazine-2-yl) piperazine-1-yl) -2- (tert-butyl)- 4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (24); 4-((2- (2- (2- (2- (4- (benzo [4,5] imidazo [1,2-a] piperazine-2-yl) piperazine-1-yl) ethoxy) ) Ethoxy) ethoxy) ethyl) amino) -2- (2,6-dioxopiperidine-3-yl) isoindrin-1,3-dione (25); 4-((14-(4- (benzo [4) , 5] Imidazo [1,2-a] pyrimidin-2-yl) piperazine-1-yl) -3,6,9,12-tetraoxatetradecyl) amino) -2- (2,6-dioxopiperidine) -3-yl) Isoindrin-1,3-dione (26); (2S, 4R) -1-((S) -2- (2- (2- (2- (2- (4- (dimethylamino) dimethylamino) ) Phenyl) quinoline-6-yloxy) ethoxy) ethoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) piperazine-2- Carboxamide (27); (2S, 4R) -1-((S) -2- (2- (2- ( 2- (2- (4- (dimethylamino) phenyl) quinoline-6-yloxy) ethoxy) ethoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1-( 4- (4-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (28); (2S, 4R) -1-((S) -2-tert-butyl-14-(2- ( 4- (dimethylamino) phenyl) quinoline-6-yloxy) -4-oxo-6,9,12-trioxa-3-azatetradecane) -4-hydroxy-N- (4- (4-methylthiazole-5-) Il) benzyl) pyrrolidine-2-carboxamide (29); (2S, 4R) -1-((S) -2-tert-butyl-14- (2- (4)
-(Dimethylamino) Phenyl) Kinolin-6-yloxy) -4-oxo-6,9,12-Trioxa-3-azatetradecane) -4-Hydroxy-N-((S) -1- (4- (4) -Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (30); (2S, 4R) -1-((S) -2-tert-butyl-17- (2- (4- (dimethyl) Amino) Phenyl) Kinolin-6-Iloxy) -4-oxo-6,9,12,15-Tetraoxa-3-
Azaheptanedecane) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (31); (2S, 4R)- 1-((S) -2-tert-butyl-17-(2- (4- (dimethylamino) phenyl) quinoline-6-yloxy) -4-oxo-6,9,12,15-tetraoxa-3- Azaheptanedecane) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (32); (2S, 4R)- 1-((S) -2-(2- (4- (2- (4- (dimethylamino) phenyl) quinoline-6-yloxy) butoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy -N- (4- (4-Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (33); (2S, 4R) -1-((S) -2- (2- (4- (2) -(4- (Dimethylamino) phenyl) quinoline-6-yloxy) butoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4-methyl) Thiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (34); (2S, 4R) -1-((S) -2- (2- (3- (3- (2- (4- (4- (4- (4-) Dimethylamino) phenyl) quinoline-6-yloxy) propoxy) propoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine- 2-Carboxamide (35); (2S, 4R) -1-((S) -2- (2- (3- (3- (2- (4- (dimethylamino) phenyl) quinoline-6-yloxy) propoxy) ) Propoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (36); (2S, 4R) -1-((S) -2- (2-(5- (2- (4- (dimethylamino) phenyl) quinoline-6-yloxy) pentyloxy) acetamide) -3 , 3-Dimethylbutanoyl) -4-Hydroxy-N- (4- (4-Methylthiazole-5-yl) benzyl) Pyrrolidine-2-carboxamide (37); (2S, 4R) -1- ( (S) -2- (2- (5- (2- (4- (Dimethylamino) phenyl) quinoline-6-yloxy) pentyloxy) acetamide) -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) quinoline-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)) Kinolin-6-yloxy) -3,6,9,12-tetraoxapentadecylamino) -2- (2,6-dioxopiperidin-3-yl) isoindrin-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) isoindrin-1,3-dione (41); 4-((14-(4- (benzo [4,,, benzo]) 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) Isoindrin-1,3-dione (42); (2S, 4R) -1-((2S) -2-tert-butyl-15- (2- (4- (dimethylamino) ) Phenyl) quinoline-6-yloxy) -14-hydroxy-4-oxo-6,9,12-trioxa-3-azapentadecane) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) ) Benzyl) pyrrolidine-2-carboxamide (43); 4- (2- (2- (2- (2- (3- (2- (4- (dimethylamino) phenyl) quinoline-6-yloxy) propoxy) ethoxy) ethoxy) Ethylamino) -2- (2,6-dioxopiperidine-3-yl) isoindrin-1,3-dione (44); 4- (15-(2- (4- (dimethylamino) phenyl) quinoline- 6-Iloxy) -14-hydro Xi-3,6,9,12-tetraoxapentadecylamino) -2- (2,6-dioxopiperidine-3-yl) isoindolin-1,3-dione (45); (2S, 4R)- 1-((2S) -2-tert-butyl-18-(2- (4- (dimethylamino) phenyl) quinoline-6-yloxy) -17-hydroxy-4-oxo-6,9,12,15- Tetraoxa-3-azaoctadecane) -4-hydroxy-N-(4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (46); 4- (2- (2- (2- (2- (2- (2- 3- (2- (4- (dimethylamino) phenyl) quinoline-6-yloxy) -2-hydroxypropoxy) ethoxy) ethoxy) ethylamino) -2- (2,6-dioxopiperidine-3-yl) iso Indole-1,3-dione (47); 2- (2,6-dioxopiperidine-3-yl) -4-(14-(5- (5-methyl-5H-pyrido [4,3-b]] Indole-7-yl) Pyridin-2-yloxy) -3,6,9,12-Tetraoxatetradecylamino) Isoindrin-1,3-dione (48); 3- (4- (14- (5- (5-) (5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yloxy) -3,6,9,12-tetraoxatetradecylamino) -1-oxoisoindolin-2-yl) Peridine-2,6-dione (49); 3-(4-(14-(5- (5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yloxy) -3,6 , 9,12-Tetraoxatetradecyloxy) -1-oxoisoindolin-2-yl) piperidine-2,6-dione (50); 5-((14-((5- (5H-pyrido) [ 4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecyl) oxy) -2- (2,6-dioxopiperidine-3-) Il) Isoindrin-1,3-dione (51); 5-((5-(4-(2-(3-(5-(5H-pyrido [4,3-b] indole-7-yl) pyridine -2-yl) propoxy) ethyl) piperazin-1-yl) pentyl) oxy) -2- (2,6-dioxopiperidine-3-yl) isoindolin-1,3-dione (52); 5-( 4- (3-((1s, 3s) -3-((5- (5H-pyrido [4,3-b] indole-) 7-yl) Pyridin-2-yl) Oxy) Cyclobutoxy) propyl) Piperidine-1-yl) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione (53) 5-((5- (4- (3- (5- (5- (5H-pyrid [4,3-b] indol-7-yl) pyridin-2-yl) propyl) piperidine-1-yl) pentyl) oxy) ) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (54); 5- (3- (6- (4- (3- (5- (5H-pyrido)) [4,3-b] indol-7-yl) pyridine-2-yl) propyl) piperidine-1-yl) pyridine-3-yl) propoxy) -2- (2,6-dioxopiperidine-3-yl) ) Isoindoline-1,3-dione (55); 5-((5-(4-(2-((1s, 3s) -3-((5- (5H-pirid [4,3-b] indole) -7-Il) Pyridin-2-yl) Oxy) Cyclobutoxy) Ethyl) Piperazin-1-yl) Pentyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3 -Zeon (56); 5-((14-(4- (5H-pyrido [4,3-b] indol-7-yl) piperidine-1-yl) -3,6,9,12-tetra Oxatetradecyl) oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (57); 5-((5- (2- (4- (3- (3- (3-) 5- (5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) propyl) piperazine-1-yl) ethoxy) pentyl) oxy) -2- (2,6-dioxopiperidine) -3-Il) Isoindoline-1,3-dione (58); 5-((5-(4- (2-((1r, 3r) -3-((5- (5H-pirid [4,3) -b] indol-7-yl) pyridine-2-yl) oxy) cyclobutoxy) ethyl) piperazin-1-yl) pentyl) oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline -1,3-dione (59); 5- (4- (3-((1r, 3r) -3-((5- (5H-pyrid [4,3-b] indol-7-yl) pyridine- 2-yl) oxy) cyclobutoxy) propyl) piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (60); 2- (2, 6-Ji Oxopiperidine-3-yl) -5-((5- (4- (3- (5- (5- (2,2,2-trifluoroethyl) -5H-pyrid [4,3-b] indol) -7-Il) Pyridin-2-yl) propyl) Piperidine-1-yl) Pentyl) Oxy) Isoindrin-1,3-dione (61); 3- (5-((5- (4- (3- (3- (3- (3- (3-)3-) (5- (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) propyl) piperidine-1-yl) pentyl) oxy) -1-oxoisoindrin-2 -Il) piperidine-2,6-dione (62); 2- (2,6-dioxopiperidine-3-yl) -5-((5- (4- (3- (5- (5- (5- (5- (5- (5- (5-) 5-) Methyl-5H-pyrido [4,3-b] indol-7-yl) -3- (trifluoromethyl) pyridine-2-yl) propyl) piperidine-1-yl) pentyl) oxy) isoindrin-1,3 -Zeon (63); 5- (4- (3- (5-((1r, 3r) -3-((5- (5H-pyrid [4,3-b] indol-7-yl) pyridine-2) -Il) oxy) cyclobutoxy) pyridine-2-yl) propyl) piperidine-1-yl) -2- (2,6-dioxopiperidine-3-yl) isoindrin-1,3-dione (64); 5-((5- (4-((1r, 3r) -3-((5- (5H-pyrid [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy)) Piperidine-1-yl) Pentyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindrin-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) piperidine-1-yl) Ethyl) piperazin-1-yl) -2- (2,6-dioxopiperidine-3-yl) isoindrin-1,3-dione (66); 2- (2,6-dioxopiperidine-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) Isoindrin-1,3-dione (67); 2- (2,6-dioxopiperidine-3-yl) -5- (4- (5) -((1r, 3r) -3-((5-) (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pentyl) piperazine-1-yl) isoindoline-1,3-dione (68) ); 2- (2,6-dioxopiperidine-3-yl) -5-((14-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl)- 4- (Trifluoromethyl) Pyridine-2-yl) Oxy) -3,6,
9,12-Tetraoxatetradecyl) oxy) Isoindoline-1,3-dione (69); 2- (2,6-dioxopiperidine-3-yl) -5- (2- (2- (2- (2- (2- (2-) (2-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) ethoxy) Ethoxy) ethoxy) ethoxy) isoindoline-1,3-dione (70); 2- (2,6-dioxopiperidine-3-yl) -5-((15- (5- (5-methyl-5H-) Pyrid [4,3-b] indole-7-yl) pyridine-2-yl) -3,6,9,12-tetraoxapentadeca-14-in-1-yl) oxy) isoindoline-1,3 -Zeon (71); 5-((14-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy)-3,6,9,12- Tetraoxatetradecyl) oxy) -2- (2,6-dioxopiperidine-3-yl) -4,6,7-trifluoroisoindoline-1,3-dione (72); [5-((3) -(5-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl ) Propa-2-in-1-yl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione] (73); 2- (2,6-dioxopi Perizin-3-yl) -5-((15-(5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) -3,6,9 , 12-Tetraoxapentadecyl) oxy) Isoindoline-1,3-dione (74); 2- (2,6-dioxopiperidine-3-yl) -5-(4- (5-((5-5-) ((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) pentyl) oxy) pentyl) piperidin-1-yl) isoindoline- 1,3-dione (75); 2- (2,6-dioxopiperidine-3-yl) -5-(3- (3- (4- (3- (5- (5- (5-methyl-5H-pyrido)) [4,3-b] indole-7-yl) pyridine-2-yl) propa-2-in-1-yl) piperazin-1-yl) propoxy) azetidine-1-yl) isoindoline-1,3- Zeon (76); 5-( 3- (5-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2- Il) propoxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (77); 2- (2,6-dioxopiperidine-3-yl) -5- (4-(6-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ) Hexil) Piperazin-1-yl) Isoindoline-1,3-dione (78); 2- (2,6-dioxopiperidine-3-yl) -5-(3-((5-((5-5-yl)) ((5- (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) oxy) pentyl) oxy) pentyl) oxy) azetidine-1-yl) isoindoline- 1,3-dione (79); 2- (2,6-dioxopiperidine-3-yl) -5-((1- (5-((5-((5- (5- (5- (5- (5- (5- (5- (5- (5-"5-pyridoline) -pyridoline) [4,3-b] Indole-7-yl) Pidrid-2-yl) Oxy) Pentyl) Oxy) Pentyl) Azetidine-3-yl) Oxy) Isoindoline-1,3-dione (80); 5- ( (14-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) -3,6,9,12-tetraoxatetradecyl) oxy) -2 -(2,6-dioxopiperidine-3-yl) -6-fluoroisoindoline-1,3-dione (81); 2- (2,6-dioxopiperidine-3-yl) -5-(((2,6-dioxopiperidine-3-yl) 5- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) Piperidine-1-yl) pentyl) oxy) isoindoline-1,3-dione (82); 5-((5-(5-((1r, 3r) -3-((5- (5H-pyrido)) [4,3-b] Indol-7-yl) Pylindo-2-yl) Oxy) Cyclobutoxy) Pylin-2-yl) Pentyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione (83); 2- (2,6-dioxopiperidine-3-yl) -5-((6- (3-((1r, 3r) -3-((5-5-) (5-Methyl-5H-pirid [4,3 -b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Phenoxy) Hexil) Oxy) Isoindrin-1,3-dione (84); 2- (2,6-dioxopiperidine-3) -Il) -5-((1r, 3r) -3-((5-((5-((5- (5- (5-Methyl-5H-pyrido [4,3-b] Indol-7-Il) Pyridine- 2-yl) oxy) pentyl) oxy) pentyl) oxy) cyclobutoxy) isoindrin-1,3-dione (85); 4-((14- (4- (5H-pyrid [4,3-b] indol) -7-Il) Phenoxy) -3,6,9,12-Tetraoxatetradecyl) Amino) -2- (2,6-dioxopiperidin-3-yl) Isoindrin-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-dioxopiperidine-3-yl) -1H-pyrrolo [3,4-c] Pyridine-1,3 (2H) -dione (87); 2- (2,6-) Dioxopiperidine-3-yl) -5-((14-((5- (5- (2,2,2-trifluoroethyl) -5H-pyrido [4,3-b] indol-7-yl)) Pyridine-2-yl) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) Isoindrin-1,3-dione (88); 2- (2,6-dioxopiperidine-3-yl) )-5-(4- (3,3,3-Trifluoro-2-) ((5-((5- (5- (5-methyl-5H-pyridine [4,3-b] indol-7-yl ) Pyridine-2-yl) Oxy) Pentyl) Oxy) ethoxy) propyl) Piperidine-1-yl) Isoindrin-1,3-dione (89); 2- (2,6-dioxopiperidine-3-) Il) -5- (4-((4-(((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) pig- 2-In-1-yl) Oxy) Butoxy) Butoxy) Isoindrin-1,3-dione (90); 2- (2,6-dioxopiperidine-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) piperazine-1 -Il) Lee Isoindoline-1,3-dione (91); 5-((14-((3-Chloro-5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) Il) 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) Hexil) 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) Pyridine-2-yl) Penta-4-in-1-yl) Oxy) Isoindoline-1,3-dione (94); 2- (2,6-dioxopiperidine-3-yl) -5-((5-(5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl)) Oxy) Cyclobutoxy) Pyridine-2-yl) Pentyl) Oxy) Isoindoline-1,3-dione (95); 2- (2,6-dioxopiperidine-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) isoindoline-1,3-dione (96); 2- (2,6-dioxopiperidin-3-yl) -5-((6- (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) Hexa-5-in-1-yl) oxy) isoindoline-1,3-dione (97); 2- (2,6-dioxopiperidin-3-yl) -5-((6- (5-(5-( (1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) Hexil) Oxy) Isoindoline -1,3-dione (98); 2- (2,6-dioxopiperidine-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) azetidine-3-yl) oxy) isoindoline-1 , 3-dione (99); 2- (2,6-dioxopiperidine-3-yl) -5-(6- (4- (4-((5- (5- (5-methyl-5H-pyrido] [4,, 3-b] Indol-7-yl) Pyridine-2-yl) Oxy) Butoxy) Butoxy) -2-Azaspiro [3.3] Heptane-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) pyridine-2) -Il) oxy) cyclobutoxy) propoxy) propyl) azetidine-3-yl) oxy) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (101); 2- (2,6-dioxopiperidine-3-yl) -5-((6- (6-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,3-b ] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-3-yl) Hexa-5-in-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-tetraoxa Tetradecyl) 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) Azetidine-1-yl) Isoindoline-1,3-dione (104); 2- (2,6-dioxopiperidin-3-yl) -5-((1- (1- (1- (1- 3- (3-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) -3- (trifluoromethyl) pyridine-2) -Il) Oxy) Cyclobutoxy) propoxy) propyl) azetidine-3-yl) oxy) isoindoline-1,3-dione (105); 2- (2,6-dioxopiperidin-3-yl) -5-((5-(5-(5-( (5-(3-((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) azetidine-1-yl) pentyl) oxy) pentyl ) Oxy) Isoindoline-1,3-dione (106); 2- (2,6-dioxopiperidine-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] heptane-2-yl) butoxy) butoxy) isoindoline-1,3-dione (107); 2- (2,6-dioxopiperidine-3-yl) -5-((6-((6-(((1r, 3r) -3-((5- (5-methyl-5H-) Pyrid [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl) oxy) hexyl) oxy) isoindoline-1,3-dione (108); 2 -(2,6-dioxopiperidine-3-yl) -5-((6-((4-((1r, 3r) -3-((5- (5-methyl-5H-pyridoline [4,3) -b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl) oxy) hexyl) oxy) isoindoline-1,3-dione (109); 2- (2,6) -Dioxopiperidine-3-yl) -5-((6- (6-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7) -Il) Pylin-2-yl) Oxy) Cyclobutoxy) Pylin-3-yl) Hexil) Oxy) Isoindoline-1,3-dione (110); 2- (2,6-dioxopiperidine-3-yl) )-5-(3-((3- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine- 2-yl) oxy) cyclobutoxy) pyridine-2-yl) propa-2-in-1-yl) oxy) azetidine-1-yl) isoindoline-1,3-dione (111); 5-((14) -((5- (8,9-difluoro-5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) -3,6,9, 12-Tetraoxatetradecyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione (112); 5-((14-((4-Chloro-5) -(5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-
Il) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) -2- (2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (113); 2- (2,6-dioxopiperidine-3-yl) -5-((5- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,3-b ] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Butoxy) Pentyl) Oxy) Isoindoline-1,3-dione (114); 2- (2,6-dioxopiperidine-3-yl) )-5-((5-((5-((1- (5- (5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) azetidine-3- Il) Oxy) Pentyl) Oxy) Pentyl) Oxy) Isoindoline-1,3-dione (115); 2- (2,6-dioxopiperidin-3-yl) -5-((2- (4- (4- (4- (4- (4- (4- 4-((5- (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) butoxy) butyl) -2-azaspiro [3.3] heptane-6- Il) 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) propa-2-in-1- Il) 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) Pyridine-2 -Il) Propa-2-in-1-yl) Oxy) Azetidine-1-yl) Isoindoline-1,3-dione (118); (2S, 4R) -1-((S) -17-(((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-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2 -Carboxamide (119); (2S, 4R) -1-((S) -2- (2-(((5- (5H-pyrido [4,3-b] indol-7-yl) pyridine- 2-yl) Oxy) ethoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) Pyrolidin-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-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (121); (2S, 4R) -1-((S) -23-((5- (5H-pyrido [4,3-pyrid]) b] Indol-7-yl) Pyridine-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-dioxopiperidine) -3-il) -5-((5- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyrid [4,3-b] indol-7-il)- 3- (Trifluoromethyl) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) Pentyl) Oxy) Isoindrin-1,3-dione (123); 2- (2,6-dioxopi Peridine-3-yl) -5-((6- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) ) Pyridine-2-yl) Oxy) Cyclobutoxy) Phenyl) Hexa-5-in-1-yl) Oxy) Isoindrin-1,3-dione (124); 2- (2,6-dioxopiperidine-3) -Il)-5-(3-(3-(3-((1r,3r)-3-((5-(5-Methyl-5H-pyrid [4,3-b] Indol-7-Il))- 3- (Trifluoromethyl) Pyridine-2-yl) Oxy) Cyclobutoxy) Propoxy) Propoxy) Azetidine-1-yl) Isoindrin-1,3-dione (1) 25); 2- (2,6-dioxopiperidine-3-yl) -5-((5- (6- (methyl ((1r, 3r) -3-((5- (5-methyl-5H-) Pyrido [4,3-b] indole-7-yl) pyridin-2-yl)
Oxy) Cyclobutyl) Amino) -2-Azaspiro [3.3] Heptane-2-yl) Pentyl) Oxy) Isoindoline-1,3-dione (126); 3- (5- (4-((1- (5-) 5-) (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) piperidin-4-yl) methyl) piperazine-1-yl) -1-oxoisoindoline- 2-Il) Piperidine-2,6-dione (127); 3-(5-(4- (2- (1- (5- (5-Methyl-5H-pyridoline [4,3-b] indol) -7-Il) Pyridine-2-yl) Piperidine-4-yl) Ethyl) Piperazine-1-yl) -1-oxoisoindoline-2-yl) Piperidine-2,6-dione (128) 2- (2,6-dioxopiperidine-3-yl) -5-((1,1,1-trifluoro-6-)-(2-(2-((5- (5- (5-methyl-)- 5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) ethoxy) ethoxy) ethoxy) hexane-2-yl) oxy) isoindoline-1,3-dione (129); 2- (2,6-dioxopiperidine-3-yl) -5-(3- (3- (3- (4-((5- (5-methyl-5H-pyridoline [4,3-b] indol) -7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) piperidin-1-yl) propoxy) propoxy) azetidine-1-yl) isoindoline-1,3-dione (130) 2- (2,6-dioxopiperidine-3-yl) -5-((17-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine- 2-yl) oxy) -3,6,9,12,15-pentaoxaheptadecyl) oxy) isoindoline-1,3-dione (131); 2- (2,6-dioxopiperidine-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) azetidine-1-yl) isoindoline- 1,3-dione (133); 2- (2,6-dioxopiperidine-3-yl) -5-((6- (6-((1r, 3r) -3-((5- (5- (5- (5-) 5-) Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridazine-3-yl) hexa-5-in-1-yl) oxy) isoindoline- 1,3-dione (134); 2- (2,6-dioxopiperidine-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] heptane-6-yl) oxy) butoxy) isoindoline -1,3-dione (135); 2- (2,6-dioxopiperidine-3-yl) -5-(4-((2-((1s, 3s) -3-((5- (5) -Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutane-1-carbonyl) -2-azaspiro [3.3] heptane-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] heptane-2-yl) -5 -Oxopentyl) oxy) Isoindoline-1,3-dione (137); 5-((14-((5- (5- (difluoromethyl) -5H-pyrido [4,3-b] indol-7- Il) Pyridine-2-yl) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) -2- (2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (138); 2- (2,6-dioxopiperidine-3-yl) -5-((14-((3-fluoro-5- (5-methyl-5H-pyrido [4,3-b] indol) -7-Il) Pyridine-2-yl) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) Isoindoline-1,3-dione (139); 2- (2,6-dioxopipe) Lysine-3-yl) -5-((14-((3-Methyl-5- (5-Methyl-5H-pyrido [4,3-b] Indol-7-yl) Pyridine-2-i) Le) 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) cyclo Butoxy) Pyridine-2-yl) Hexa-5-in-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- (trifluoro) Methyl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Azetidine-3-yl) Oxy) Isoindoline-1,3-dione (142); 2 -(2,6-dioxopiperidine-3-yl) -5-((14-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) -6-( Trifluoromethyl) Pyridine-2-yl) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) Isoindoline-1,3-dione (143); 2- (2,6-dioxopiperidine) -3-yl) -5-(6-(6-((1s, 3s) -3-(5-(5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2 -Iloxy) Cyclobutoxy) Pyridine-3-yl) Hexa-5-inyloxy) Isoindoline-1,3-dione (144); 2- (2,6-dioxopiperidine-3-yl) -5- (6 ---
(6-((1s, 3s) -3- (5- (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) Pyridine-2-yloxy) Cyclobutoxy) Pyridine-3-yl ) Hexyloxy) Isoindoline-1,3-dione (145); 2- (2,6-dioxopiperidin-3-yl) -5-((6- (6- (3-((5- (5) 5) -Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) propoxy) pyridin-3-yl) hexa-5-in-1-yl) oxy) isoindoline- 1,3-dione (146); 2- (2,6-dioxopiperidine-3-yl) -5-((6- (4-((1r, 3r) -3-((5- (5- (5- (5-)5-yl) Methyl-5H-pyrido [4,3-b] indol-7-yl) pyrididine-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-) Ill) Oxy) Cyclobutoxy) Propoxy) Propoxy) Azetidine-1-yl) -2- (2,6-dioxopiperidin-3-yl) Isoindoline-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-Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridazine-3-yl) Hexil) 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] heptane-2-yl) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (150); 2- (2,6-dioxopiperidine) Peridine-3-yl) -5-((6- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) ) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyrimidin-2-yl) Hexil) Oxy) Isoindoline-1,3-dione (151); 2- (2,6-Geo) Isopiperidine-3-yl) -5-((1- (3- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol) -7-Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Azetidine-3-yl) Oxy) Isoindoline-1,3-dione (152) ); 2- (2,6-dioxopiperidine-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) azetidine-1-yl) isoindoline-1 , 3-dione (153); 2- (2,6-dioxopiperidine-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) azetidine-1- Il) Isoindoline-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) azetidine-1 -Isolindoline-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) azetidine-1-yl ) Isoindoline-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) cyclobutane-1-carbonyl) -2-azaspiro [3.3] heptane-6-yl) oxy ) Butoxy) Isoindoline-1,3-dione (157); 2- (2,6-dioxopiperidin-3-yl) -5-(2-((6- (4-((1r, 3r))- 3-((5- (5-me) Chill-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) pyridazine-4-yl) oxy) ethoxy) isoindoline- 1,3-dione (158); 2- (2,6-dioxopiperidine-3-yl) -5-((3- (5-((1s, 3s) -3-((5-) (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propa-2-in-1-yl) oxy) Azetidin-1-yl) Isoindoline-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) azetidine- 1-Il) Isoindoline-1,3-dione (160); 2- (2,6-dioxopiperidin-3-yl) -5-(3- (2- (2- (2-((1r, 1r,)) 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ethoxy) ethoxy) ethoxy) azetidine-1 -Isolindoline-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) azetidine-1-yl) isoindoline- 1,3-dione (162); 2- (2,6-dioxopiperidine-3-yl) -5-(3- (2- (2-((1r, 1r,)
3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ethoxy) ethoxy) azetidine-1-yl ) Isoindoline-1,3-dione (163);
5- (6- (4-((1r, 3r) -3- (5- (5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yloxy) cyclobutoxy) piperidine- 1-Il) -6-oxohexyloxy) -2- (2,6-dioxopiperidine-3-yl) Isoindrin-1,3-dione (164); 5-((5-((1- (- (1r, 3r) -3-((5- (5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutane-1-carbonyl) piperidine-4-yl ) Oxy) Pentyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindrin-1,3-dione (165); 5-((5-(((1s, 3s)) )-3-((5- (5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutane-1-carbonyl) piperidine-4-yl) oxy) pentyl ) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindrin-1,3-dione (166); 2- (2,6-dioxopiperidine-3-yl) -5-( 3-((3- (5- (3-((5- (5-Methyl-5H-pyridine [4,3-b]]
Indole-7-yl) Pyridine-2-yl) Oxy) Propoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Azetidine-1-yl) Isoindoline-1,3-dione (167) ); 2- (2,6-dioxopiperidine-3-yl) -5-(3- (3- (5- (3-((5- (5-methyl-5H-pyrido] [4,3-b ] Indole-7-yl) Pyridine-2-yl) Oxy) Propoxy) Pyridine-2-yl) Propoxy) Azetidine-1-yl) Isoindoline-1,3-dione (168); 2- (2,6- Dioxopiperidine-3-yl) -5-(3-(((3-((((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b]] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Methyl) Oxetane-3-yl) methoxy) Propoxy) Azetidine-1-yl) Isoindoline-1,3-dione (169); 2- ( 2,6-dioxopiperidine-3-yl) -5-(3-(3-(3-((1s, 3s) -3-((5- (5-methyl-5H-pyrido] [4,3-) b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Propoxy) Propoxy) Azetidine-1-yl) Isoindoline-1,3-dione (170); 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) ) Piperidine-1-yl) Pentil)
Oxy) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (171); 5-((6- (5-((1r, 3r) -3-(( 5- (5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl) hexa-5-in-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] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl) propa-2-in-1-yl) oxy) ethoxy)- 2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (173); 2- (2,6-dioxopiperidine-3-yl) -5- (4-((( 3-(((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) methyl) Bicyclo [1.1.1] pentan-1-yl) methoxy) butoxy) isoindoline-1,3-dione (174); 2- (2,6-dioxopiperidine-3-yl) -5-((5-5-yl) ((3-(3-((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) azetidine-1-carbonyl) bicyclo [1.1. 1] Pentan-1-yl) methoxy) pentyl) oxy) isoindoline-1,3-dione (175); 5-(3- (3- (3-((1r, 3r) -3-((5-5-) (8,9-difluoro-5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) propoxy) azetidin-1-yl) -2 -(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (176); 3-(5-(3-(3-((1r,3r) -3-( (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) propoxy) propoxy) azetidine-1-yl) -1-oxoiso Indole-2-yl) piperidine-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) azetidine-1- Isoindoline-1,3-dione (178); 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) propa-2-in-1 -Il) Oxy) ethoxy) Isoindoline-1,3-dione (179); 3-(5-((3- (5-((1r, 3r) -3-((5- (5H-pyrido]] , 3-b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) -1-oxoisoindoline-2-yl ) Piperidine-2,6-dione (180); 2- (2,6-dioxopiperidine-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) azetidine-1-yl) iso Indoline-1,3-dione (181); 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido [4,3-b] indole-7-) Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Propoxy) Propoxy) Azetidine-1-yl) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-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) Propa-2-in-1-yl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione (183); 2- ( 2,6-dioxopiperidine-3-yl) -5-((7-(3-(3-((5- (5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl)) Pyridine-2-yl) Oxy) Azetidine-1-carbonyl) Bicyclo [1.1.1] Pentan-1-yl) Heptyl) Oxy) Isoindoline-1,3-dione (184); (2S, 4R) -N- (2-(2-((5- (5H-Pyrrolidine [4,3-b] indole-7-yl) pyridine-2-yl) oxy) ethoxy) -4- (4-methylthiazole-5-yl) Benzyl) -4-hydroxy-1-((S) -3-methyl-2- (1-oxoisoindoline-2-yl) butanoyl) pyrrolidine-2-carboxamide (185); (2S, 4R) -N- (2-(2-(((5- (5H-Pyrrolidine [4,3-b] indole-7-yl) pyridine-2-yl) oxy) ethoxy) ethoxy) ethoxy) -4- (4-methylthiazole) -5-yl) benzyl) -4-hydroxy-1-((S) -3-methyl-2- (1-oxoisoindoline-2-yl) butanoyl) pyrrolidine-2-carboxamide (186); (2S, 4R) -N- (2- (2-(2-((5-(5H-pyrride [4,3-b] indole-7-yl) pyridine-2-yl) oxy) ethoxy) ethoxy) Ethoxy) -4- (4-methylthiazole-5-yl) benzyl) -4-hydroxy-1-((S) -3-methyl-2- (1-oxoisoindoline-2-yl) butanoyl) pyrrolidine- 2-Carboxamide (187); 5- (2-((3- (4-((1r, 3r) -3-((5- (5H-pyrrol [4,3-b] indole-7-yl) pyridine) -2-yl) oxy) cyclobutoxy) phenyl) propa-2-in-1-yl) oxy) ethoxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (188); 5-((3- (4-((1r, 3r) -3-((5- (5H-pyrrol [4,3-b] indole-7-yl) pyridin-2-yl) oxy) ) Cyclobutoxy) phenyl) propa-2-in-1-yl) oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (189); 2- (2) , 6-dioxopiperidine-3-yl) -5-(3-(2-(2-(2-((1r, 3r) -3-((5- (5-methyl-5H-pyridoline [4,, 3-b] Indole-7-yl) Pyrrolidine-2-yl) Oxy) Cyclobutoxy) ethoxy) ethoxy) Ethyl) Azetidine-1-yl) Isoindoline-1,3-dione (190); 2- (2, 6-Dioxopiperidine-3-yl) -5-(3-((3- (2-((1r, 3r) -3-((5- (5-methyl-5H-pyrrolidine [4,3-) b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) ethoxy) propoxy) methyl) azetidine-1-yl) isoindoline-1,3-dione (191); 2- (2,6-) Dioxopiperidine-3-yl) -5-(3-((2- (2-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole) -7-Indole) Pyridin-2-yl) Oxy) Cyclobutoxy) ethoxy) ethoxy) Methyl) Azetidine-1-yl) Isoindoline-1,3-dione (192); 2- (2,6-dioxopiperidine) -3-yl) -5-(3-(3-(2-(6-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) ) Oxy) -2-azaspiro [3.3] heptane-2-yl) -2-oxoethoxy) propoxy) azetidine-1-yl) isoindoline-1,3-dione (193); 5- (3-((3) -(5-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl ) Propa-2-in-1-yl) Oxy) Azetidine-1-yl) -2- (2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (194); 5- ( (14-((5- (4-Chloro-5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12-tetra Oxatetradecyl) oxy) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (195); (2S, 4R) -N- (2- (2- (2) -(2-(((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethoxy) -4- (4- (4- (4- Methylthiazole-5-yl) benzyl) -4-hydroxy-1-((S) -3-methyl-2- (1-oxoisoindoline-2-yl) butanoyl) pyrrolidine-2-carboxamide (196); 5 -(6-((2,2-difluoro-5-((1r,3r) -3-((5-(5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine- 2-Indole) Oxy) Cyclobutoxy) Pentyl) Oxy) -2-Azaspiro [3.3] Heptane-2-yl) -2- (2,6-dioxopi Peridine-3-yl) Isoindoline-1,3-dione (197); 2- (2,6-dioxopiperidine-3-yl) -5-((3- (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) propa-2-in-1-yl) oxy) isoindoline-1,3-dione (198); 3-((4-((2-(2,6-dioxopiperidine-3-yl))- 1,3-dioxoisoindoline-5-yl) oxy) butoxy) methyl) -N-methyl-N-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,, 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutyl) Bicyclo [1.1.1] Pentan-1-carboxamide (199); 2- (2,6-dioxopiperidine-3-yl) -5- (3-((7-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl)) Oxy) Cyclobutoxy) Heptyl) Oxy) Azetidine-1-yl) Isoindoline-1,3-dione (200);
(2S, 4R) -N- (2-((14-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy)-3,6,9 , 12-Tetraoxatetradecyl) oxy) -4- (4-methylthiazole-5-yl) benzyl) -4-hydroxy-1-((S) -3-methyl-2- (1-oxoisoindrin-) 2-yl) butanoyl) pyrrolidine-2-carboxamide (201); 2-((1- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindrin-5-yl) ) Azetidine-3-yl) methoxy) -N-methyl-N- (3-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7) -Il) Pyridine-2-yl) Oxy) Cyclobutoxy) propyl) Acetamide (202); 2-((14-((2- (2,6-dioxopiperidine-3-yl) -1,3-di Oxoisoindolin-5-yl) oxy) -3,6,9,12-tetraoxatetradecyl) oxy) -5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) Nicotinonitrile (203); 5-((3- (5-((1r, 3r) -3-((5- (8,9-difluoro-5H-pyridine [4,3-b] indole-7- Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindrin- 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] indole-7-yl) pyrididine-2-yl) oxy) cyclobutoxy) piperidin-1-yl) phenyl) propoxy) isoindrin-1,3- Zeon (205); 2- (2,6-dioxopiperidin-3-yl) -5-((2-(2-(2-((1r, 3r) -3-((5- ( 5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyrididine-2-yl) oxy) cyclobutoxy) ethoxy) ethoxy) ethoxy) methyl) azetidine-1-yl) isoindolin-1, 3-dione (206); 5-((14-((5- (benzo [4,5] imidazo [1,2-a] pyrimidine-2-yl) pyridin-2-yl) oxy) -3,6 , 9,12-Tetraoxatetradecyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione (207); 2- (2,6-dioxopiperidine) -3-yl) -5- (2- (2- (2-(((1- (5- (5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine- 2-yl) azetidine-3-yl) oxy) ethoxy) ethoxy) ethoxy) ethoxy) isoindoline-1,3-dione (208); 2- (2,6-dioxopiperidine-3-yl) -5- (2-(2-((3-((((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-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-dioxopiperidine-3) -Il)-5-((15-(4- (5-Methyl-5H-pyrido [4,3-b] indole-7-il) piperazin-1-yl) -3,6,9,12-tetra Oxapentadecyl) oxy) Isoindoline-1,3-dione (210); 2- (2,6-dioxopiperidine-3-yl) -5-(3- (3- (2- (6-((((() 5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) -2-azaspiro [3.3] heptane-2-yl) ethoxy) propoxy) azetidine- 1-Il) Isoindoline-1,3-dione (211); 2- (2,6-dioxopiperidine-3-yl) -5-(3- (2-((4-((1r, 3r)) -3-((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) buta-2-in-1-yl) oxy ) Ethoxy) Azetidine-1-yl) Isoindoline-1,3-dione (212); 2- (2,6-dioxopiperidine-3-yl) -5- (6- (2- (2-(((() 1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) ethoxy) ethoxy) -2- Azaspiro [.3] heptane-2-yl) isoindoline-1,3-dione (213); 2- (2,6-dioxopiperidine-3-yl) -5-(4- (3- (3) -((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) propoxy) propyl) Piperazin-1-yl) Isoindoline-1,3-dione (214); 2- (2,6-dioxopiperidine-3-yl) -5-((1R, 3r) -3- (isopropyl (2-) (3-((1r, 3R) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) propoxy) Ethyl) amino) cyclobutoxy) isoindoline-1,3-dione (215); 2- (2,6-dioxopiperidine-3-yl) -5- (4- (2- (3-((1r, 1r,)) 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) propoxy) ethoxy) piperidine-1 -Il) Isoindoline-1,3-dione (216); 2- (2,6-dioxopiperidine-3-yl) -5-((1R, 3r) -3-((2- (3- (3- (3) (1r, 3R) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) propoxy) ethyl) amino) Cyclobutoxy) Isoindoline-1,3-dione (217); 2- (2,6-dioxopiperidine-3-yl) -5-((14-((5- (4-fluoro-5-methyl-) 5H-pyrido [4,3-b] indole-7-yl) pyridin-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] indole-7-yl)) Pyridin-2-yl) Oxy) Cyclobutoxy) Pyridin-2-yl) Propa-2-in-1-yl) Oxy) -1-oxoisoindoline-2-yl) Piperidine-2,6-dione ( 219); 3- (5-(2-((3- (5-((1r, 3r) -3-((5- (5H-pyrid [4,3-b] indole-7-yl) pyridine- 2-yl) oxy) cyclobutoxy) pyridine-2-yl) propa-2-in-1-yl) oxy) ethoxy) -1-oxoisoindoline-2-yl) piperidine-2,6- Zeon (220); 3-(5- (3-((3- (5-((1r, 3r) -3-((5- (5H-pyrid [4,3-b] Indol-7-il)) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Azetidine-1-yl) -1-oxoisoindrin-2-yl) Piperidine- 2,6-Zeon (221); 3- (5-((3- (5-((1r, 3r) -3-((5- (5H-Pyridine [4,3-b] Indol-7-Il) ) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyrimidin-2-yl) Propa-2-in-1-yl) Oxy) -1-oxoisoindrin-2-yl) Piperidine-2,6-dione (222); 3- (5-((3- (6- ((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indol-7-yl) pyridin-2-) Il) Oxy) Cyclobutoxy) Pyridine-3-yl) Propa-2-in-1-yl) Oxy) -1-oxoisoindrin-2-yl) Piperidine-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) Pyridine-2-yl) Propoxy) Propa-1-in-1-yl) -1-oxoisoindrin-2-yl) Piperidine-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) cyclo Butoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) propyl) -1-oxoisoindrin-2-yl) Piperidine-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) pyridine -2-yl) propa-2-in-1-yl) oxy) -4,6-difluoro-1-oxoisoindrin-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) pyridine- 2-Il) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-a Le) Oxy) Cyclobutoxy) -1-oxoisoindoline-2-yl) Piperidine-2,6-dione (227); 3- (5- (4- (3- (5- ((1r, 3r)) ) -3-((5- (5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl) propa-2-in-1- Ill) piperidine-1-yl) -1-oxoisoindoline-2-yl) piperidine-2,6-dione (228); 2-((3- (5-((1r, 3r) -3-) ((5- (5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl) propa-2-in-1-yl) oxy) -N-(2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl)-N-methylacetamide (229); 3-(5-((1R, 3r)) -3-((3- (5-((1r, 3R) -3-((5- (5H-pyrid [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ) Pyridin-2-yl) Propa-2-in-1-yl) Oxy) Cyclobutyl) -1-oxoisoindoline-2-yl) Piperidine-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) pyridazine- 3-Il) Propa-2-in-1-yl) Oxy) -1-oxoisoindoline-2-yl) Piperidine-2,6-dione (231); 3- (5-((3- (3- (3-( 5-((1r,3r) -3-((5-(5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyrazine-2-yl) propa -2-In-1-yl) Oxy) -1-oxoisoindoline-2-yl) Piperidine-2,6-dione (232); 3- (5- (2-((3- (5- (5- (5-) 5-yl)) ((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl ) Propa-2-in-1-yl) Oxy) ethoxy) -1-oxoisoindoline-2-yl) Piperidine-2,6-dione (233); 3- (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) propa-2-in-1-yl) oxy) -1-oxoisoindoline- 2-Indole Piperidine-2,6-dione (234); 2-((1r, 3r) -3-((6- (3- (2-((2- (2,6-dioxopiperidine)) -3-yl) -1,3-dioxoisoindoline-5
-Il) Oxy) ethoxy) Propa-1-in-1-yl) Pyridine-3-yl) Oxy) Cyclobutoxy) -5- (5-Methyl-5H-pyrido [4,3-b] Indol-7- Il) Nicotinonitrile (235); 5- (2-((3- (5-((1r, 3r) -3-((5- (5- (difluoromethyl) -5H-pyridin [4,3-pyrid] b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) ethoxy) -2- (2,6-dioxopiperidine) -3-yl) Isoindrin-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) Propa-2-in-1-yl) Oxy) ethoxy) Isoindrin-1,3-dione (237); 2-((1r, 3r) -3-((6- (3- (2-((2)) -(2,6-dioxopiperidin-3-yl) -1-oxoisoindrin-5-yl) oxy) ethoxy) propa-1-in-1-yl) pyridin-3-yl) oxy) cyclobutoxy) -5- (5-Methyl-5H-pyridine [4,3-b] indol-7-yl) nicotinonitrile (238); 3- (5- (2-((3- (5- ((1r, 1r, 1r,)) 3r) -3-((5- (5- (difluoromethyl) -5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) Propa-2-in-1-yl) oxy) ethoxy) -1-oxoisoindrin-2-yl) piperidin-2,6-dione (239); 3- (5- (2-((3-3-) (5-((1r, 3r) -3-((3-Methyl-5- (5-Methyl-5H-pyrido [4,3-b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclo) Butoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) ethoxy) -1-oxoisoindrin-2-yl) Piperidine-2,6-dione (240); 3- (5) -((3- (3- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) ) Oxy) Cyclobutoxy) Piperidine-1 -Il) phenyl) propa-2-in-1-yl) oxy) -1-oxoisoindoline-2-yl) piperidin-2,6-dione (241); 2- (2,6-dioxopipe) Lysine-3-yl) -5-((3- (4- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7) -Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Isoindoline-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) Piperidine-1-yl) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) -1-oxoisoindoline-2-yl) Pi Peridine-2,6-dione (243); 2- (2,6-dioxopiperidine-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) propa -2-in-1-yl) Oxy) Isoindoline-1,3-dione (244); 3-(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) propa-2 -In-1-yl) Oxy) -1-oxoisoindoline-2-yl) Piperidine-2,6-dione (245); 2- (2,6-dioxopiperidine-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) Piperidine-1-yl) Pyrimidin-4-yl) Propa-2-in-1-yl) Oxy) Isoindoline-1,3-dione (246); 3- (5-( (3-(2-(4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) ) Cyclobutoxy) Piperidine-1-yl) Pyrimidin-4-yl) Propa-2-in-1-i Le) Oxy) -1-oxoisoindoline-2-yl) piperidine-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] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) Piperidine-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] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) piperidin-1-yl) propoxy) ethoxy) -1-oxoiso Indole-2-yl) piperidine-2,6-dione (249); 2- (2,6-dioxopiperidin-3-yl) -5-((6- (4-((1r, 3r)) -3-((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) hexa-2 -In-1-yl) oxy) Isoindoline-1,3-dione (250); 3-(5-((6- (4-((1r, 3r) -3-((5- (5-methyl) -5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) hexa-2-in-1-yl) oxy) -1 -Oxoisoindoline-2-yl) piperidine-2,6-dione (251); 2- (2,6-dioxopiperidine-3-yl) -5-(2- (2- (2- (2- (2- 2- (3-((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) azetidine-1-yl) ethoxy) ethoxy)
Ethoxy) ethoxy) isoindoline-1,3-dione (252); N-(2-((1- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline) -5-yl) Azetidine-3-yl) Oxy) Ethyl) -N-methyl-4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b]] Indole-7-yl) Pyridin-2-yl) Oxy) Cyclobutoxy) Butanamide (253); 2- (2,6-dioxopiperidine-3-yl) -5-((1- (2- (4- (4- (4- (4-) 4-yl) ((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) piperidine-1 -Il) -2-oxoethyl) Azetidine-3-yl) Oxy) Isoindoline-1,3-dione (254); 2- (2,6-dioxopiperidine-3-yl) -5- (3- (3-( 2- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) Piperidin-1-yl) -2-oxoethoxy) Azetidine-1-yl) Isoindoline-1,3-dione (255); 2- (2,6-dioxopiperidine-3-yl) -5- (3-(3-(4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) ) Cyclobutoxy) piperidin-1-yl) phenoxy) azetidin-1-yl) isoindoline-1,3-dione (256); 2- (2,6-dioxopiperidine-3-yl) -5- (3-(3-(3-(((1s, 3s) -1-hydroxy-3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine- 2-yl) oxy) cyclobutyl) methoxy) propoxy) propoxy) azetidine-1-yl) isoindoline-1,3-dione (257); 2- (2,6-dioxopiperidine-3-yl) -5- (2-(9-(2-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) ) Cyclobutoxy) ethyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-yl) ethoxy) isoindoline-1,3-dione (258); 2- (2,6-dioki) Isoindoline-3-yl) -5-((4- (9-(((1s, 3s) -1-hydroxy-3-((5- (5-methyl-5H-pyrido [4,3-pyrid],3-) b] Indol-7-yl) Pylin-2-yl) Oxy) Cyclobutyl) Methyl) -1-oxa-4,9-Diazaspiro [5.5] Undecane-4-yl) But-2-in-1-yl) Oxy ) Isoindoline-1,3-dione (259); 2- (2,6-dioxopiperidine-3-yl) -5-((3- (3- (4-(((1s, 3s)) -1) -Hydroxy-3- ((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) oxy) cyclobutyl) methyl) piperazin-1-yl) phenyl) Propa-2-in-1-yl) oxy) isoindoline-1,3-dione (260); 2- (2,6-dioxopiperidine-3-yl) -5-((3- (3- (3- (3- (3- 4-(((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) oxy) cyclobutyl) methyl) piperazine -1-yl) phenyl) propa-2-in-1-yl) oxy) isoindoline-1,3-dione (261); 2- (2,6-dioxopiperidine-3-yl) -5-( 2- (3- (3-((((1s, 3s)) -1-hydroxy-3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine-2) -Il) Oxy) Cyclobutyl) Methyl) Propoxy) Propoxy) ethoxy) Isoindoline-1,3-dione (262); 2- (2,6-dioxopiperidine-3-yl) -5- (2- (3) -(3-((3-Hydroxy-1- (5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) azetidine-3-yl) methoxy) Propoxy) Propoxy) ethoxy) Isoindoline-1,3-dione (263); 2- (2,6-dioxopiperidine-3-yl) -5- (3- (3- (3-((5'-) (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) -3'H-spiro [cyclobutane-1,2'-flo [2,3-b] pyridine] -3-yl) Oxy) Propoxy) Propoxy) Azetidine-1-yl) Isoindoline-1,3-dione (264); 5-((14-((5- (6,8-Difluoro-5-methyl-5H-pyri)) Do [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecyl) oxy) -2- (2,6-dioxopiperidine- 3-Ile) Isoindoline-1,3-dione (265); 2- (2,6-dioxopiperidine-3-yl) -5-((14-((1- (5-methyl-5H-pyrido)) [4,3-b] indole-7-yl) piperidin-4-yl) oxy) -3,6,9,12-tetraoxatetradecyl) oxy) isoindoline-1,3-dione (266) 2- (2,6-dioxopiperidine-3-yl) -5-(3-(2-((1R, 3r) -3- (2-((1r, 3R) -3-((5-) (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) ethyl) cyclobutyl) ethoxy) azetidine-1-yl) isoindoline-1,3 -Zion (267); 2- (2,6-dioxopiperidine-3-yl) -5-(3-((1S, 2R) -2-((4-((1r, 3R) -3- ( (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) butoxy) methyl) methyl) cyclopropyl) azetidine-1-yl) isoindoline -1,3-dione (268); 2- (2,6-dioxopiperidine-3-yl) -5-(3-(4-(((1R, 2R) -2-((1r, 3R)) -3-((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutyl) cyclopropyl) methoxy) butoxy) azetidine-1-yl ) Isoindoline-1,3-dione (269); 2
-(2,6-dioxopiperidine-3-yl) -5-(2-(2-((((1R, 2R) -2-((1r, 3R) -3-((5- ( 5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutyl) cyclopropyl) methoxy) ethoxy) ethoxy) ethoxy) azetidine-1-yl) isoindoline-1, 3-dione (270); 2- (2,6-dioxopiperidine-3-yl) -5-(3-(2-((1R, 3r) -3-(((1r, 3R) -3-) ((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) methyl) cyclobutoxy) ethoxy) azetidine-1-yl) iso Indole-1,3-dione (271); 5-(3-(3-(2,2-difluoro-3-((1r,3r)-3-((5-(5-methyl-5H-pyrido]] 4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) propoxy) propoxy) azetidine-1-yl) -2- (2,6-dioxopiperidine-3-yl) iso Indole-1,3-dione (272); 5-(3-(2,2-difluoro-3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido]] 4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) propoxy) propoxy) azetidine-1-yl) -2- (2,6-dioxopiperidine-3-yl) iso Indole-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] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl) propa-2-in-1-yl) Oxy) propoxy) Isoindoline-1,3-dione (274); 2- (2,6-dioxopiperidine-3-yl) -5-(2-((4- (5-((1r, 3r)) -3-((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl) pig-3-in -2-yl) oxy) ethoxy) isoindoline-1,3-dione (275); 5-(2-((1,1-difluoro-3- (5-((1r, 3r) -3-(((1r, 3r) -3-(( 5- (5-me Chill-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propa-2-in-1-yl) oxy) ethoxy)- 2- (2,6-dioxopiperidin-3-yl) isoindrin-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) buta-3-in-1-yl) oxy) -1 -Oxoisodrine-2-yl) Pyridine-2,6-dione (277); 3-(5-(((3- (5-((1r, 3r) -3-((5- (5H) -Pyrido [4,3-b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Methyl) -1-oxo Isoindolin-2-yl) Pyridine-2,6-dione (278); 3-(5-(3-((4- (5-((1r, 3r) -3-((5- (5H) -Pyrido [4,3-b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Buta-3-in-1-yl) Oxy) Azetidine-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) pig-3-in-1-yl) oxy) azetidine-1-yl ) -2- (2,6-dioxopiperidin-3-yl) Isoindrin-1,3-dione (280); 5-(3-((5- (5-((1r, 3r) -3-yl) ((5- (5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) penta-4-in-1-yl) oxy) Azetidine-1-yl) -2- (2,6-dioxopiperidin-3-yl) Isoindrin-1,3-dione (281); 3- (5- (3- ((5- (5- (5- (5- (5- (5-) (1r, 3r) -3-((5- (5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) penta-4- In-1-yl) Oxy) Azetidine-1-yl) -1- Oxoisoindoline-2-yl) piperidine-2,6-dione (282); 2- (2,6-dioxopiperidine-3-yl) -5-((1- (4- (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) Buta-3-in-1-yl) Azetidine-3-yl) Oxy) Isoindoline-1,3-dione (283); 3-(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) pig-3- In-1-yl) Azetidine-3-yl) Oxy) -1-oxoisoindoline-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) isoindoline-1,3-dione (285); 2-((1r, 3r) -3 -((6-(3-((2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) oxy) propa-1-in-1-yl) pyridine- 3-Il) Oxy) Cyclobutoxy) -5-(5H-Pyridine [4,3-b] Indol-7-Il) 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) propa -2
-In-1-yl) Oxy) -1-oxoisoindoline-2-yl) Piperidine-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) propa-2- In-1-yl) Oxy) -1-oxoisoindoline-2-yl) Piperidine-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) propa-2-in -1-yl) Oxy) -1-oxoisoindoline-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) propa-2 -In-1-yl) Oxy) -1-oxoisoindoline-2-yl) Piperidine-2,6-dione (290); 2- (2,6-dioxopiperidine-3-yl) -5 -(2-((3- (3-(((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) Il) Oxy) Cyclobutoxy) Methyl) Bicyclo [1.1.1] Pentan-1-yl) Propa-2-in-1-yl) Oxy) ethoxy) Isoindoline-1,3-dione (291); 2- ( 2,6-dioxopiperidine-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) propa-2-in-1-yl) oxy) ethoxy) isoindoline-1, 3-Zeon (292); 3- (5- (4-((3- (5-((1r, 3r) -3-((5- (5H-pyrid [4,3-b] Indol-7-) Ill) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Piperidine-1-yl) -1-oxoisoindoline-2-yl) Piperidine-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) ) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) ethoxy) -2- (2,6-dioxopiperidine-3-yl) -1H-pyrrolo [3,4-c] Pyridine- 1,3 (2H) -dione (294); 2- (2,6-dioxopiperidine-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) azetidine-1-yl) isoindrin-1,3-dione (295); 2- (2-(2-((2-(2,6-dioxopiperidin-3-yl) -1,) 3-Dioxoisoindrin-5-yl) oxy) ethoxy) propa-1-in-1-yl) -5-((1r, 3r) -3-((5- (5-methyl-5H-pyridin] 4,3-b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Isonicotinonitrile (296); 2- (3- (2-((2- (2,6-dioxopipe)) Pyridine-3-yl) -1-oxoisoindrin-5-yl) Oxy) ethoxy) propa-1-in-1-yl) -5-((1r, 3r) -3-((5- (5- (5- (5-) 5-yl) Methyl-5H-pyrido [4,3-b] indol-7-yl) pyrididine-2-yl) oxy) cyclobutoxy) isonicotinonitrile (297); 2- (2,6-dioxopiperidine-3-) Il) -5- (2-((3- (4-Methyl-5-((1r, 3r) -3-((5- (5-Methyl-5H-pyridine [4,3-b] Indol-7) -Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) ethoxy) Isoindrin-1,3-dione (298); 3- (5) -(2-((3- (4-Methyl-5-((1r, 3r) -3-((5- (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine) -2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) ethoxy) -1-oxoisoindrin-2-yl) Piperidine-2,6-dione (299); 3- (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) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) ethoxy) -1-oxoisoindrin-2-yl) Piperidine-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) Pyridine-2-yl) Oxy) Cyclobutoxy) -4- (Trifluoromethyl) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Ethoxy) Isoindrin-1,3-dione (301); 6-(3-(2-((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindrin-5) -Il) Oxy) ethoxy) Propa-1-in-1-yl) -3-((1r,3r) -3-((5-(5-Methyl-5H-pyrido [4,3-b] indol- 7-Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Picolinonitrile (302); 6-(3- (2-((2- (2,6-dioxopiperidine-3-yl) -1-yl) -1-) Oxoisoindrin-5-yl) oxy) ethoxy) propa-1-in-1-yl) -3-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,3) -b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Picolinonitrile (303); 2- (2,6-dioxopiperidine-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) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) ethoxy) Isoindrin-1,3-dione (304); 3- (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) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) ethoxy) -1-oxoisoindrin-2-yl) Piperidine-2,6-dione (305); 2- (2,6) -Dioxopiperidine-3-yl) -5- (2-((3- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2) -Il) Oxy) Cyclobutoxy) -6- (Trifluoromethyl) Pylin-2-yl) Propa-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] indole-7-yl) pyridine-2) -Il) Oxy) Cyclobutoxy) -6- (Trifluoromethyl) Pylin-2-yl) Propa-2-in-1-yl) Oxy) ethoxy) -1-oxoisoindoline-2-yl) Piperidine -2,6-dione (307); 2- (2,6-dioxopiperidine-3-yl) -5-(((2-Methyl-4- (5-((1r, 3r) -3) -((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl) pig-3-in-2 -Il) 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) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl) buta-3-in-2-yl) oxy ) Ethoxy) -1-oxoisoindoline-2-yl) piperidine-2,6-dione (309); 3-(5-(2-(((5-((1r, 3r))-3) -((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2-yl) ethynyl) cyclopropoxy) ethoxy) -1-oxoisoindoline-2-yl) piperidine-2,6-dione (310); 2- (2,6-dioxopiperidine-3-yl) -5-(2-(1-((( 5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2-yl) oxy) cyclobutoxy) pyridine-2 -Il) ethynyl) cyclopropoxy) ethoxy) isoindoline-1,3-dione (311); 4- (3-((2- (2,6-dioxopiperidine-3-yl) -1,3-di Oxoisoindoline-5-il) Oki S) Propa-1-in-1-yl) -2- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyrid [4,3-b] indol-7-) Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) Benzonitrile (312); 4- (3-((2- (2,6-Dioxopiperidine-3-yl))- 1-oxoisoindrin-5-yl) oxy) propa-1-in-1-yl) -2- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyridin] 4,3-b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) Benzonitrile (313); 3- (5-((3- (4-Methyl) -3- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ) Piperidine-1-yl) phenyl) propa-2-in-1-yl) oxy) -1-oxoisoindrin-2-yl) piperidine-2,6-dione (314); 3-( 5-((3- (3- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) Il) Oxy) Cyclobutoxy) Piperidine-1-yl) -4- (Trifluoromethyl) phenyl) Propa-2-in-1-yl) Oxy) -1-oxoisoindrin-2-yl) Pipe Lysine-2,6-dione (315); 3-(5-((3- (4- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyridin [4,, 3-b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) -5- (Trifluoromethyl) Pyridine-2-yl) Propa-2-in-1 -Il) Oxy) -1-oxoisoindrin-2-yl) piperidine-2,6-dione (316); 6-(3-((2- (2,6-dioxopiperidine-3-yl)) ) -1-oxoisoindolin-5-yl) oxy) propa-1-in-1-yl) -4-(4-((1r, 3r) -3-((5- (5-methyl-5H-) Pyrido [4,3-b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) Nicotinonitrile (317); 3- (3-((2-((2-( 2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindrin- 5-Indole) Oxy) Propa-1-in-1-yl) -5-(4-((1r, 3r) -3-((5- (5-Methyl-5H-pyridine [4,3-b]] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) Benzonitrile (318); 3-(3-((2- (2,6-dioxopiperidine-3) -Il) -1-oxoisoindolin-5-yl) Oxy) propa-1-in-1-yl) -5-(4-((1r, 3r) -3-((5- (5-methyl-) 5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidine-1-yl) benzonitrile (319); 3-(5-((3-3-) (3-Methyl-5-(4-((1r, 3r) -3-((5-(5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl)) Oxy) Cyclobutoxy) Piperidine-1-yl) Phenyl) Propa-2-in-1-yl) Oxy) -1-oxoisoindolin-2-yl) Piperidine-2,6-dione (320) 3-(5-((3
-(3-(4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclo Butoxy) Piperidine-1-yl) -5- (Trifluoromethyl) phenyl) Propa-2-in-1-yl) Oxy) -1-oxoisoindrin-2-yl) Piperidine-2,6 -Zeon (321); 3-(5-((3- (4- (4- ((1r, 3r) -3-((5- (5-Methyl-5H-pyrid [4,3-b] indol) -7-Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) -6- (Trifluoromethyl) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) -1-oxoisoindrin-2-yl) piperidine-2,6-dione (322); 3-(5-((3- (2- (4-((1r, 3r) -3-((( 5- (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidine-1-yl) -6- (trifluoromethyl) Pyridine-4-yl) propa-2-in-1-yl) oxy) -1-oxoisoindrin-2-yl) piperidine-2,6-dione (323); 2- (2,6-dioxopi Peridine-3-yl) -5-((2-Methyl-4- (3- (4-((1r, 3r) -3-((5- (5-Methyl-5H-pyrido] 4,3-) b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) Phenyl) Buta-3-in-2-yl) Oxy) Isoindrin-1,3-dione ( 324); 3- (5-((2-Methyl-4- (3- (4-((1r, 3r) -3-((5- (5-Methyl-5H-pyridine [4,3-b]] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) Phenyl) Buta-3-in-2-yl) Oxy) -1-oxoisoindrin-2-yl) Piperidine-2,6-dione (325); 3-(5-((2-methyl-4-(4-(4-((1r, 3r) -3-((5- (5-methyl-) 5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidine-1-yl) pyridin-2-yl) buta-3-in-2-yl ) Oxy) -1-oxoisoindrin-2-yl) piperidine-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)
Piperidine-1-yl) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) -1-oxoisoindoline-2-yl) Piperidine-2,6-dione (327); 3- (5-((2-Methyl-4- (4- (4-((1r, 3r) -3-((5- (5-Methyl-5H-pyridine [4,3-b] indole-7) -Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) Pirimidine-2-yl) Buta-3-in-2-yl) Oxy) -1-oxoisoindoline-2-yl ) Piperidine-2,6-dione (328); 6-(3-((2- (2,6-dioxopiperidine-3-)
Ill) -1-oxoisoindoline-5-yl) oxy) -3-methylbut-1-in-1-yl) -4-(4-((1r, 3r) -3-((5- (5- (5-) 5-) Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy)
Cyclobutoxy) piperidine-1-yl) nicotinonitrile (329); 2- (3- (2-((2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-) 5-yl) Oxy) ethoxy) -3-methylbut-1-in-1-yl) -5-((1r, 3r) -3-((5- (5-methyl-5H-pyridine [4,3-yl) b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Isonicotinonitrile (330).

The present specification, where applicable, includes compositions comprising pharmaceutically acceptable salts of the compounds of the present disclosure, in particular acid or base addition salts.

The term "pharmaceutically acceptable salt" is used throughout the specification to describe the salt form of one or more of the compounds described herein where appropriate. , Shows increased solubility of the compound in the gastric juice of the patient's gastrointestinal tract, promoting lysis and bioavailability of the compound. Pharmaceutically acceptable salts include, where appropriate, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, such as alkaline earth metals such as calcium and magnesium, and ammonium salts, among many other acids and bases known, especially in the pharmaceutical arts. Can be mentioned. Salts of sodium and potassium are particularly preferred as neutralizing salts of phosphates according to the present disclosure.

The acid used to prepare a pharmaceutically acceptable acid addition salt of the above-mentioned basic compounds useful in the present disclosure is a non-toxic acid addition salt, that is, a salt containing a pharmacologically acceptable anion. For example, among many other acids, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, heavy sulfate, phosphate, perphosphate, acetate, lactate, etc. Citrate, percitrate, tartrate, heavy tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfon Acids that form acid salts, p-toluenesulfonates, and pamoates [ie, 1,1'-methylene-bis- (2-hydroxy-3 naphthoic acid)].

A pharmaceutically acceptable base addition salt can also be used to produce a pharmaceutically acceptable salt form of a compound or derivative according to the present disclosure. A chemical base that can be used as a reagent for preparing a pharmaceutically acceptable base salt of this compound, which is acidic in nature, is a base that forms a non-toxic base salt with such compound. Such non-toxic base salts are in particular derived from pharmaceutically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium, zinc and magnesium). Included are the base salts, ammonium or water-soluble amine-added salts such as N-methylglucamine- (meglumin), and lower alkanolammoniums, as well as other pharmaceutically acceptable organic amine base salts.

Composition:
In another aspect, the specification provides a composition comprising a salt thereof as described herein, and a pharmaceutically acceptable carrier. In certain embodiments, the composition is a therapeutic or pharmaceutical composition comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier.

The amount of a compound in a pharmaceutical composition of the present disclosure that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the disease, the particular mode of administration. Generally, an amount of 0.1 mg / kg body weight to 1000 mg / kg body weight of the active ingredient per day is administered depending on the efficacy of the agent. The toxicity and therapeutic effects of such compounds are standard pharmaceuticals in cell cultures or laboratory animals, such as determining LD50 (lethal dose to 50% of the population) and ED50 (therapeutic effective dose in 50% of the population). It can be determined by the procedure. The dose ratio between toxicity and therapeutic effect is an indicator of treatment and can be expressed as the LD50 / ED50 ratio. Compounds that exhibit a large therapeutic index are preferred. Although compounds with toxic side effects can be used, design delivery systems that target such compounds to affected tissue sites in order to minimize the potential for damage to unaffected cells and reduce side effects. You have to be careful. Data obtained from cell culture assays and animal experiments can be used to develop dosage ranges for use in humans. The dose of such compound is preferably within the circulating concentration range containing ED50, which is almost or not toxic. The dosage can vary within this range, depending on the dosage form adopted and the route of administration utilized. For any compound used in the disclosed methods, a therapeutically effective dose may be initially estimated from the cell culture assay. Dose to achieve a circulating plasma concentration range containing IC50 determined in cell culture (ie, test compound concentration achieving 50% inhibition of symptoms) may be formulated in the animal model. Such information can be used to more accurately determine useful doses in humans. Plasma levels may be measured, for example, by high performance liquid chromatography.

The compositions of the present disclosure may be formulated by conventional methods using one or more pharmaceutically acceptable carriers, and may be administered as a controlled release formulation. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions are, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphate. Salt, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica , Magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylic acid salt, wax, polyethylene-
Examples include polyoxypropylene block polymers, polyethylene glycol, and wool fat.

In either of the embodiments and embodiments described herein, PTM, ULM, or both, are 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, It has an affinity (IC ₅₀ ) for each target protein less than 0.01 μM, 0.001 μM, 0.1 nM, 0.01 nM, 0.001 nM. The determination of the IC ₅₀ can be carried out in view of the present disclosure using methods known to those of skill in the art.

In either embodiment or embodiment, the compounds described herein achieve ubiquitination of the target protein at a level or amount sufficient to exert the action of the target protein or induce degradation.

The active compound in a pharmaceutically acceptable carrier or diluent is sufficient to deliver a therapeutically effective amount to the patient for the desired indication and does not cause serious toxic effects on the patient being treated. Is contained. Preferred doses of the active compound for all of the conditions referred to herein are in the range of about 10 ng / kg to 300 mg / kg, preferably in the range of 0.1-100 mg / kg per day, more generally the recipient. / The range is 0.5 to about 25 mg per kg of patient body weight per day. Typical topical doses can range from 0.01 to 5% wt / wt in a suitable carrier.

The compound is conveniently administered in any suitable unit dosage form containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form, but is not limited thereto. About 25-250 mg
Oral doses of are often convenient.

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

The concentration of active compound in the drug composition will depend on the rate of absorption, distribution, inactivation, and excretion of the drug, as well as other factors known to those of skill in the art. Note that dosage values will also vary depending on the severity of the alleviated condition. Furthermore, the particular dosing regimen should be adjusted over time according to the individual's request and the professional judgment of the person who administers or controls the administration of the composition to any particular subject. It should be understood that the concentration ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at one time, or may be divided into a number of smaller doses and administered at various time intervals.

When administered intravenously, the preferred carrier is saline or phosphate buffered saline (PBS).
).

In one embodiment, the active compound is prepared with a carrier that protects the compound from rapid excretion from the body, such as release controlled formulations such as implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods of preparation of such formulations will be apparent to those skilled in the art.

Liposomal suspensions can also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, such as those described in US Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations dissolve suitable lipids (eg, stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine, and cholesterol, etc.) in an inorganic solvent and then evaporate to dry lipids on the container surface. It may be prepared by leaving a thin film. Then an aqueous solution of the active compound is placed in a container. The container is then rotated by hand to remove the lipid material from the sides of the container, disperse the lipid mass and form a liposome suspension.

Dosage Form In either of the embodiments or embodiments described herein, the therapeutic composition comprising the compounds described herein is any suitable configured to be delivered by any suitable route. It may be a suitable dosage form. The compound can be administered by any suitable route, eg oral, parenteral, intravenous, intradermal, subcutaneous, or topical, eg transdermally in liquid, cream, gel, or solid form, rectal. It can be administered intranasally, nasally, orally, vaginally, or via a transplant container or in the form of an aerosol.

As used herein, the term "parenteral" refers to subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrasubarachnoid, intrahepatic, intralesional, and intracranial injections or. Includes drip technology. The composition is preferably administered orally, intraperitoneally, or intravenously.

The compounds described herein may be administered in single doses or in divided doses by oral, parenteral or topical routes. Administration of the active compound may range from continuous (intravenous drip) to several oral doses per day (eg Q.I.D.), oral, topical, parenteral, intramuscular, intravenous, among other routes of administration. Intramuscular, subcutaneous, transdermal (which may include permeation enhancers), oral, sublingual, and suppository administrations may be included. Enteric coated oral tablets may be used to enhance bioavailability of the compound from the route of administration. The most effective dosage form will depend on the pharmacokinetics of the particular drug selected, as well as the severity of the patient's disease.

The compound may be administered as a spray, mist, or aerosol for intranasal, intratracheal, or pulmonary administration. The compounds described herein may be administered in immediate release, intermediate release, or sustained release or controlled release form. Sustained-release or controlled-release forms are preferably given orally, but suppositories and transdermal or other topical forms are also given. Intramuscular injection in the liposome form may be used to control or maintain the release of the compound at the injection site.

The sterile injection form of the compositions described herein may be an aqueous suspension or an oily suspension. These suspensions may be formulated by techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a 1,3-butanediol solution. Among the acceptable vehicles and solvents that can be adopted are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterilized fixed oil is customarily used as a solvent or suspension medium. Any brand of fixed oil may be employed for this purpose, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injections, as there are naturally pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. be. These oily solutions or suspensions may contain long chain alcohol diluents or dispersants such as Ph. Helv or similar alcohols.

The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or aqueous solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. Typically, a lubricant such as magnesium stearate is also added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. If an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and suspending agent. If desired, certain sweeteners, flavors, or colorants may also be added. Oral compositions will generally include an inert diluent or edible carrier. It may be encapsulated 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 an excipient and used in the form of tablets, troches, or capsules. A pharmaceutically compatible binder and / or adjuvant substance is included as part of the composition.

Tablets, pills, capsules, troches and the like may contain any of the following components or compounds of similar nature: excipients such as microcrystalline cellulose, tragacant rubber or gelatin; excipients such as starch or lactose. Shapes such as dispersants such as alginic acid, Primogel or corn starch; lubricants such as magnesium stearate or Sterotes; flow promoters such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or for example peppermint, salicylic acid Flavors such as methyl or orange flavors. When the dosage unit dosage form is a capsule, it can include, for example, a liquid carrier such as a fatty acid in addition to the above-mentioned types of substances. In addition, the dosage unit dosage form can contain a variety of other substances that modify the physical shape of the physical dosage unit, such as, for example, sugar coatings, shellac, or enteric solvents.

The active compound or a pharmaceutically acceptable salt thereof can be administered as a component such as elixir, suspension, syrup, wafer, chewing gum and the like. In addition to the active compound, the syrup may contain sucrose as a sweetening agent, or certain preservatives, dyes and colorants, as well as flavorings.

Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. They can be prepared by mixing with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such substances include cocoa butter, beeswax and polyethylene glycol.

The pharmaceutical compositions of the present disclosure may be administered topically. Suitable topical formulations are readily prepared for each of these regions or organs. Topical application to the lower intestinal tract can be effective with a rectal suppository formulation (see above) or a suitable enema. Locally acceptable transdermal patches may be used. For topical application, the pharmaceutical composition may be formulated with a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the disclosed compounds include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified wax and water. In certain preferred embodiments of the present disclosure, the compound may be coated onto a stent that is surgically implanted in the patient, thereby reducing or reducing the likelihood of occlusion in the stent within the patient.

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

For ophthalmic applications, the pharmaceutical composition is as a micronized suspension of isotonic, pH adjusted sterile saline, or preferably as a solution of isotonic, pH adjusted sterile saline. It may be formulated, and the presence or absence of a preservative such as benzylalconium chloride may or may not be present. Alternatively, for ophthalmic applications, the pharmaceutical composition may be formulated with an ointment such as petrolatum.

The pharmaceutical compositions of the present disclosure may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the pharmaceutical formulation field, and as a solution of saline, benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / Or may be prepared by adopting other conventional solubilizers or dispersants.

Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may contain the following components: eg water for injection, aqueous saline, fixed oils, polyethylene glycol, glycerin, Sterilized diluents such as propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bicarbonate; chelating agents such as ethylenediamine tetraacetic acid; eg acetates, Buffers such as citrates, or phosphates, and tension-regulating agents such as sodium chloride or dextrose. Parenteral preparations may be encapsulated in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

Specific dosage and treatment regimens for any particular patient include activity, age, weight, general health, gender, diet, dosing time, rate of excretion, drug combination, and treatment of the specific compound used. It should also be understood that it depends on the judgment of the physician doing the treatment and various factors including the severity of the particular disease or condition being treated.

Patients or subjects in need of treatment with the compounds described herein are optionally pharmaceutically acceptable with an effective amount of the compound, including pharmaceutically acceptable salts, solvates or polymorphs thereof. It can be treated by administration to a patient (subject) alone or in combination with other known agents in a possible carrier or diluent.

Co-administration Symptom states that can be treated using the compounds or compositions according herein include, but are not limited to, cancer (eg, prostate cancer) and Kennedy's disease. In certain embodiments, the therapeutic or pharmaceutical composition comprises an additional biological or bioactive agent, eg, an effective amount of a co-administered agent effective in treating cancer.

The term "co-administration" or "combination therapy" refers to a patient in which at least two compounds or compositions are administered simultaneously to the patient, whereby the effective amount or concentration of each of the two or more compounds is given to the patient for a given period of time. It shall mean that it can exist in. The compounds according to the present disclosure may be co-administered to a patient at the same time, but the term refers to two or more agents as long as the effective concentration of all co-administered compounds or compositions is present in the patient for a given time. It also includes administration at the same time or at different times. In certain preferred embodiments of the present disclosure, one or more of the compounds described above are co-administered in combination with at least one additional bioactive agent, particularly including an anti-cancer agent. In a particularly preferred embodiment of the present disclosure, co-administration of compounds results in synergistic treatment, including anti-cancer treatment.

In another aspect, the specification provides a composition comprising two or more effective amounts of the PROTAC compounds described herein, and a pharmaceutically acceptable carrier. In certain embodiments, the composition further comprises an effective or synergistic amount of another bioactive agent that is not a PROTAC compound.

The combination of an effective amount of at least one bifunctional compound according to the present disclosure and one or more effective amounts of the compounds separately described herein is a pharmaceutically effective amount of the carrier, additive, and the like. Alternatively, the pharmaceutical composition contained in combination with an excipient represents a further aspect of the present disclosure.

The term "biological activator" is used to describe agents other than the PROTAC compounds described herein and of the therapeutic, inhibitory, and / or control / preventive effect of the intended use of this compound. It is used in combination with this compound as a biologically active agent to assist its exertion. Preferred bioactive agents for use herein include agents that assist in achieving the desired therapeutic effect, such as P-gp inhibitors, or pharmacological activity of interest for which the compound is used or administered. Examples of the agent having a pharmacological activity similar to that of the above include an antineurotic degenerative agent.

The term "P-gp" is used to describe the "permeable glycoprotein" or P-glycoprotein (ABCB1) discovered in 1976 in rodent cells. The presence of "endogenous or physiological" P-gp is a potential challenge in achieving targeted exposure to therapeutic agents. P-gp is also expressed in barrier tissues to protected sites (eg, blood-brain barrier) and in secretory / absorptive tissues (eg, gastrointestinal tract) (Cordon-Cardo et al., 1989, 1990). This protein acts as a cell defense substance, affecting its overall pharmacokinetic profile by actively pushing (excreting) a large number of drugs from the intracellular environment, allowing them to penetrate barrier tissues. Reduce. In particular, P-gp excretion may reduce the permeation of the drug through the gastrointestinal mesentery, leading to reduced systemic exposure of the drug. P-gp excretion also reduces the ability of the drug to cross the blood-brain barrier. P-gp inhibitors can indirectly contribute to efficacy by increasing PROTAC exposure, especially CNS exposure.

The term "additional anti-neurodegenerative agent" is used to describe an anti-neurodegenerative agent that can be used in combination with the PROTAC compounds herein to treat neurodegenerative diseases.

In certain embodiments, PROTAC is used with a P-gp inhibitor.
In certain additional embodiments, the P-gp inhibitors are amiodarone, Azithromycin, Captopril, Clarithromycin, Cyclosporine, Piperine, quercetin. (Quercetin), Quinidine, Quinine, Reserpine, Ritonavir, Tariquidar, Elacridar and Verapamil. Not done.

Therapeutic method In another aspect, the disclosure provides a method of regulating ubiquitination and degradation of a protein in a subject such as, for example, a cell, tissue, mammal, or human patient, which method is described herein. Consists of administering to a subject an effective amount of the PROTAC compound described in, or a composition comprising an effective amount of the compound, wherein the compound, or a composition comprising the compound, is protein ubiquitinated in the subject. And is effective in regulating proteolysis. In certain embodiments, the protein is tau protein.

In certain embodiments, the present specification provides a method of controlling the protein activity of tau protein by denaturing tau aggregates in a patient in need thereof, wherein the method is an amount in the patient. Includes administration of the compounds described herein to said patients.

In a further additional embodiment, the present specification provides a method of treating a condition or condition of a patient, in which case the protein activity of the decontrolled state (aggregation and accumulation of tau) is the condition or condition. The method comprises administering to the patient an effective amount of a compound described herein to control the protein activity in the patient. In certain embodiments, the protein is tau.

As used herein, the terms "treat," "treat," and "treatment" refer to any action that benefits the patient and is regulated via the protein to which the compound binds. The compound may be administered for its benefit, including treatment of any condition or condition. Pathologies or conditions, including neurological and neurodegenerative diseases that can be treated using the compounds according to the present disclosure, are described above herein.

In another aspect, the disclosure provides a method of regulating ubiquitination and degradation of tau protein in a subject such as, for example, a cell, tissue, mammal, or human patient, which method is described herein. The subject comprises administering to the subject an effective amount of the described compound, or a composition comprising an effective amount of the compound described herein, wherein the compound, or a composition comprising the compound, is in the subject. It is effective in regulating tau protein ubiquitination and proteolysis.

In another aspect, the disclosure provides a method of treating or ameliorating symptoms of a disease associated with tau accumulation or aggregation in a subject such as, for example, a cell, tissue, mammal, or human patient. Includes the administration of an effective amount of a compound described herein, or a composition comprising an effective amount of the compound, to a subject in need thereof, wherein the compound, or a composition comprising the compound, is administered. , Effective in treating or ameliorating the symptoms of diseases associated with tau aggregation in the subject.

In certain embodiments, the disease or disorder is clear septal defect, acquired epileptic aphrodisiac, acute diffuse encephalomyelitis, ADHD, Addy pupil, Addy syndrome, adrenal leukodystrophy, bridge bridge defect, deficit, eye. Cardi Syndrome, AIDS-Neurologic Complications, Alexander's Disease, Alpers Syndrome, Pediatric Alternate Hemiplegia, Alzheimer's Disease, Muscle Atrophic Lateral Sclerosis, Aneurysm, Aneurysm, Angelman Syndrome, Hemangiomatosis, Anoxic Symptoms, aphrodisiac, asthma, spider cyst, spider inflammation, Arnoldchiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, ataxia, capillary dilatation, ataxia and cerebral degeneration / spinal cord degeneration, attention deficit- Hyperactivity disorder, autism, autonomic dysfunction, back pain, Bath syndrome, Batten's disease, Beckermyotny, Bechet's disease, bell paralysis, benign essential eyelid spasm, benign localized muscle atrophy, benign intracranial pressure Hyperactivity, Bernhard Lot Syndrome, Binswanger's Disease, Eyelid Spasm, Blochsalzberger Syndrome, Arm plexus delivery trauma, Traumatic arm plexus palsy, Pure autonomic dysfunction, Brain and spinal cord tumors, Cerebral aneurysms, Brain trauma, Brown Sekar Syndrome, bulbar spinal muscle atrophy, canavan disease, carpal canal syndrome, causalgia, cavernoma, spongy hemangiomas, spongy vascular malformations, central cervical spinal cord syndrome, central spinal cord syndrome, central pain syndrome, Head disorder, cerebral degeneration, cerebral dysplasia, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral leg qi, cerebral giant disease, cerebral hypoxia, cerebral paralysis, brain-eye-face-skeletal syndrome, Charcomary Tooth's disease, Chiari malformation, butoh's disease, spinous erythroid butoh's disease, chronic inflammatory demyelinating polyneuritis (CIDP), chronic orthostatic hypotension, chronic pain, cocaine syndrome type II, coffin lorry syndrome, COFS, brain beam Defects, coma and persistent phytostate, complex local pain syndrome, congenital bilateral facial nerve palsy, congenital myasthenia, congenital myopathy, congenital Vascular Cavernous, malformations, cerebral cortical basal nucleus degeneration Syndrome, head arteritis, skull fusion, Kreuzfeld-Jakob disease, cumulative trauma disease, Cushing syndrome, giant cell encapsulation, cytomegalovirus infection, Opsocronus myocronus syndrome, Dandy-Walker syndrome, Dawson's disease, Domorcia Syndrome, Deep Brain Stimulation Therapy for Parkinson's Disease, Arm Neural Neuropathy, Dementia, Multiple Infarct Dementia, Semantic Dementia, Subcortical Dementia, Levy Body Dementia, Myocronus cerebral collaborative contractile dysfunction, dentate nucleus erythema atrophy, dermatitis, developmental Dyspraxia, Devic's disease, diabetic neuropathy, diffuse sclerosis, autonomic dysfunction, writing disorders , Loss of reading, swallowing disorder, integrated dyskinesia, myoclonic dyskinesia, progressive cerebral dyskinesia, dystonia, early infantile epileptic encephalopathy, Turkish saddle cavity syndrome, drowsiness encephalitis, cerebral hernia, encephalopathy, cerebral trigeminal nerve Regional hemangiomatosis, epilepsy, superior and inferior paralysis, elve paralysis, Fabry's disease, foul disease, fainting, familial autonomic imbalance, familial hemangiomas, familial basal nucleus calcification, familial periodic paralysis , Familial spastic paralysis, febrile spasm, Fisher syndrome, floppy infant syndrome, Friedrich ataxia, frontotemporal dementia, Gaucher disease, Gerstmann syndrome, Gerstmann-Stroisler-Scheinker disease, giant cell arteritis , Giant cell inclusion disease, Glovoid cell leukodystrophy, Glossopharyngeal nerve pain, Gillan Valley syndrome, Hallerfolden-Spatz disease, Head injury, Headache, Persistent hemilateral headache, Unilateral facial spasm, Alternate hemiplegia, Hereditary Neuropathy, hereditary spastic vs. paralysis, polyneuritis-type hereditary dysfunction, herpes zoster, ear herpes zoster, Hirayama syndrome, Holmes Addy syndrome, total anterior encephalopathy, HTLV-1-related myelopathy, Huntington's disease, hydrocephalus, Hydrocephalus, normal pressure hydrocephalus, hydromyelopathy, hyperactivity, hyperadrenal cortex, hypersleep, hypertonia, hypotension-infant, hypoxia, immune-mediated encephalomyelitis, encapsulated myositis, Pigment imbalance, pediatric muscle tone hypotonia, pediatric neuroaxial dystrophy, pediatric phytanoic acid accumulation, pediatric leftam disease, pediatric spasm, inflammatory myopathy, occipital cerebral prolapse, enteric lipopostrophy, intracranial cyst, increased intracranial pressure , Isaac Syndrome, Jubert Syndrome, Keens-Sair Syndrome, Kennedy's Disease, Opsocronus-Myocronus Syndrome (Kinsbourne syndrome), Kleine-Levin Syndrome, Klipel-File Syndrome, Klippel-Trenone-Weber Syndrome (KTS), Kluber-Beaucy Syndrome, Korsakov Oblivion Syndrome, Krabbe's Disease, Kugelberg-Welander's Disease, Cool-, Lambert-Eaton Muscle Incompetence Syndrome, Landow-Klefner Syndrome, Lateral Femoral Skin Nervous Stranglement, Lateral Marrow Syndrome, Learning Disorders, Lee's Disease, Lennox- Gustow Syndrome, Resh -Naihan Syndrome, Cerebral White Atrophy, Levine-Critchley Syndrome, Levy Body Dementia, Lipid Accumulation, Brain Circular Deficiency, Confinement Syndrome, Lou Gehrig's Disease, Red spot Wolves-Nervous Type, Secular, Lime's Disease-Nervous Types, complications, Machado-Joseph disease, encephalopathy, manic disease, giant encephalomyelopathy, Mercarson-Rosenthal syndrome, meningitis, meningitis and encephalitis, Menquez's disease, dyssensitivity femoral nerve pain, metachromatic, cerebral White atrophy, small head disease, migraine, Millerfisher syndrome, mild stroke, mitochondrial myopathy, Mobius syndrome, Hirayama disease, motor neuropathy, moyamoya disease, Mucolipidoses, mucopolysaccharide, polyfocal motor neuropathy , Multiple infarct dementia, Multiple sclerosis, Multisystem atrophy, Multisystem atrophy with orthostatic hypotension, Muscle dystrophy, Myasthenia-congenital, Severe myasthenia, Diffuse sclerosis of the medullary sheath , Pediatric myochrony encephalopathy, myocronus, myopathy, myopathy-congenital, myopathy-thyroid addiction, myotney, congenital myotney, narcolepsy, neurospinous erythrocytosis, neurodegeneration with iron accumulation in the brain, neurofibromatosis, Nerve-relaxing drug-induced malignant syndrome, AIDS nervous system complications, Lime disease nervous system complications, cytomegalovirus infections affecting the nervous system, Pompe disease nervous system signs, erythema vulgaris nervous system Secular, optic neuromyelitis, neuromuscular tonicity, neuroceroid adipose brown deposits, nerve cell migration disorders, neuropathy-hereditary, neurosarcoidosis, neurotoxicity, spongy vein homozygous (Nevus Cavernosus), Niemannpic disease , Normal pressure hydrocephalus, occipital nerve pain, obesity, split spinal cord, Otawara syndrome, Olive Bridge cerebral atrophy, eyeball myocronus, orthostatic hypotension, O'Sullivan-McLeod Syndrome, overuse syndrome, pain- Chronic, pain, pantothenic kinase-related neurodegeneration, tumor-associated syndrome, sensory impairment, Parkinson's disease, paroxysmal butoh atetose, paroxysmal migraine, hemi-facial atrophy, Peritzus-Merzbacher's disease, Penashocker syndrome type II, Peri-neuronal cyst, periodic limb palsy, terminal neuropathy, periventricular leukomalacia, protracted vegetative state, diffuse developmental disorder, phytanoic acid accumulation, Pick's disease, misplacement, pear muscle syndrome, pituitary tumor, Polymyositis, Pompe's disease, encephalopathy, post-herpes nerve pain, post-infection encephalomyelitis, post-porio syndrome, orthostatic hypotension, orthostatic orthostatic Tachycardia syndrome, orthostatic tachycardia syndrome, primary Dentatum Atrophy, primary lateral sclerosis, primary progressive ataxia, prion disease, progressive facial hemiplegia, progressive gait Ataxia, progressive polyfocal leukoencephalopathy, progressive sclerosing polyojistrophy, progressive supranuclear palsy, face loss, pseudobrain tumor, Ramsey Hunt Syndrome I (past name), Ramsey Hunt Syndrome II (past name) Name),
Rasmussen's encephalitis, reflex sympathetic dystrophy syndrome, Leftham's disease, Leftham's disease-pediatric, repetitive motility disorder, repetitive hypermotor injury, itchy leg syndrome, retrovirus-related myelopathy, Let's syndrome, Rye's syndrome, Relay-Day syndrome, Sacral nerve root cyst, butoh disease, salivary gland disease, Sandhoff's disease, Sylder's disease, fissure encephalopathy, Seitelberger's disease, paroxysmal disease, semantic dementia, septal optic dysplasia, shaken kid syndrome, herpes zoster, shy Drager syndrome, Schegren syndrome, sleep aspiration syndrome, African sleep disease, Sotos disease, spasm, dichotomy, spinal cord infarction, spinal cord injury, spinal cord tumor, spinal muscle atrophy, spinal cerebral atrophy, spinal cerebral degeneration, steel -Richardson-Orszevsky Syndrome, Stiffperson Syndrome, Striatal melanosis, Stroke, Sturge-Weber Syndrome, Subacute sclerosing panencephalitis, Subcortical arteriosclerotic encephalopathy, SUNCT Headache Swallowing Disorders), Sidenum butoh disease, fainting, plum toxic spinal sclerosis, spinal water cavities, spinal cavities, systemic erythema cyst, spinal cord epilepsy, late-onset dyskinesia, tarlob cysts, Teisax disease, temporal arteritis, Moored spinal syndrome, Thomsen's Myotonia, thoracic outlet syndrome, thyroid addictive myopathy, trigeminal nerve pain, Todd palsy, Turret syndrome, transient cerebral ischemic attack, transmissible spongy encephalopathy, transverse myelitis, trauma Sexual brain injury, tremors, trigeminal nerve pain, tropical spastic deficiency vs. paralysis, nodular sclerosis, vascular Erectile Tumor, vasculitis-induced temporal arteritis (Vasculitis including Temporal Arteritis), von Echo Nomo Diseases, von Hippel-Lindow's disease (VHL), von Recklinghausen's disease, Wallenberg's syndrome, Weldnig-Hoffmann's disease, Welnicke-Korsakov's syndrome, West syndrome, whiplash, Whipple's disease, William's syndrome, Wilson's disease, X-chain sphere Spinal muscle atrophy, or neuropathy including Zellberger's syndrome.

In certain embodiments, the disease or disorder includes Huntington's disease, muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten's disease, spinal cord and brain damage, paroxysmal disorders, epilepsy, brain tumors, meningitis, eg, polysclerosis. Autoimmune disease, neurofibromatosis, depression, muscular atrophic lateral sclerosis, arteriovenous malformation, cerebral aneurysm, dural arteriovenous fistula, headache, memory disorder, peripheral neuropathy, post-herpes zoster nerve pain, spinal cord Tumor, and at least one of stroke.

In certain embodiments, the disease or disorder is Alzheimer's disease.
In another aspect, the disclosure provides a method of treating or ameliorating symptoms of a disease associated with tau accumulation or aggregation in a subject such as, for example, a cell, tissue, mammal, or human patient. Includes administering to a subject in need an effective amount of a compound described herein or a composition comprising an effective amount of such compound and an effective amount or synergistic amount of another bioactive agent. Here, the composition containing the compound is effective in treating or ameliorating the symptoms of diseases associated with the accumulation or aggregation of tau by degrading / inhibiting tau in the subject.

In certain embodiments, the disease being treated is a neuropathy. In a preferred embodiment, the subject is a human.

In certain additional embodiments, the additional bioactive agent is an anti-neurodegenerative agent.
In another aspect, the present disclosure provides a method of treating a pathological condition by degrading a protein or polypeptide, wherein the pathological condition or condition is regulated via the protein or polypeptide. The method comprises administering to said patient or subject an effective amount of at least one of the above-mentioned compounds, optionally in combination with an additional bioactive agent. Many nervous system conditions or conditions can be treated by using the disclosed methods to administer an effective amount of at least one compound described herein.

In another aspect, the present disclosure provides a method of identifying the degrading effect of a protein of interest in a biological system using the compounds according to the present disclosure.

Kit In another aspect, the present specification provides a kit comprising the compounds or compositions described herein. The kit may be advertised, distributed, or sold as a unit for carrying out the methods of the present disclosure. In addition, the kits of the present disclosure may preferably include instructions describing their proper use. Such kits can be conveniently used to treat patients with neuropathy, for example in clinical situations.

Examples The PROTAC compounds of the present disclosure are effective in tau degradation. Exemplary compounds are presented in Tables 1 and 2, and Tables 2 and 3 show in vitro data of some selected compounds showing degradation of tau protein. An in vivo experiment showing the degradation of tau protein is shown in the figure.

General method of chemical synthesis
The synthesis of the claimed chimeric compound can be carried out according to a general synthetic procedure known in the literature. The synthetic pathways shown in the schemes of the present disclosure are described as one of the methods that can be used to obtain the desired compound. Other methods can be used by those skilled in the art of synthesis. The ULMs and PTMs described in the scheme represent only one of the many ULMs and PTMs in this application.

LC-MS method for purity analysis (quality control)
LCMS method :
Instruments: Agilent infinity 1260 LC; Agilent 6230 TOF mass spectrometer analysis performed at 45 ° C on a Poroshell 120 EC C18 column (50 mm x 3.0 mm internal diameter 2.7 μm packing diameter).
The solvents used are:
A = 0.1% v / v aqueous solution of formic acid.
Acetonitrile solution of formic acid with B = 0.1% v / v.
The gradients adopted are:

UV detection is an average signal from wavelengths from 210 nm to 350 nm, and the mass spectrum is recorded in the mass spectrometric account using positive mode electrospray ionization.

Abbreviation:
ACN: acetonitrile
Boc ₂ O: Di-tert-butyl dicarbonate
D CM: Dichloromethane.
DIPEA: N, N-diisopropylethylamine
DMA: N, N-dimethylacetamide
DMF: N, N-dimethylformamide
EA: Ethyl acetate
HATU: 2- (7-aza-1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
HPLC: High Performance Liquid Chromatography
LC-MS: Liquid Chromatography-Mass Spectrometry
Min: Minutes
MTBE: Methyl tert-butyl ether
PE: Petroleum ether
RT: Room temperature
SPB: Sodium perborate
tBu: tert-butyl
TBACl: Ammonium chloride 4-butyl
TFA: Trifluoroacetic acid
THF: Tetrahydrofuran
TLC: Thin Layer Chromatography
TMS: Trimethylsilyl t _R : Retention time
TsCl: p-toluenesulfonyl chloride Ubiquitin E3 Ligase Targeting moiety (ULM) and protein targeting moiety (PTM) intermediate Intermediate 1: (2S, 4R) -1-[(2S) -2-amino-3, 3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide hydrochloride (ULM-1)

Step 1: Preparation of 4- (4-Methyl-1,3-thiazole-5-yl) benzonitrile
4-Methyl-1,3-thiazole (21.88 g, 220.67 mmol), palladium (II) acetate in a stirred solution of 4-bromobenzonitrile (20 g, 109.88 mmol) in DMA (250 mL) at room temperature under a nitrogen atmosphere. (743 mg, 3.31 mmol) and potassium acetate (21.66 g, 220.71 mmol) were added. 1 of the obtained mixed solution
It was heated to 50 ° C. and stirred at this temperature for 5 hours, at which point LC-MS indicated that the reaction was complete. The mixture was cooled to room temperature, diluted with 1 L of water and extracted with ethyl acetate (300 mLx3). The organic layers were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was subjected to flash silica gel column chromatography (eluent: acetate). Purification with ethyl / petroleum ether, v: v = 1: 5) gave the title compound (yield: 91%) as a colorless solid.

Step 2: Preparation of [4- (4-Methyl-1,3-thiazole-5-yl) phenyl] methaneamine
LiAlH ₄ (20 g, 526.32 mmol) was added to a stirred solution of 4- (4-methyl-1,3-thiazole-5-yl) benzonitrile (35 g, 174.77 mmol) in tetrahydrofuran (1000 mL) at 0 ° C. under a nitrogen atmosphere. ,Ten
Added in small portions over a minute. The resulting mixture was then stirred at 60 ° C. for 3 hours, at which point LC-MS indicated completion of the reaction. Cool the mixture to 0 ° C, then water (add 20 mL slowly)
, NaOH aqueous solution (15%, 20 mL), and water (60 mL) were added for quenching. The resulting mixture was then extracted with ethyl acetate (300 mLx2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was subjected to flash silica gel column chromatography (eluent: dichloromethane). Purification with / methanol (v: v = 10: 1)) gave the title compound (yield: 56%) as a yellow oil.

Step 3: (2S, 4R) -4-hydroxy-2-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine-1-carboxylate tert-butyl Preparation
(2S, 4R) -1-[(tert-butoxy) carbonyl] -4-hydroxypyrrolidin-2-carboxylic acid (2.7 g, 11.68 mmol) in a stirred solution of N, N-dimethylformamide (20 mL) in DIPEA ( 2.52 g, 19.50 mmol), HATU (4.47 g, 11.76 mmol) and [4- (4-methyl-1,3-thiazole-5-yl) phenyl] methaneamine (2 g, 9.79 mmol) were added at room temperature. The resulting mixture was stirred overnight at room temperature, at which point LC-MS indicated completion of the reaction. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mLx3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was subjected to flash silica gel column chromatography (eluent: dichloromethane). Purification with / methanol (v: v = 20: 1)) gave the title compound (yield: 56%) as a yellow solid.

Step 4: Preparation of (2S, 4R) -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide
(2S, 4R) -4-Hydroxy-2-([[4- (4-Methyl-1,3-thiazol-5-yl) phenyl] methyl] carbamoyl) Pyrrolidine-1-carboxylate tert-butyl (45g, A dioxane solution of hydrogen chloride (4N, 300 mL) was added to a 1 L round bottom flask containing a dioxane solution of 107.78 mmol). The resulting solution was stirred at room temperature for 2 hours. The solids were collected by filtration to give the title product (yield: 98%) as a yellow solid.

Step 5: N-[(2S) -1-[(2S, 4R) -4-hydroxy-2-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl] ) Pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutane-2-yl
Il] Preparation of tert-butyl carbamic acid
DIPEA (29.2) in a stirred solution of N, N-dimethylformamide (500 mL) of (2S) -2-{[(tert-butoxy) carbonyl] amino} -3,3-dimethylbutanoic acid (15.7 g, 68.0 mmol). g, 225.9 mmol), HATU (25.9 g, 68.1 mmol) and (2S, 4R) -4-hydroxy-N-{[4- (4-methyl-1,3-thiazole-5-yl) -phenyl] methyl } Pyrrolidine-2-carboxamide hydrochloride (20.0 g, 56.5 mmol) was added.

The resulting solution was stirred at room temperature for 16 hours and LC-MS showed that the desired product was formed. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mLx3). The organic layers are combined into one, washed with a saturated aqueous solution of sodium chloride (50 mLx2), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which is subjected to flash silica gel chromatography (elution). Liquid: Purification with ethyl acetate / petroleum ether (v: v = 2: 1)) to give the title compound (yield: 51%) as a yellow solid.

Step 6: (2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-) 5-Il) Phenyl] Methyl] Pyrrolidine-2-Carboxamide Hydrochloride (ULM-1) Synthesis
N-[(2S) -1-[(2S, 4R) -4-hydroxy-2-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine- 1-yl] -3,3-dimethyl-1-oxobutane-2-yl]
A solution of hydrogen chloride in dioxane (4N, 80 mL) was added to a stirred solution of tert-butyl carbamic acid (12 g, 22.61 mmol) in dioxane (20 mL) at room temperature. The resulting solution was stirred at room temperature for 2 hours, at which point LC-MS indicated completion of the reaction. The precipitated solid was collected by filtration to give the title product (yield: 48%) as a yellow solid.

d: 48%) As a yellow solid.
¹ HNMR (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 ⁺ ): m / z 431.11 [MH ⁺ ], t _R = 0.73 minutes.

Intermediate 2: (2S, 4R) -1- [(S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[(S) -1- (4- (4-methyl) Thiazole-5-yl) phenyl) ethyl] -pyrrolidine-2-carboxamide hydrochloride (ULM-2)

Step 1: Preparation of (S) -tert-butyl-1- (4-bromophenyl) -ethylcarbamate salt
In a mixed solution of (S) -1- (4-bromophenyl) ethaneamine (3.98 g, 19.9 mmol) and י ₃ (1.24 g, 14.8 mmol) in H ₂ O (10 mL) and ethyl acetate (10 mL). (Boc) ₂ O (5.20 g, 23.8 mmol) was added at 5 ° C. The reaction was continued for 2 hours. TLC showed that the reaction was complete. 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 hours. The mixture was filtered and the solids were collected and dried in an oven at 50 ° C. to give the title compound as white solids (5.9 g, 98.7%).

¹ HNMR (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-methylthiazole-5-yl) phenyl) ethaneamine hydrochloride (S) -tert-butyl-1- (4-bromophenyl) -ethylcarbamate (4.0g, 13.3 mmol)
, 4-Methylthiazole (2.64 g, 26.6 mmol), Palladium acetate (II) (29.6 mg, 0.13 mmol)
), And a mixture of potassium acetate (2.61 g, 26.6 mmol) in DMF (10 mL) was stirred under N ₂ for 18 hours at 90 ° C. After cooling to atmospheric temperature, the reaction mixture was filtered. H ₂ O (50 mL) in the filtrate
) Was added, and the obtained mixture was stirred at atmospheric temperature for 4 hours. The reaction mixture was filtered. The solids are collected by filtration and dried in an oven at 50 ° C to dry 1- (4- (4-methylthiazole-5-yl) phenyl) ethylcarbamic acid (S) -tert-butyl (3.48 g, 82.3). %) Was obtained as a gray solid.

¹ HNMR (400 MHz, DMSO-d ₆ ): δ 1.33 (d, J = 7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64-4.68 (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
This solid material (1.9 g, 6.0 mmol) is dissolved in 4N hydrochloride (5 mL, 20 mmol, prepared from acetyl chloride and methanol) in methanol, the mixture is stirred at atmospheric temperature for 3 hours and then concentrated. And powdered with ether. The mixture is filtered, the solids are collected, dried in an oven at 60 ° C. and dried to (S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethaneamine hydrochloride (1.3). g, 85%) was obtained as a light green solid.

¹ HNMR (400 MHz, DMSO-d6): δ .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
HATU (2.15 g, 5.7 mmol), (S) -2- (tert-butoxycarbonyl) amino-3,3-dimethylbutanoic acid (1.25 g, 5.4 mol), (2S, 4R) -methyl 4-hydroxypyrrolidine -2-Carboxylate salt (0.98 g, 5.4 mmol) and DIPEA (2.43 g, 18.9 mmol) were added to a solution of DMF (10 mL) under nitrogen at 0 ° C. The mixture was stirred at atmospheric temperature for 18 hours. TLC showed that the reaction was complete.
The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (15 mLx4). Combine the organic layers into one, 5% citric acid (10mLx2), saturated NaHCO ₃ solution (10mLx2), brine (10mLx2)
Washed with Na ₂ SO ₄ and dried with Na 2 SO 4. The organic solution is filtered and concentrated to concentrate (2S, 4R) -methyl 1-{(S) -2-[(tert-butoxycarbonyl) amino] -3,3-dimethylbutanoyl} -4-hydroxypyrrolidin- 2-Carboxylate was obtained as a pale yellow oil (1.93 g, 100% yield). The crude product (1.93 g) and lithium hydroxide hydrate (2.2 g, 54 mmol) were dissolved in THF (20 mL) and H ₂ O (10 mL). The resulting mixture was stirred at atmospheric 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 using 3N HCI. The resulting suspension was filtered and washed with H ₂ O (6 mLx2). The solids were collected by filtration and dried in an oven at 50 ° C. to give the title compound as white solids (1.4 g, 75% for two steps).

¹ HNMR (400 MHz, DMSO-d ₆ ): δ 6.50 (d, J = .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 = .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: (2S, 4R) -1- [(S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[(S) -1-(
Preparation of 4- (4-Methylthiazole-5-yl) phenyl) ethyl] -pyrrolidine-2-carboxamide hydrochloride (ULM-2)
HATU (1.6 g, 4.2 mmol), (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-methylthiazole-5-yl) phenyl) ethaneamine hydrochloride (0.9 g, 3.5 mmol), and DIPEA (1.36 g, 10.5). It was added to an anhydrous THF (15 mL) stirring solution containing mmol) at 0 ° C. The resulting mixture was heated to atmospheric temperature and continued to stir for 2 hours. TLC showed that the reaction was complete. 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 give a white solid. This solid was dissolved in methanol (10 mL) and activated carbon (150 mg) was added. The obtained mixture was heated to 80 ° C. and stirred for 1 hour. The mixture was filtered while maintaining a high temperature. Water (5 mL) was added to the filtrate at 80 ° C. The resulting mixture was cooled to atmospheric temperature and continued to stir for 18 hours. The suspension was filtered. The solids are collected and dried in an oven at 50 ° C to tert-butyl-{(S) -1-[(2S, 4R) -4-hydroxy] -2-[(S) -1- (4-). (4-Methylthiazole-5-yl) phenyl) -ethylcarbamoyl] pyrrolidine-1-yl} -3,3-dimethyl-1-oxobutan-2-yl-carbamate (1.41g, 74.2%) as a white solid I got it as a thing.

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).

This solid (1.04 g, 1.9 mmol) was dissolved in 4N hydrogen chloride (3.0 mL) in methanol to dissolve it.
The mixture was stirred at atmospheric temperature for 3 hours. TLC showed the reaction was complete. The reaction mixture was concentrated to remove all volatile components under reduced pressure to give a bright yellow solid. The solid was added to TBME (5 mL) and the resulting mixture was stirred at atmospheric temperature for 4 hours. The reaction mixture was filtered, the solid was collected and dried in an oven at 50 ° C. to give the title compound (0.92 g, 100%).

¹ H NMR (400 MHz, DMSO-d6): δ .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-methylthiazole-5-yl) benzyl) -1-((S) -3-methyl-2-( 1-oxoisoindoline-2-yl) butanoyl) pyrrolidine-2-carboxamide (ULM-3)

Step 1: Preparation of 2-hydroxy-4- (4-methylthiazole-5-yl) benzonitrile
Anhydrous NMP (125 mL) 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). ) Was stirred at 110 ° C. for 6 hours under a nitrogen atmosphere. TLC showed that the reaction was complete. The mixture was first cooled to room temperature and then partitioned between EtOAc and water. The organic layers were combined into one, filtered, the filtrate washed with water and 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 chilled MeOH (80 mL). The resulting precipitate was collected by filtration, washed with MeOH (20 mL) and dried under vacuum to give the title compound (10.5 g, 64%) as a bright yellow solid.

LC / MS: 217.2 [M + 1] ⁺ .
¹ HNMR (400 MHz, DMSO-d6): δ2.49 (s, 3H), 7.07 (dd, J = 8.0, 1.6Hz, 1H), 7.13 (d, J = 1.6Hz, 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-methylthiazole-5-yl) phenol
To a solution of 2-hydroxy-4- (4-methylthiazole-5-yl) benzonitrile (2.9 g, 13.41 mmol) in anhydrous THF (150 mL), add LiAlH ₄ (1.5 g, 40.23 mmol) in small portions at 0 ° C. rice field. The obtained mixture was stirred at 50 ° C. for 3 hours under a nitrogen atmosphere. TLC showed that the reaction was complete. Cool the mixture in an ice tank, then carefully add Na ₂ SO _{4.1H 2} O (5 g) and 1 at this temperature ^.
Stir for hours. The mixture was filtered and the filtered cake was washed four times with a DCM solution of 10% MeOH. The filtrates were combined and concentrated to give 2- (aminomethyl) -5- (4-methylthiazole-5-yl) phenol as a clear yellow solid (2.0 g, 68%). This was used in the next step without further purification.

LCMS: 221.2 [M + H] ⁺ .
¹ HNMR (400MHz, DMSO-d6): δ2.43 (s, 3H), 3.54 (br, 2H), 6.11 (d, J = 7.2Hz, 1H),
6.40 (d, J = 11.6Hz, 1H), 6.83 (d, J = 7.6Hz, 1H), 8.81 (s, 1H).

Step 3: Preparation of (S) -3-methyl-2- (1-oxoisoindoline-2-yl) butanoic acid
L-valine (4.37 g, 37.3 mmol), dicarboxyaldehyde phthalate (5.0 g, 37.3 mmol)
) Was added to a solution of acetonitrile (350 mL). The resulting mixture was refluxed for 5 hours. The reaction mixture was filtered at a high temperature, and the filtrate was slowly cooled to room temperature. The resulting precipitate was filtered and dried to give (S) -3-methyl-2- (1-oxoisoindoline-2-yl) butanoic acid as a white solid (6.45 g, 74%). ).

¹ HNMR (400 MHz, DMSO-d6): δ .85 (d, J = 6.8Hz, 3H), 1.0 (d, J = 6.8Hz, 3H), 2.25-2.34 (m, 1H), 4.51 (d, J = 4.4Hz, 1H), 4.54 (d, J = 3.6Hz, 1H), 4.64 (d, J = 18.0Hz, 1H), 7.48-7.54 (m, 1H), 7.63 (d, J = 3.6 Hz, 2H), 7.72 (d, J = 7.6Hz, 1H), 13.01 (br, 1H).

Step 4: Preparation of 4-hydroxy-1-((S) -3-methyl-2- (1-oxoisoindoline-2-yl) butanoyl) pyrrolidine-2-carboxylic acid (2S, 4R) -methyl
4-Hydroxy-L-proline methyl ester hydrochloride (1.0 g, 5.52 mmol), (S) -3-methyl-2- (1-oxoisoindrin-2-yl) butanoic acid (1.16 g, 4.97 mmol), HATU (3.8 g, 10 mmol) was added to an anhydrous DMF (15 mL) solution containing DIPEA (2.58 g, 20 mmol) at 0 ° C. The obtained mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc and water. The organic layer was washed with water and brine and dried over anhydrous Na ₂ SO ₄ . The residue was purified by silica gel chromatography using 30% -50% EtOAc in hexanes as an eluent to give the title compound as a bright yellow solid (1.21 g, 67.6%).

LCMS: 361.3 [M + 1] ⁺ .
Step 5: (2S, 4R) -4-hydroxy-1-((S) -3-methyl-2- (1-oxoisoindoline-2-yl))
Butanoyl) Preparation of pyrrolidine-2-carboxylic acid
4-Hydroxy-1-((S) -3-methyl-2- (1-oxoisoindoline-2-yl) butanoyl) pyrrolidine-2-carboxylic acid (2S, 4R) -methyl (1.2 g, 3.33 mmol) , LiOH ^. H ₂ O (559 mg, 13.32 mmol) containing THF (20 mL) and H ₂ O (10 mL) mixed solution was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction mixture was acidified to pH 1-2 with 1N HCl and extracted with EtOAc.
The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated to give the title compound as a bright yellow solid (1.05 g, 91% yield).

^{1 1} HNMR (400MHz, CDCl ₃ ): δ0.91 (d, J = 6.4Hz, 3H), 1.05 (d, J = 6.8Hz, 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 = 17.6Hz, 1H), 4.50-4.55 (m, 2H), 4.66 (t, J = 8.4Hz, 1H), 4.75 (d, J = 17.6Hz, 1H), 4.83 (d, J = 11.2Hz, 1H), 7.42-7.45 (m, 2H), 7.51-7.56 (m, 1H), 7.78 (d, J = 7.6 Hz, 1H).

Step 6: (2S, 4R) -4-hydroxy-N- (2-hydroxy-4- (4-methylthiazole-5-yl) benzyl) -1-((S) -3-methyl-2- (1) -Oxoisoindoline-2-yl) butanoyl) pyrrolidine-2-yl
Preparation of carboxamide
(2S, 4R) -4-hydroxy-1-((S) -3-methyl-2- (1-oxoisoindrin-2-yl) butanoyl) pyrrolidine-2-carboxylic acid (1.0 g, 2.89 mmol), HATU (2.2 g) in a DMF (20 mL) solution containing 2- (aminomethyl) -5- (4-methylthiazole-5-yl) phenol (954 g, 4.33 mmol), and DIPEA (1.5 g, 11.55 mmol). , 5.77 mmol) was added at 0 ° C. The obtained mixture was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. The mixture was partitioned between EtOAc and water. The organic layer was washed with water and brine and dried over anhydrous Na ₂ SO ₄ . The residue was purified by silica gel column chromatography using 2% -5% MeOH in DCM to give the title compound as a bright yellow solid (650 mg, 43% yield).

LCMS: 549.2 [M + H] ^{+
1 1} HNMR (400MHz, CDCl ₃ ): δ0.80 (d, J = 6.8Hz, 3H), 0.88 (d, J = 6.8Hz, 3 H), 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 = 2,0Hz, 1H), 7.14 (d, J = 8.0Hz, 1H), 7.39-7.44 (m, 2H), 7.51-7.54 (m, 1H), 7.76 (d, J = 7.6Hz, 1H), 8.03 (t, J = 6.4Hz, 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-methyl) Thiazole-5-yl) phenyl) ethyl] -pyrrolidine-2-carboxamide hydrochloride (ULM-4)

This compound was synthesized using the same method described in the preparation of ULM-2 using (2R, 4S) -methyl 4-hydroxypyrrolidine-2-carboxylate. ¹ HNMR (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 = .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-thiazole-5-yl) phenyl] ethyl] carbamoyl} pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutane-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-thiazole-5-yl) phenyl] ethyl] carbamoyl} pyrrolidine-1-yl] -3,3-dimethyl- 1-oxobutane-2-yl] carbamate (ULM-5-B)

Step 1: Synthesis of 2- (4-bromophenyl) oxylan
Mixing 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) The solution was heated to 55 ° C. for 4 hours. The resulting solution was partitioned between water and diethyl ether, the organic layer was washed with water, dilute hydrochloric acid, and brine and dried over sodium sulfate. The organic solvent was removed under reduced pressure to give a crude product of 2- (4-bromophenyl) oxylane (2.20 g, 81.8% yield), which was used in the next reaction without further purification.

¹ H 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 Hz).

Step 2: Synthesis of 2-azido-2- (4-bromophenyl) ethanol
Sodium azide (3.28 g, 50.5 mmol) was added to a stirred suspension of distilled water (70 mL) of 2- (4-bromophenyl) oxylane (5.0 g, 25.3 mmol), and the resulting mixture was heated to 60 ° C. Stir for 4 hours with TLC
Monitored at. After completion of the reaction, the mixture is extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and 2-azido-2- (4-bromophenyl) ethanol (5.5). g, 90.2%) was obtained as a pale yellow oil. The crude product was used directly in the next step.

¹ H 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 = .4 Hz).

Step 3: Synthesis of 2-amino-2- (4-bromophenyl) ethanol hydrochloride
Triphenylphosphine (4.35 g, 16.6 mmol) was added 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). The reaction mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The residue was dissolved in HCl / dioxane (4M, 10.0 mL) and stirred for 1 hour at room temperature. After concentration, the solid was washed with dichloromethane to give 2-amino-2- (4-bromophenyl) ethanol hydrochloride (1.5 g, 72.1% yield) as a white solid.

¹ H 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) ethaneamine
Imidazole (1.95 g, 2.87 mmol) and tert-butyldimethylsilyl chloride (TBSCl) (1.63) in a solution of 2-amino-2- (4-bromophenyl) ethanol hydrochloride (1.80 g, 7.17 mmol) in dichloromethane (50 mL). g, 10.8 mmol) was added at room temperature. The reaction mixture was stirred at room temperature overnight and then quenched with water. The aqueous layer was extracted with dichloromethane (30 mLx3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude compound. This crude compound is subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 5).
: Purification according to 1) gave 1- (4-bromophenyl) -2- (tert-butyldimethylsilyloxy) ethaneamine (1.50 g, 63.6%) as a white solid.

LC / MS: 330.1 [M + H] ⁺ ;
Step 5: Synthesis of tert-butyl 1- (4-bromophenyl) -2- (tert-butyldimethylsilyloxy) ethylcarbamic acid
In a solution of 1- (4-bromophenyl) -2- (tert-butyldimethylsilyloxy) ethaneamine (1.50 g, 4.56 mmol) in tetrahydrofuran (20 mL), triethylamine (0.69 g, 6.84 mmol) and di-carboxylic acid di- tert-Butyl (1.49 g, 6.84 mmol) was added. The reaction mixture was stirred at room temperature overnight and then quenched with water. The aqueous layer was extracted with ethyl acetate (50 mLx3) and washed with brine. The organic layers were combined into one, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude compound. This crude compound is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100: 1) and tert-butyl 1- (4-bromophenyl) -2- (tert-butyldimethylsilyloxy) ethylcarbamate. (1.80 g, 92.0%) was obtained as a pale yellow oil.

^{1 1} H 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 = .0 Hz), 7.39 (1H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.4 Hz).

Step 6: Synthesis of 2-hydroxy-1-(4- (4-methylthiazole-5-yl) phenyl) -tert-butyl ethylcarbamate
1- (4-Bromophenyl) -2- (tert-butyldimethylsilyloxy) tert-butyl ethylcarbamic acid (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) was dissolved in dimethylacetamide and stirred under argon. The mixture was heated to 140 ° C., stirred for 15 hours and then diluted with water. The aqueous layer was extracted with ethyl acetate (50 mLx3) and washed with brine. The organic layers are combined, dried over sodium sulfate, filtered and concentrated under vacuum to give a crude compound, which is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100: 1). Then, 2-hydroxy-1- (4- (4-methylthiazole-5-yl) phenyl) -tert-butyl ethylcarbamate was obtained as a pale yellow solid (1.30 g, 41.8%).

^{1 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 minutes Step 7: Synthesis of 2-amino-2- (4- (4-methylthiazole-5-yl) phenyl) ethanol hydrochloride
2-Hydroxy-1- (4- (4-methylthiazole-5-yl) phenyl) ethylcarbamic acid tert-
Butyl (300 mg, 0.536 mmol) was dissolved in hydrochloric acid / dioxane (5 mL, 4 M). The obtained reaction mixture was stirred at room temperature for 3 hours. The solvent was concentrated in vacuo to give 2-amino-2- (4- (4-methylthiazole-5-yl) phenyl) ethanol hydrochloride as a white solid, which could be followed without further purification. Used in the process of.

Step 8: tert-Butyl N-[(2S) -1-[(2S, 4R) -4-hydroxy-2-{[(1R) -2-hydroxy-1- [4- (4-methyl-1,1) 3-Thiazole-5-yl) Phenyl] Ethyl] Carbamoyl}
Pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutane-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-thiazole-5-yl) phenyl] ethyl] carbamoyl} pyrrolidine-1-yl]- Synthesis of 3,3-dimethyl-1-oxobutane-2-yl] carbamate (ULM-5-B)
2-Amino-2- (4- (4-methylthiazole-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 A solution of N, N-dimethylformamide (50 mL) of -dimethylbutanoyl) -4-hydroxypyrrolidin-2-carboxylic acid (1273 mg, 3.70 mmol) and triethylamine (747 mg, 7.40 mmol) overnight under argon at room temperature. Was stirred with, and then water (80 mL) was added to the mixture. The aqueous layer was extracted with ethyl acetate (50 mLx5). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product is purified by preparative TLC (dichloromethyl / methanol = 15: 1) and (S) -1-((2S, 4R) -4-hydroxy-2-((R) -2-hydroxy-). 1-(4- (4-Methylthiazol-5-yl) phenyl) ethylcarbamoyl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutane-2-ylcarbamate tert-butyl (700mg) yellow Obtained as an oil, and (S) -1-((2S, 4R) -4-hydroxy-2-((S) -2-hydroxy-1- (4- (4-methylthiazole-5-yl)) Phenyl) ethylcarbamoyl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutane-2-ylcarbamate tert-butyl (500 mg) was obtained as a pale yellow oil.

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, m) 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 = .2 Hz), 7.36-7.46 (4H, m), 8.41 (1H, d,
J = .0 Hz), 8.99 (1H, s); LC / MS 561.2 [M + H] ⁺ ; Rt = 1.897 minutes
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 = .6 Hz), 4.76-4.81 (1H, m), 4.87 (1H, t, J = .6 Hz), 5.146 (1H, d, J = 2.8 Hz), 6.47 (1H, d, J) = 8.8 Hz), 7.37 (2H, d, J = .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 minutes Intermediate 7: (2S, 4R) -N-[(4-chloro-2-hydroxyphenyl) methyl] -4-hydroxy-1- [3-methyl -2- (3-Methyl-1,2-oxazol-5-yl) butanoyl] Pyrrolidine-2-carboxamide (ULM-6)

This important intermediate was prepared using the synthetic pathway described above. The required 3-methylisoxazole-5-acetic acid was prepared according to the literature (J. Org. Chem. 66, 6595-6603, 2001). Alkylation with 2-iodopropane has been described in the literature. The desired ULM-6 was prepared using the same synthetic method as described in the preparation of the intermediate ULM-3.

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 = .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, 0.5) H), 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 + 1] ⁺ ; Rt = 3.57 minutes.

PTM synthesis:
Preferred PTM embodiments of the present disclosure can be prepared according to the synthetic pathways of Schemes 1-3 below. These routes can be modified and adapted to the synthesis of a particular PTM embodiment using common methods known to those of skill in the art.

Illustrative PROTAC synthesis:
Intermediate 1

Step 1: 2- (2,6-dioxopiperidine-3-yl) -5-(2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) isoindoline-1,3-dione

2- (2,6-dioxopiperidine-3-yl) -5-hydroxyisoindoline-1,3-dione (500 mg)
, 1.82 mmol) in a solution of DMF (10 mL) with K ₂ CO ₃ (756 mg, 5.47 mmol) and 4-methyl-benzenesulfonic acid 2- (2- (2-hydroxyethoxy) ethoxy) ethyl (832 mg, 2.73 mmol). ) Was added at 25 ° C. The resulting solution was stirred at 70 ° C. for 5 hours. After cooling to room temperature, the reaction 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 on a silica gel column to give the desired product (95 mg, 13% yield).

Step 2: 2- (2- (2-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-)
5-Il) Oxy) ethoxy) ethoxy) acetaldehyde

2- (2,6-dioxopiperidine-3-yl) -5-(2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) isoindoline-1,3-dione (95 mg, 0.23 mmol) CH IBX (130 mg, 0.46 mmol) was added to a solution of ₃ CN (5 mL) at 25 ° C. The reaction mixture was stirred at 80 ° C. for 2 hours. After cooling to room temperature, the mixture is filtered through cerite and the filtrate is concentrated to concentrate the crude intermediate 1,2- (2-(((2- (2,6-dioxopiperidine-3-yl))-. 1,3-Dioxoisoindoline-5-yl) oxy) ethoxy) ethoxy) acetaldehyde (90 mg) was obtained and used without further purification.

Intermediate 2

2- (2,6-dioxopiperidine-3-yl) -5-fluoroisoindoline-1,3-dione (10 g, 36.2 mmol) in a solution of NMP (70 mL) with piperazine-1-carboxylic acid tert- Butyl (13.47 g, 72.5 mmol) and DIPEA (18.6 g, 14.5 mmol) were added. The obtained mixture was stirred for 16 hours at 90 ° C. After cooling to room temperature, the reaction was quenched with water (100 mL) and the mixture was extracted with ErOAc (300 mLx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (PE / EA = 100-2 / 1) to give the desired product 2- (2,6-dioxopiperidine-3-yl) -5- (piperazine-). 1-Il) Isoindoline-1,3-dione (14 g, 31.67 mmol, yield 87.5%) was obtained as a bright yellow solid.

Scheme for Synthesis of Exemplified Compound 51 Step 1: 3- (4-Bromophenyl) -4-nitropyridine

Stirring solution of 3-bromo-4-nitropyridine (100 g, 492.6 mmol), (4-bromophenyl) boronic acid (98.6 g, 492.6 mmol), and toluene (1000 ml) of potassium carbonate (203.9 g, 1.47 mol)-
Tetrakis (triphenylphosphine) palladium (14.8 g, 12.8 mmol) was added to a stirred solution of water (100 ml) at room temperature under a nitrogen atmosphere, and the mixture was degassed with nitrogen three times. The resulting mixture was stirred at 50 ° C. overnight. TLC showed that the reaction was complete. The solids were removed by filtration and washed with ethyl acetate (100 mlx3). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (100 mlx2). The organic layers are combined into one, washed with brine (400 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is a silica gel pad (10-33% acetate in hexanes). Purification by (eluting with ethyl) gave 3- (4-bromophenyl) -4-nitropyridine (89 g, yield 65%) as a yellow solid.

Step 2: 7-bromo-5H-pyrido [4,3-b] indole

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

Step 3: 7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b] indole

7-bromo-5H-pyrido [4,3-b] indol (400 mg, 1.63 mmol), (6-fluoropyridine-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 a mixture of dioxane / water (20 mL, 20: 1) under N ₂ for 4 hours, 90 Heated to ° C. 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) and 7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b. ] Indole (250 mg, 59% yield) was obtained.

Step 4: 14-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecane-1-ol

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

Step 5-(6-((14-Hydroxy-3,6,9,12-Tetraoxatetradecyl) Oxy) Pyridine-3-yl) -5H-Pirido [4,3-b] Indole-5- Tert-Butyl Carboxylic Acid

14-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecane-1-ol (150 mg, NEt ₃ (94.5 mg, 0.93 mmol) and Boc ₂ O (102.0 mg, 0.47 mmol) were added to a DCM (10 mL) solution of 0.31 mmol). The resulting solution was stirred at atmospheric 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 layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the desired product (120 mg, 66% yield), which was used in the next step without further purification.

Step 6: 7-(6-((14-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) oxy) -3,6, 9,12-Tetraoxatetradecyl) Oxy) Pyridine-3-yl) -5H-pyrido [4,3-b] indole-5-carboxylate tert-butyl

7-(6-((14-Hydroxy-3,6,9,12-tetraoxatetradecyl) oxy) pyridine-3-yl) -5H-pyrido [4,3-b] indol-5-carboxylic acid tert -MsCl (38.9 mg, 0.34 mmol) was added to a DCM (10 mL) solution of butyl (120 mg, 0.31 mmol) and NEt ₃ (93.9 mg, 0.93 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 layer was concentrated to give the intermediate mesylate.

2- (2,6-dioxopiperidine-3-yl) -5-hydroxyisoindoline-1,3-dione (45.6 mg) in a stirred solution of anhydrous DMF (10 mL) of mesylate (100 mg, 0.15 mmol) , 0.17 mmol) and K 2 CO _{3 (} 31.4 mg, 0.23 mmol) were added. The obtained 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 layer was evaporated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH = 20/1) to give the desired product in yellow form (15 mg, 23.6% yield).

Step 7: 5-((14-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy)-3,6,9,12-tetraoxatetra Decyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

7-(6-((14-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) oxy)-3,6,9,12 -Tetraoxatetradecyl) Oxy) Pyridine-3-yl) -5H-Piridine [4,3-b] Indole-5-Carboxylic acid tert-butyl (30 mg, 0.036 mmol) in DCM (2 mL) solution in TFA (5 mL) ) Was added. The mixture was stirred at atmospheric temperature for 4 hours. The mixture was evaporated under reduced pressure. The residue was purified by prep-HPLC to give the title compound as a white solid (10 mg, 38% yield). ¹ H 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.

Compound 50 was also prepared using a procedure similar to compound 51.
Exemplary Compound 52 Synthesis Scheme Step 1: 4- (2-Hydroxyethyl) piperazine-1-carboxylate tert-butyl

A solution of 2- (piperazine-1-yl) ethanol (5 g, 38.5 mmol) and TEA (12 g, 115 mmol), DCM
The mixture was stirred at 0 ° C., Boc ₂ O was added, and then the mixture was stirred overnight at 10 ° C. Water was added. The mixture was then extracted with DCM, dried and concentrated and filtered through a silica gel pad to give 8.1 g of product (92% yield).

Step 2: 4- (2- (propa-2-in-1-yloxy) ethyl) piperazine-1-carboxylic acid tert-
Butyl

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

Step 3: 4-(2-((3- (5-bromopyridin-2-yl) propa-2-in-1-yl) oxy) ethyl) piperazine-1-carboxylate tert-butyl

4- (2- (Propa-2-in-1-yloxy) ethyl) piperazine-1-carboxylate tert-butyl (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 were stirred at 5 ° C. overnight and EA was added. The mixture was washed with water and concentrated. It was then filtered through silica gel (EA) to give 450 mg of product (57% yield).

Step 4: 4- (2- (3- (5- (5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propoxy) ethyl) piperazine-1-carboxylate tert-butyl

7- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -5H-pyrido [4,3-b] indol-5-carboxylate [Exemplary compound 63 Prepared using a procedure similar to Step 1] (300 mg, 0.76 mmol), Pd (aMphose) Cl ₂ (50 mg, 10%), and CsF ₍ 450 mg, 2.96 mmol), CH ₃ CN / H 2 . In O (10: 1), the mixture was stirred in a microwave oven for 40 minutes at 120 ° C. The mixture was cooled to room temperature and EA was added. The organic layer was washed with water and then filtered through a silica gel pad (DCM: MeOH = 20: 1) to 100 mg 4-(2- (3- (5- (5H-pyrid [4,3-b] indol-). 7-Il) Pyridine-2-yl) Propa-2-inyloxy) Ethyl) Piperazine-1-carboxylate tert-butyl was obtained. The crude product was dissolved in MeOH, Pd / C was added, the mixture was stirred for 2 hours at 30 ° C. under 2Mpa H ₂ and filtered and concentrated to give 100 mg of product (yield 26). %).

Step 5: 7- (6- (3- (2- (Piperazine-1-yl) ethoxy) propyl) Pyridine-3-yl) -5H-pyrido [4,3-b] indole

4- (2- (3- (5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propoxy) ethyl) piperazine-1-carboxylate tert-butyl (100 mg, 100 mg, A 0.2 mmol) HCl / dioxane (2 mL) solution was stirred for 1 hour at 5 ° C. Concentration gave 100 mg of crude product.

Step 6: 5-((5- (4- (2- (3- (5- (5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propoxy) ethyl) piperazine- 1-Indole) Pentyl) Oxy) -2- (2,6-Dioxopiperidine-3-
Il) Isoindoline-1,3-Zeon

5- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yloxy)
Pentanol (86 mg, 0.24 mmol), NaBH ₄ CN (55 mg, 0.48 mmol) and CH ₃ COOH (cat.) Were stirred in MeOH at 5 ° C. for 3 hours. Then DCM was added. The organic layer was washed with water, concentrated and filtered through a silica gel pad (DCM: MeOH = 8: 1) to give 11 mg of product.

¹ HNMR (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.

Exemplary Compound 53 Synthesis Scheme Step 1: (((1s, 3s) -3- (allyloxy) cyclobutoxy) methyl) benzene

NaH (60%, 0.336 g, 8.4 mmol) was added to a solution of (1s, 3s) -3- (benzyloxy) cyclobutanol (1.0 g, 5.61 mmol) in DMF (10 mL) at 0 ° C. After stirring for 30 minutes, 3-bromopropa-1-ene was added dropwise at room temperature. The resulting solution was stirred at room temperature for 3 hours. After quenching with saturated NH ₄ Cl solution (20 mL), the mixture was extracted with EtOAc (20 mLx2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by a silica gel column using PE / EA = 10 to 1 as an eluent to obtain the desired product (1.0 g, 82%) as a colorless oil.

Step 2: 3-((1s, 3s) -3- (benzyloxy) cyclobutoxy) propan-1-ol

(((1s, 3s) -3- (allyloxy) cyclobutoxy) methyl) benzene (1.0 g, 4.58 mmol) in THF (20 mL) with dicyclohexylborane in THF (1.0 M, 9.0 mL) at 0 ° C. added. After stirring 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 was quenched with Na ₂ S ₂ O ₃ (20 mL). The mixture was dissolved in DCM. The organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified on 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.

Step 3: 4- (3-((1s, 3s) -3- (benzyloxy) cyclobutoxy) propyl) piperazine-1-carboxylate tert-butyl

3-((1s, 3s) -3- (benzyloxy) cyclobutoxy) propan-1-ol (1.0 g, 4.58 mmol)
MsCl (0.97 g, 9.2 mmol) was added to a DCM (10 mL) solution of TEA (2.0 g, 19.8 mmol) at 0 ° C.
After stirring at room temperature for 2 hours, the reaction was quenched with a saturated solution of sodium bicarbonate (20 mL).
The mixture was extracted with DCM (20 mLx2). The combined organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum to give the desired product (1.1 g, crude), which was used in the next reaction without further purification. ..

To a solution of the above intermediate (1.1 g, crude) in DMF (10 mL) was added tert-butyl piperazine-1-carboxylate (1.60 g, 9.2 mmol). The resulting solution was heated at 90 ° C. for 4 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and the mixture was extracted with EtOAc (20 mLx3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified on a silica gel column using PE / EA = 2: 1 as the eluent to give the desired product (980 mg, 58%) as a colorless oil.

Step 4: 4- (3-((1s, 3s) -3-hydroxycyclobutoxy) propyl) piperazine-1-carboxylate tert-butyl

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

Step 5: 4- (3-((1s, 3s) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propyl ) Piperazine-1-carboxylate tert-butyl

4- (3-((1s, 3s) -3-hydroxycyclobutoxy) propyl) piperazine-1-carboxylate tert-butyl (180 mg, 0.57 mmol) and 7- (6-fluoropyridin-3-yl) -5H -NaH (60%, 100 mg, 2.5 mmol) was added to a solution of pyrido [4,3-b] indole (100 mg, 0.379 mmol) in NMP (10 mL) at room temperature. The resulting solution was heated at 90 ° C. for 2 hours. After cooling to room temperature, the reaction was quenched with NH ₄ Cl saturated solution (20 mL) and the mixture was extracted with EtOAc (20 mLx3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by prep-TLC with DCM / CH ₃ OH (15: 1) to give the desired product (120 mg, 0.21 mmol) as a brown solid.

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

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

Step 7: 5- (4-(3-((1s, 3s) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclo Butoxy) propyl) piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

7-(6-((1s, 3s) -3- (3- (piperazine-1-yl) propoxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b] indole (80 mg, 2- (2,6-dioxopiperidine-3-yl) -5-fluoroisoindoline-1,3-dione (100 mg) in a mixed solution of NMP (2.0 mL) of crude) and DIEA (300 mg, 2.36 mmol) , 0.36 mmol) was added. The mixture was heated to 130 ° C. in the microwave for 45 minutes. After cooling to room temperature, the reaction was dissolved in EtOAc (100 mL). The mixture was washed with brine (20 mLx3). The organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by prep-TLC with DCM / CH ₃ OH / NH ₃ H ₂ O (15: 1: 0.1) to give the title product (16.0 mg, 13%) as a yellow solid.

¹ H 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 = .4 Hz, 1H) , 7.87-7.92 (m, 3H), 7.68 (d, J = .4 Hz, 1H), 7.60 (s,
1H), 7.48-7.50 (m, 1H), 7.38 (d, J = .6 Hz, 1H), 7.06 (m, 1H), 6.84 (d, J = .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 = .2 Hz, 2H), 2.15 -2.18 (m, 2H), 1.81 (t, J = .8 Hz, 2H). (M ⁺ H) +714.3
Exemplary Compound 55 Synthesis Scheme Step 1: I-4- (5- (3-Methoxy-3-oxoprop-1-en-1-yl) Pyridine-2-yl) Piperazine-1-carboxylate tert-butyl

In a solution of 4- (5-formylpyridin-2-yl) piperazine-1-carboxylate tert-butyl (1.0 g, 3.44 mmol) and 2- (dimethoxyphosphoryl) methyl acetate (750 mg, 4.12 mmol) in THF (15 mL) , DBU (1.57 g, 10.3 mmol) was added. The reaction mixture was stirred at room temperature overnight. After quenching with H ₂ O (10 mL), the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with brine and dried over Na ₂ SO ₄ . It was filtered and concentrated under vacuum. The residue was disrupted with petroleum ether to give the desired product (800 mg, 2.3 mmol, 66.9% yield) as a pale solid.

Step 2: 4- (5- (3-Hydroxypropyl) Pyridine-2-yl) piperazine-1-carboxylate tert-butyl

I-4- (5- (3-Methoxy-3-oxoprop-1-en-1-yl) Pyridine-2-yl) Piperazine-1-
NaBH ₄ (874 mg, 23.0 mmol) was added to a solution of tert-butyl carboxylate (800 mg, 2.3 mmol) in 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 was quenched with 2N NH ₄ Cl and the mixture was extracted with EtOAc (80 mLx3). The organic layers were combined, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column (EA: PE = 1: 1) to give the desired compound (420 mg, 1.31 mmol, yield 57.0%) as a yellow oil.

Step 3: 4- (5-(3-((Methylsulfonyl) oxy) propyl) pyridin-2-yl) piperazine-1-carboxylate tert-butyl

In a DCM (2 mL) solution of 4- (5- (3-hydroxypropyl) pyridin-2-yl) piperazine-1-carboxylate tert-butyl (50 mg, 0.16 mmol) and Et ₃ N (48 mg, 0.48 mmol). MsCl (27 mg, 0.23 mmol) was added. The reaction was stirred at room temperature for 1 hour. After quenching with H ₂ O (30 mL), the mixture is DCM
Extracted with (20 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the desired crude compound (64 mg) as a yellow oil, which could be followed without further purification. Used for the reaction of.

Step 4: 4- (5-(3-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) oxy) propyl) pyridine-2- Il) Piperazine-1-carboxylate tert-butyl

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

Step 5: 2- (2,6-dioxopiperidine-3-yl) -5-(3- (6- (piperazin-1-yl) pyridin-3-yl) propoxy) isoindoline-1,3-dione

4- (5-(3-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) oxy) propyl) pyridine-2-yl) piperazine A solution of 6N HCl in dioxane (2 mL, 12.0 mmol) was added to a solution of tert-butyl -1-carboxylate (200 mg, 0.39 mmol) in dioxane (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the title crude product (200 mg) as a yellow solid.

Step 6: (6- (3-Hydroxyprop-1-in-1-yl) Pyridine-3-yl) Boronic acid

PdCl ₂ (PPh ₃ ) in a solution of (6-bromopyridin-3-yl) boronic acid (1.0 g, 4.95 mmol) and propa-2-in-1-ol (830 mg, 14.8 mmol) in THF (30 mL). 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 cerite and 1N NaOH (10 mL) was added to the filtrate. The mixture was extracted with DCM. The pH was adjusted to about 6 with 2N HCl. Aqueous solution was extracted with ethyl acetate. The combined EtOAc layers were dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure until dry to give the desired compound (500 mg, 2.82 mmol, 57% yield) as a pale solid. ..

Step 7: 3- (5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propa-2-in-1-ol

7-bromo-5H-pyrido [4,3-b] indole (50 mg, 0.20 mmol) and (6- (3-hydroxyprop-1-in-1-yl) pyridin-3-yl) boronic acid (53 mg,) 0.30 mmol) dioxane (10 mL) and water (1.0 mL)
), 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) were added. The mixture was stirred at 100 ° C. for 3 hours in an N ₂ atmosphere. After cooling to room temperature, the reaction was quenched with water (3 mL) and the mixture was extracted with EtOAc (20 mLx3). The organic layers were combined, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified on a silica gel column (MeOH: DCM = 1: 20-1: 10) to give the desired compound (30 mg, 0.10 mmol, 50.0% yield) as a yellow solid.

Step 8: 3- (5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propan-1-ol

3- (5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propa-2-in-1-ol (30 mg, 10 mmol) in MeOH (2 mL) solution, Pd (OH) ₂ / C (20%, 10 mg) and cat. Concentrated HCl (0.1 mL)
) Was added. The reaction solution was stirred at room temperature for 2 hours under an H ₂ atmosphere. The mixture was filtered through cerite and the filtrate was concentrated to give the desired crude compound (30 mg) as a yellow oil.

Step 9: 3- (5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propanal

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

Step 10: 5-(3- (6- (4- (3- (5- (5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propyl) piperazine-1-yl) ) Pyridine-3-yl) Propoxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione

3- (5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propanal (100 mg,
2- (2,6-dioxopiperidine-3-yl) -5-(3- (6- (piperazin-1-yl) pyridin-3-yl) propoxy) iso in a crude) solution of MeOH (10 mL) Indoline-1,3-dione (100 mg, 0.21 mmol) and NaBH ₃ CN (41 mg, 0.66 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (6 ml) and extracted with DCM (20 mLx2). The organic layers were combined, washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the desired product (15 mg, 0.02 mmol) as a white solid.

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
Scheme of synthesis of exemplary compound 56
5-((5- (4- (2-((1s, 3s) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy)) Cyclobutoxy) ethyl) piperazine-1-yl) pentyl) oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

Step 1: (1s, 3s) -3- (benzyloxy) cyclobutane-1-ol

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

Step 2: (((1s, 3s) -3- (2,2-diethoxyethoxy) cyclobutoxy) methyl) benzene

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

Step 3: 2-((1s, 3s) -3- (benzyloxy) cyclobutoxy) acetaldehyde

(((1s, 3s) -3- (2,2-diethoxyethoxy) cyclobutoxy) methyl) benzene (220 mg, 0.74 mmol) in CH ₃ CN (5 mL) solution in HCl (2 mL, 2.5 mol / L) Aqueous solution) was added. The resulting mixture was stirred for 2 hours at 70 ° C. 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 layer was washed with NaHCO ₃ and brine. The solution was dried over DDL ₄ and concentrated to give the desired compound (170 mg) as a yellow oil, which was used in the next step without further purification.

Step 4: 4- (2-((1s, 3s) -3- (benzyloxy) cyclobutoxy) ethyl) piperazine-1-carboxylate tert-butyl

2-((1s, 3s) -3- (benzyloxy) cyclobutoxy) acetaldehyde (170 mg, crude, 0.772 mmol) in MeOH (10 mL) solution with tert-butyl piperazine-1-carboxylate (215 mg, 1.16). mmol), AcOH (1 drop) and NaBH ₃ CN (97 mg, 154 mmol) were added. The obtained mixture was stirred for 18 hours at 10 ° C. The reaction mixture was diluted with water (50 ml) and the mixture was extracted with EA. The organic layer was washed with brine, dried over DDL ₄ and concentrated. The residue was purified by chromatography (silica gel, PE: EA (1: 1, v: v)) to give the desired compound (280 mg) as a colorless oil.

4- (2-((1s, 3s) -3- (benzyloxy) cyclobutoxy) ethyl) piperazine-1-carboxylate tert-butyl, using the procedures described above for exemplary compound 42 and exemplary compound 53. Then, according to the following scheme, the title compound 5-((5- (4- (2-((1s, 3s) -3-((5- (5H-pyrid [4,3-b] indol-7) -Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Ethyl) Piperazine-1-yl) Pentyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione Converted to.

Exemplary Compounds 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 = .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).

Exemplified compound 54 and exemplary compound 58 were prepared using a procedure similar to that described above, according to the scheme below.

Exemplary Compound 57 Synthesis Scheme Step 1: 4- (5H-pyrido [4,3-b] indole-7-yl) -3,6-dihydropyridine-1 (2H) -benzyl carboxylate

7-bromo-5H-pyrido [4,3-b] indol (492 mg, 2 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3, Dioxane / H ₂ O (20 mL / 2 mL) of 6-dihydropyridine-1 (2H) -benzyl carboxylate (755 mg, 2.2 mmol), Pd (Amphose) Cl ₂ (146 mg, 0.2 mmol) and CsF (1.2 g, 8 mmol) ) Was stirred at 90 ° C. for 16 hours. After cooling to room temperature, the reaction was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column eluting with dichloromethane / methanol to give 260 mg of the desired product (0.68 mmol, 34%).

Step 2: 7- (Piperidin-4-yl) -5H-Pirido [4,3-b] Indole

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

Step 3: 5-((14-(4- (5H-pyrido [4,3-b] indole-7-yl) piperidine-1-yl) -3,6,9,12-tetraoxatetradecyl) oxy )-2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

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-Dioxoisoindoline-5-yl) oxy) -3,6,9,12-tetraoxatetradecanal (175 mg, 0.36 mmol) [prepared as described above for intermediate 101] NaBH ₃ CN (40 mg, 0.64 mmol) and a drop of CH ₃ COOH were added to the CH ₃ OH (10 mL) solution at room temperature. After stirring for 2 hours, the reaction was quenched by the addition of water (20 mL). The resulting solution was extracted with DCM (20 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by prep-TLC with DCM / CH ₃ OH (10: 1) to give the desired product (18 mg, 0.025 mmol, 8%). ¹ H 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 = .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) +78.3.

Scheme of synthesis of exemplary compound 60
5- (4- (3-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propyl ) Piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl)
Isoindoline-1,3-dione

Step 1: 4-(3-((1r, 3r) -3-((4-nitrobenzoyl) oxy) cyclobutoxy) propyl) piperazine-1-carboxylate tert-butyl

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-
DIAD (1.02 g, 5.06 mmol) was added dropwise to a solution of nitrobenzoic acid (310 mg, 1.85 mmol) in THF (10 mL) under N ₂ at room temperature. After stirring at room temperature for 3 hours, the mixture was quenched with water (20 mL) and the mixture was extracted with EtOAc (20 mLx2). The combined organic layers were concentrated under vacuum. The residue was purified by a silica gel column using PE / EA = 2: 1 to 1: 1 as an eluent to obtain the desired product (350 mg, 45%) as a semi-solid.

4- (3-((1r, 3r) -3-((4-nitrobenzoyl) oxy) cyclobutoxy) propyl) piperazine-1-carboxylate tert-butyl, using the procedure described above for exemplary compound 53. According to the following scheme, the title compound 5- (4- (3-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridine-2) -Il) Oxy) Cyclobutoxy) propyl) Piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione was converted.

Compound 60: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.07 (s, 1H), 9.76 (s, 1H), 8.67 (d, J = 6.0Hz, 1H), 8.60 (s, 1H), 8.52 (d, J = .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 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) +74.3.

Synthesis scheme of exemplary compound 61
2- (2,6-dioxopiperidine-3-yl) -5-((5- (4- (3- (5- (5- (2-,2-trifluoroethyl) -5H-pyrido] 4,3-b] Indole-7-yl) Pyridine-2-yl) Propyl) Piperazine-1-yl) Pentyl) Oxy) Isoindoline-1,3-dione

Step 1: 7- (6-(3-((tert-butyldimethylsilyl) oxy) propyl) Pyridine-3-yl) -5H-pyrido [4,3-b] indole

3- (5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propan-1-ol (Compound 55; 100 mg, prepared as described for 0.33 mmol) ) To a solution of DCM (5 mL) was added with imidazole (44.8 mg, 0.66 mmol) and TBSCl (59.6 mg, 0.40 mmol). 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 under vacuum. Residues silica gel column chromatography (DCM / MeOH = 20/1, 0.2)
Purification with% Net ₃ ) gave the title product (100 mg, 73% yield).

Step 2: 7- (6-(3-((tert-butyldimethylsilyl) oxy) propyl) pyridin-3-yl) -5- (2,2,2-trifluoroethyl) -5H-pyrido [4, 3-b] Indole

7-(6-(3-((tert-butyldimethylsilyl) oxy) propyl) pyridin-3-yl) -5H-pyrido [4,3-b] indole (60 mg, 0.14 mmol) in DMF (5 mL) NaH (8.6 mg, 0.22 mmol) was added 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 an additional hour, the reaction was diluted with EtOAc (40 mL), washed with brine and dried over anhydrous sodium sulfate. The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH = 40: 1, 0.2% NH ₃ · H ₂ O) to give the title product (55 mg, 92% yield).

Step 3: 3- (5-(5- (2,2,2-trifluoroethyl) -5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propan-1-ol

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

Step 4: 3- (5-(5- (2,2,2-trifluoroethyl) -5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propanal

3- (5-(5- (2,2,2-trifluoroethyl) -5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propan-1-ol (90 mg) , 0.23 mmol) DMSO ( 2 mL) solution to which IBX (130.9 mg, 0.47 mL) was added. The obtained mixture was stirred at 40 ° C. for 2 hours. The mixture was quenched with saturated Na ₂ S ₂ O ₃ aqueous solution (5 mL) and saturated NaHCO ₃ aqueous solution (5 mL). This mixture is mixed with EtOAc (20 mLx5)
). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the desired crude product (89.5 mg), which was used in the next reaction without further purification.

Step 5: 4- (5-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) oxy) pentyl) piperazine-1-carboxylic acid tert -Butyl

5-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) oxy) pentanal (150 mg, 0.42 mmol) [Prepared according to the procedure described above In a solution of MeOH (5 mL), piperazine-1-carboxylate tert-butyl (77.9 mg, 0.42 mmol) and NaBH ₃ CN (52.6 mg, 0.84 mm)
ol) was added. 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 layer 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 give the desired product (200 mg, 90% yield).

Using BOC deprotection and a reductive amination procedure similar to that described above, the compounds of steps 4 and 5 were combined with the final compound 2- (2,6-dioxopiperidine-3-yl) -5-yl. ((5-(4- (3- (5- (5- (2,2,2-trifluoroethyl) -5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl)) It was converted to propyl) piperazine-1-yl) pentyl) oxy) isoindoline-1,3-dione.

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 = .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 --. 16 (m, 1H), 4.95 (s, 4H), 4.59 (s, 2H), 4.18 (t, J = .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.

Synthesis scheme of exemplary compound 62
3- (5-((5- (4- (3- (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propyl) piperazine-1 -Il) Pentyl) Oxy) -1-oxoisoindoline-2-yl) Piperazine-2,6-dione

Step 1: 5-Amino-4-(5-((5-hydroxypentyl) oxy) -1-oxoisoindoline-2-yl) -5-oxopentanoic acid tert-butyl

5-Amino-4- (5-hydroxy-1-oxoisoindoline-2-yl) -tert-butyl-5-oxopentanoate (500.0 mg, 1.0 eq), pentane-1,5-diol (187 mg, 1.2 eq) ), And a solution of PPh3 (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 was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane / methanol (10: 1) to give the desired product (560 mg, 1.33 mmol, 89%).

Step 2: 3- (5-((5-Hydroxypentyl) oxy) -1-oxoisoindoline-2-yl) piperidine-2,6-dione

MeCN (20 mL) solution of 5-amino-4- (5-((5-hydroxypentyl) oxy) -1-oxoisoindoline-2-yl) -tert-butyl-5-oxopentate (560 mg, 1.0 eq) To p-TsA (253 mg, 3.0 eq) was added at room temperature. The resulting solution was stirred at 90 ° C. for 6 hours. The reaction was then cooled to room temperature and quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (15 mLx3). The combined organic layers were washed with brine (10 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. Dichloromethane / methanol (10: 1)
The silica gel column was loaded with the desired product (190 mg, 0.55 mmol, 46%).

Step 3: 5-((2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) oxy) pentanal

3- (5-((5-Hydroxypentyl) oxy) -1-oxoisoindoline-2-yl) piperidine-2,6-dione (190 mg, 1.0 eq) in DCM (20 mL) solution at room temperature (IBX) 100 mg, 2 equivalents) was added. The resulting solution was stirred at room temperature for 2 hours. The solid was then filtered and the filtrate was concentrated under vacuum to give a crude product (190 mg), which was used in the next reaction without further purification.

Step 4: 7-bromo-5-methyl-5H-pyrido [4,3-b] indole]

Sodium hydride (in mineral oil, 1.4 g, 35.6 mmol) in a solution of 7-bromo-5H-pyrido [4,3-b] indole (8.0 g, 32.4 mmol) in N, N-dimethylformamide (50 ml), 60%) at 0 ° C,
The reaction mixture was stirred for 30 minutes at 0 ° C. Iodomethane (4.6 g, 32.4 mmol) was added to the obtained mixture at 0 ° C., the reaction mixture was heated to room temperature, and the mixture was stirred overnight. TLC showed that the reaction was complete. The reaction mixture was quenched with water (30 mL) at 0 ° C. and extracted with ethyl acetate (50 mLx2). Combine the organic layers into one, wash with water (80 ml), then brine (90 ml)
Washed with anhydrous sodium sulfate, concentrated under reduced pressure to give a crude residue, purified by silica gel flash chromatography (eluted with 20-40% ethyl acetate in hexanes), and brown solid. As a substance, 7-bromo-5-methyl-5H-pyrido [4,3-b] indole (6.0 g, yield 71%) was obtained.

Using the above procedure for exemplary compound 61, 5-((2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) oxy) pentanal, the title compound. 3- (5-((5- (4- (3- (5- (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) propyl) piperazine- It was converted to 1-yl) pentyl) oxy) -1-oxoisoindoline-2-yl) piperidine-2,6-dione according to the following scheme.

Exemplary Compounds 62: ^{1 1} HNMR (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) +74.3.

Exemplary compound 63
2- (2,6-dioxopiperidine-3-yl) -5-((5- (4- (3- (5- (5- (5-methyl-5H-pyrido [4,3-b] indole-7-) Indole -3- (trifluoromethyl) pyridin-2-yl) propyl) piperazine-1-
Il) Pentil) Oxy) Isoindoline-1,3-dione

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

KOAc (114 mg, 1.15 mmol), Pd (dppf) Cl ₂ (35 mg, 0.05) in a dioxane solution of 7-bromo-5-methyl-5H-pyrido [4,3-b] indol (150 mg, 0.577 mmol). mmol), followed by 4,4,4', 4', 5,5,5', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (294 mg, 1.15 mmol). Was added. The resulting solution was heated at 100 ° C. under N ₂ for 2 hours. After cooling to room temperature, the reaction was quenched with water and the mixture was extracted with EtOAc (10 mLx2). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum to give the desired crude product (180 mg, crude), which was used in the next reaction without further purification.

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

5-bromo-2-chloro-3-trifluoromethylpyridine (135 mg, 0.7 mmol) and 5-methyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-) Il) -5H-pyrido [4,3-b] indol (180 mg, 0.58 mmol) in a mixed solution of dioxane / H ₂ O (v / v = 10/1, 10 mL) with Pd (dppf) ₂ C
l ₂ (20 mg, 10%) and CsF (180 mg, 1.16 mmol) were added. 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 under vacuum. The residue was purified by silica gel column chromatography to give the desired product (170 mg, 95% yield).

Step 3: 4- (3- (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) -3- (trifluoromethyl) pyridin-2-yl) propa-2- In-1-yl) piperazine-1-carboxylate tert-butyl

7- (6-chloro-5- (trifluoromethyl) pyridine-3-yl) -5-methyl-5H-pyrido [4,3-b] indol (170 mg, 0.58 mmol), and 4- (propa-) 2-Inyl) Piperazine-1-carboxylate tert-butyl (156 mg, 0.69 mmol) in a mixed solution of DMF (10 Ml), 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 mm)
ol) was added. The mixture was heated to 150 ° C. in the microwave 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 under vacuum. The residue was purified by silica gel column chromatography to give the desired product (200 mg).

Step 4: 4- (3- (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) -3- (trifluoromethyl) pyridin-2-yl) propyl) piperazine- 1-Carboxylic acid tert-butyl

4- (3- (5- (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) propa-2-in-1 -Pd / C (20 mg) was added to an ethanol solution of tert-butyl (yl) piperazine-1-carboxylate (200 mg). Mix solution at 30 ° C for 8 hours under H ₂ atmosphere (3Mpa)
Was stirred with. The mixture was filtered through cerite and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC to give the desired product (25 mg).

BOC deprotection, and 4-(3-(5-(5-methyl-5H-pyrido [4,3-b] indol-7-yl) -3- (5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) -3-" using the procedure of reductive amination described above. (Trifluoromethyl) pyridine-2-yl) propyl) piperazin-1-carboxylate tert-butyl was added to the title compound 2- (2,6-dioxopiperidine-3-yl) -5-yl according to the following scheme. ((5- (4- (3- (5- (5-Methyl-5H-pyrido [4,3-b] indol-7-
Il) -3- (trifluoromethyl) Pyridine-2-yl) Propyl) Piperazine-1-yl) Pentyl) Oxy) Isoindoline-1,3-dione was converted.

Exemplary Compounds 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 = .4 Hz, 1H), 7.66 (s, 1H), 7.59 (d, J = .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.

Exemplary compound 73
Step 1: 7- (6-((1s, 3s) -3- (benzyloxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b] indole

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

Step 2: (1s, 3s) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutane-1-ol

7-(6-((1s, 3s) -3- (benzyloxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b] indol (1.42 g, 3.37 mmol) and palladium carbon ( A mixed solution of methanol (30 ml) -tetrahydrofuran (10 ml) (10%, 150 mg) was stirred under a hydrogen atmosphere (hydrogen balloon) for 2 hours at 50 ° C. TLC showed that the reaction was complete. Palladium on carbon was removed by filtration and washed with methanol (10 mlx2). Concentrate the combined filtrates under reduced pressure to (1s, 3s) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl). Oxy) cyclobutanol (1.57 g, crude) was obtained as a white solid.

Step 3: 7-(6-((1s, 3s) -3-hydroxycyclobutoxy) Pyridine-3-yl) -5H-pyrido [4,3-b] indole-5-carboxylate tert-butyl

(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 ( Di-tert-butyl carbonate (1.2 g, 5.55 mmol) was added to a suspension of tetrahydrofuran (20 ml) -water (5 ml) of 1.1 g, 10.69 mmol) at room temperature. The mixture was stirred at room temperature for 17 hours. TLC showed that the reaction was complete. The mixture was concentrated and the residue was partitioned between ethyl acetate (20 ml) and water (30 ml). The organic layer is collected, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is subjected to silica gel flash chromatography (1-2% methanol in dichloromethane). Purified by (elution with), and as a white solid, 7- (6-((1s, 3s) -3-hydroxycyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b] indol-5- Tert-butyl carboxylate (1.1 g, 73% in two steps) was obtained.

Step 4: 7-(6-((1s, 3s) -3-((methylsulfonyl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b] indole-5-carboxylic acid tert-butyl

7-(6-((1s, 3s) -3-hydroxycyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b] indol-5-carboxylate tert-butyl (500mg, 1.16 mmol) And methanesulfonyl chloride (530 mg, 4.63 mmol) was added to a suspension of dichloromethane (10 ml) of triethylamine (352 mg, 3.47 mmol) at 0 ° C. The obtained mixture was heated to room temperature and stirred at room temperature for 5 hours. TLC
It was shown that the reaction was completed. The reaction mixture was diluted with dichloromethane (10 ml) and washed with water (10 ml). The organic layer is collected, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to 7- (6-((1s, 3s) -3-hydroxycyclobutoxy) pyridine-3-. Ill) -5H-pyrid [4,3-b] indol-5-carboxylate tert-butyl (700 mg, crude) was obtained and used in the next step without further purification.

Step 5-(6-((1r, 3r) -3-((6-iodopyridine-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b] Indole

7-(6-((1s, 3s) -3-hydroxycyclobutoxy) pyridine-3-yl) -5H-pyrido [4,3-b] indol-5-carboxylate tert-butyl (350 mg, 0.69 mmol) A mixed solution of 6-iodopyridine-3-ol (155 mg, 0.69 mmol) and cesium carbonate (452 mg, 1.39 mmol) in anhydrous N, N-dimethylformamide (4 ml) was stirred for 12 hours at 90 ° C. TLC showed that the reaction was complete. The mixture was partitioned between ethyl acetate (30 ml) and water (40 ml). The organic layer is collected, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is subjected to silica gel flash chromatography (1-2% methanol in dichloromethane). Purified by (elution with), and as a bright yellow solid, 7- (6-((1r, 3r) -3-((6-iodopyridine-3-yl) oxy) cyclobutoxy) pyridine-3-yl) -5H -Pyridine [4,3-b] indol (250 mg, 68%) was obtained.

Step 6: [5-((3- (5-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) ) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione]

7-(6-((1r, 3r) -3-((6-iodopyridine-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b] indol (150 mg) , 0.24 mmol), 2- (2,6-dioxopiperidin-3-yl) -5- (propa-2-in-1-yloxy) isoindrin-1,3-dione (111 mg, 0.35 mmol) [Example Prepared using the procedure of Step 1 of compound 180], and bis (triphenylphosphine) palladium (II) in a stirred solution of N, N-dimethylformamide (2 mL) of triethylamine (121 mg, 1.20 mmol). Chloride (8 mg, 0.01 mmol) and cuprous iodide (2 mg, 0.01 mmol) were added under a nitrogen atmosphere at room temperature. The mixture was degassed with nitrogen three times. The resulting mixture was stirred under nitrogen at 65 ° C. overnight. TLC showed that the reaction was complete. Mix water with water (30 ml)
And ethyl acetate (30 ml). The organic layer is collected, washed with brine (30 mlx2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is eluted with silica gel flash column chromatography (2% methanol in dichloromethane). ) As a white solid, 5-((3- (5-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indol-7-yl) pyridine) -2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) -2- (2,6-dioxopiperidin-3-yl) Isoindrin-1,3 -Dione (45 mg, 26% yield) was obtained.

¹ H NMR (400 MHz, DMSOd-6): δ .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 = .2 Hz, 1H), 8.25 (s, 1H), 8.30 (d, J = .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.

Exemplary Compound 77 Synthesis Scheme Step 1: 7-((1r, 3r) -3-((6- (3-((2- (2,6-dioxopiperidine-3-yl) -1) , 3-Dioxoisoindoline-5-yl) oxy) propyl) pyridine-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b] indole-5-carboxylic acid tert-butyl

7-(6-((1r, 3r) -3-((6- (3-((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline-5- Il) Oxy) Propa-1-in-1-yl) Pyridine-3-yl) Oxy) Cyclobutoxy) Pyridine-3-yl) -5H-pyrido [4,3-b] Indole-5-Carboxylic acid tert- Pd / C was added to a solution of butyl (15 mg) in MeOH. The solution was stirred under H ₂ (2Mpa) for 2 hours at 30 ° C. The mixture was filtered through cerite and the filtrate was concentrated under vacuum. The residue was purified on silica gel to give the desired product (6 mg).

Step 2: 5-(3-(5-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclo Butoxy) Pyridine-2-yl) Propoxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione

7-(6-((1r, 3r) -3-((6- (3-((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline-5- Il) Oxy) propyl) 240 Pyridine-3-yl) Oxy) Cyclobutoxy) Pyridine-3-yl) -5H-pyrido [4,3-b] indole-5-carboxylate tert-butyl (6 mg) DCM / The solution of TFA (2 mL / 1 mL) was stirred at room temperature for 4 hours. Remove the solvent under vacuum and 5- (3-(5-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2- Il) Oxy) Cyclobutoxy) Pyridine-2-yl) Propoxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione (5.5 mg) was obtained.

¹ H NMR (400 MHz, CD ₃ OD): δ .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 = .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 =. 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.

Exemplary Compound 94 Synthesis Scheme Step 1: (1r, 3r) -3-((6- (5-((triisopropylsilyl) oxy) penta-1-in-1-yl))
Pyridine-3-yl) Oxy) Cyclobutane-1-ol

Triisopropyl (penta-4-in) in a solution of (1r, 3r) -3-((6-bromopyridine-3-yl) oxy) cyclobutane-1-ol (530 mg, 2.17 mmol) in anhydrous THF (10 mL). -1-Iloxy) 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. Added under N ₂ . The resulting solution was stirred at 45 ° C. for 16 hours. The reaction was diluted with H ₂ O (10 mL). The resulting mixture was extracted with EtOAc (10 mLx2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue is purified on a silica gel column to give the desired product (1r, 3r) -3-((6- (5-((triisopropylsilyl) oxy) penta-1-in-1-yl) pyridine-. 3-Il) oxy) cyclobutane-1-ol (600 mg, 68% yield) was obtained as a colorless oil.

Step 2: 5-bromo-2-((1r, 3r) -3-((6- (5-((triisopropylsilyl) oxy) penta-1-
In-1-yl) Pyridine-3-yl) Oxy) Cyclobutoxy) Pyridine

(1r, 3r) -3-((6- (5-((triisopropylsilyl) oxy) penta-1-in-1-yl) pyridin-3-yl) oxy) cyclobutane-1-ol (300 mg, To a solution of 0.74 mmol) 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 was diluted with H ₂ O (10 mL). The resulting mixture was extracted with EtOAc (10 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel column to give the desired product 5-bromo-2-((1r, 3r) -3-((6- (5-((triisopropylsilyl) oxy) penta-1-in). -1-yl) Pyridine-3-yl) Oxy) Cyclobutoxy) Pyridine (240 mg, 58% yield) was obtained as a white solid.

Step 3: 5-Methyl-7-(6-((1r, 3r) -3-((6- (5-((triisopropylsilyl) oxy) penta-1-in-1-yl) pyridine-3- Il) Oxy) Cyclobutoxy) Pyridine-3-yl) -5H-pyrido [4,3-b] indole

5-bromo-2-((1r, 3r) -3-((6- (5-((triisopropylsilyl) oxy) penta-1-in-1-
Il) Pylin-3-yl) Oxy) Cyclobutoxy) In a solution of pyridine (180 mg, 0.32 mmol) with 1,4-dioxane (5 ml) and H ₂ O (1 mL), 5-methyl-7- (6). -(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) pyridine-3-yl) -5H-pyrido [4,3-b] indol (119 mg, 0.39 mmol), CsF (147 mg, 0.96 mmol) and Pd (aMphos) Cl ₂ (34 mg, 0.06 mmol) were added at 15 ° C. under N ₂ . The resulting mixture was stirred for 5 hours at 80 ° C. The mixture was quenched with H ₂ O (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were then washed with brine (20 mLx2), dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel column to give the desired product 5-methyl-7-(6-((1r, 3r) -3-((6- (5-((triisopropylsilyl) oxy) penta- 1-In-1-yl) Pyridine-3-yl) Oxy) Cyclobutoxy) Pyridine-3-yl) -5H-pyrido [4,3-b] Indole (80 mg, 38% yield) was obtained.

Step 4: 5-(5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) Cyclobutoxy) Pyridine-2-yl) Penta-4-in-1-ol

5-Methyl-7-(6-((1r, 3r) -3-((6- (5-((triisopropylsilyl) oxy) penta-1-in-1-yl) pyridin-3-yl) oxy) ) Cyclobutoxy) Pyridine-3-yl) -5H-pyrido [4,3-b] indol (90 mg, 0.14 mmol) in anhydrous THF (10 mL) solution in 1M TBAF in THF solution (1 mL, 0.7 mmol)
Was added under N ₂ at 15 ° C. The mixture was stirred at 40 ° C. for 1 hour under an N ₂ balloon. The mixture was concentrated. The residue is purified with prep-TLC to give the desired product 5- (5-((1r, 3r) -3-((5- (5-methyl-5H-).
Pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) penta-4-in-1-ol (30 mg, 43% yield) white Obtained as a solid.

Step 5: 2- (2,6-dioxopiperidine-3-yl) -5-((5- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido]] 4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Penta-4-in-1-yl) Oxy) Isoindoline-1,3-dione

5- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) Pyridine-2-yl) Penta-4-in- 1 -ol (25 mg, 0.05 mmol)
2- (2,6-dioxopiperidine-3-yl) -5-hydroxyisoindoline-1,3-dione (20 mg, 0.07 mmol), PPh ₃ (40 mg,) in a solution of anhydrous THF (2 mL). 0.14 mmol) was added at 15 ° C. under N ₂ . DIAD (32 mg, 0.14 mmol) was added to the mixture at 40 ° C. under _N2 . The obtained mixture was stirred for 0.5 hours at 40 ° C. The mixture was cooled to 20 ° C., quenched with H ₂ O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were then washed with brine (20 mLx5), dried over anhydrous sodium sulfate and concentrated. The residue is purified with prep-TLC to give the desired product 2- (2,6-dioxopiperidine-3-yl) -5-((5- (5-((1r, 3r) -3- (. (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) penta-4-in-1-yl ) Oxy) Isoindoline-1,3-dione (22 mg, 58% yield) was obtained as a white solid.

¹ HNMR (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 = .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.

Scheme for Synthesis of Exemplary Compound 117 Step 1: 5-Methyl-7-(6-((1r, 3r) -3-((6- (3-((Tetrahydro-2H-pyran-2-yl) oxy) Oxygen) Propa -1-in-1-yl) Pyridine-3-yl) Oxy) Cyclobutoxy) Pyridine-3-yl) -5H-
Pirido [4,3-b] indole

(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 of exemplary compound 73], 6-(3-((tetrahydro-2H-pyran-2-yl) oxy)).
A mixture of propa- 1 -in-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. Stirred. TLC showed that the reaction was complete. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (40 mL). The organic layer is collected, washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude residue, which is subjected to silica gel flash column chromatography (0-30% acetate in hexanes). Purified by (eluting with ethyl) to form a white solid 5-methyl-7-(6-((1r, 3r) -3-((6- (3-((tetrahydro-2H-pyran-2-yl)) Oxy) Propa-1-in-1-yl) Pyridine-3-yl) Oxy) Cyclobutoxy) Pyridine-3-yl) -5H-pyrido [4,3-b] indol (350 mg, 57% yield) Obtained.

Step 2: 3-(5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-ol

5-Methyl-7-(6-((1r, 3r) -3-((6-(3-((tetrahydro-2H-pyran-2-yl) oxy) propa-1-in-1-yl) pyridine) -3-yl) Oxy) Cyclobutoxy) Pyridine-3-yl) -5H-pyrido [4,3-b] Indol (350 mg, 0.62 mmol) in tetrahydrofuran (10 ml) solution with hydrogen chloride aqueous solution (5 ml, 2M) ) Was added, and the reaction mixture was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction mixture was quenched with aqueous sodium bicarbonate solution (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 mlx2). The organic layers are combined into one, washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to form a white solid 3-(5-((1r, 3r) -3- (. (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propa-2-in-1-ol (270 mg, crude) was obtained and used in the next step without further purification.

Step 3: 3-(5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl 4-Methylbenzenesulfonate

3- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) Pyridine-2-yl) propa-2-in-1-ol (200 mg, crude),
A mixed solution of triethylamine (127 mg, 1.26 mmol) and 4-methyl-benzenesulfonyl chloride (120 mg, 0.63 mmol) in dichloromethane (10 ml) was stirred for 1 hour at room temperature. 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 anhydrous sodium sulfate and evaporated under reduced pressure to give a crude residue, which was subjected to silica gel flash column chromatography (eluted with 5% methanol in dichloromethane). Purified as a white solid 3-(5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine-2) -Il) oxy) cyclobutoxy) pyridine-2-yl) propa-2-in-1-yl 4-methylbenzenesulfonate (130 mg, 49% yield) was obtained.

Step 4: 2- (2,6-dioxopiperidine-3-yl) -5-((3- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido]] 4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Isoindoline-1,3-dione

3- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) Pyridine-2-yl) propa-2-in-1-yl 4-methylbenzenesulfonate (130 mg, 0.21 mmol), potassium carbonate (85 mg, 0.62 mmol) and 2- (2,6-dioxopiperidine-3) -Il) -To a solution of -5-hydroxyisoindrin-1,3-dione (57 mg, 0.21 mmol) in N, N-dimethylformamide (10 ml), potassium iodide (35 mg, 0.21 mmol) was added under a nitrogen atmosphere. rice field. The obtained mixture was heated to 50 ° C. and stirred for 16 hours. TLC showed that the reaction was complete. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (20 ml). The organic layer is collected, washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which is eluted with silica gel flash column chromatography (8% methanol in dichloromethane). ) As a yellow solid 2- (2,6-dioxopiperidine-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) propa-2-in-1-yl) oxy) isoindoline -1,3-dione (21.3 mg, yield 14%) was obtained.

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 = .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.

The above procedure for compound 83 (method of compound 94), compound 95, compound 97 (method of compound 94), compound 98, compound 183 (method of compound 73), compound 204 (combination of methods of compound 73 and compound 176). Prepared using a procedure similar to.

Synthesis scheme of exemplary compound 102 and exemplary compound 110
2- (2,6-dioxopiperidine-3-yl) -5-((6- (6-(((1r, 3r) -3-((5- (5-methyl-5H-pyridine] 4,3 -b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-3-yl) Hexa-5-in-1-yl) Oxy) Isoindoline-1,3-dione (exemplary compound) 102), and 2- (2,6-dioxopiperidine-3-yl) -5-((6- (6-(((1r, 3r) -3-((5- (5-methyl-5H-pyrido)) [4,3-b] Indol-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-3-yl) Hexil) Oxy) Isoindoline-1,3-dione (Example compound 110)

Step 1: 7-(6-((1r, 3r) -3-((5-iodopyridin-2-yl) oxy) cyclobutoxy) pyridin-3-yl) -5-methyl-5H-pyrido [4, 3-b] Indole

(1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutanol (100 mg, 0.29 mmol) Sodium hydride (60 in mineral oil, 60) in a solution of 1-methylpyrrolidine-2-one (5 ml) [prepared using a procedure similar to the procedure described for steps 1 and 2 of compound 73]. %) (58 mg, 1.45 mmol) was added 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 showed that the reaction was complete. Reaction at 0 ° C
It was quenched with water (10 mL) and extracted with ethyl acetate (20 mLx2). The organic layers were combined into one, washed with water (20 mlx2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was subjected to silica gel flash chromatography (5 in dichloromethane).
Purified by% methanol) and purified as a white solid (6-((1r, 3r) -3-((5-iodopyridin-2-yl) oxy) cyclobutoxy) pyridine-3-yl)- 5-Methyl-5H-pyrid [4,3-b] indole (100 mg, 63% yield) was obtained.

Using the procedure described for compound 73, 7-(6-((1r, 3r) -3-((5-iodopyridin-2-yl) oxy) cyclobutoxy) pyridine-3- Il) -5-methyl-5H-pyrido [4,3-b] indol, the title 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) pyridin-3-yl) hexa -5-In-1-yl) Oxy) Isoindrin-1,3-dione (Compound 102), and 2- (2,6-dioxopiperidin-3-yl) -5-((6- (6- (6- (6- (6- (6- (6-) ((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) Pyridine-3-yl ) Hexil) Oxy) Isoindrin-1,3-dione (Compound 110)
).

Compound 102: ¹ HNMR (400 MHz, DMSO-d ₆ ): 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 = .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 = .2 Hz, 1H), 8.52 (s, 1H), 8.64 (d, J = .6 Hz, 1H), 9.40
(s, 1H), 11.11 (s, 1H). (M ⁺ H) +775.5
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 = .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 = .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
Synthesis scheme of exemplary compound 173
5- (2-((3- (5-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy)) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) ethoxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione

Step 1: 2- (propa-2-in-1-yloxy) ethane-1-ol

Etan-1,2-diol (3.9 g, 63 mmol) was added to a mixed stirring solution of anhydrous N, N-dimethylformamide (20 ml) of sodium hydride (60%, 115 mg, 2.8 mmol in mineral oil) at 0 ° C. In addition, the mixture was stirred at 0 ° C. for 0.5 hours. 3-Bromopropa-1-in (5.0 g, 42 mmol) was added to the obtained mixture at 0 ° C.
And stirred at 50 ° C. overnight. TLC showed that the reaction was complete. 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 mlx2). The organic layers were combined into one, washed with brine (80 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was subjected to silica gel flash chromatography (0-20 in hexanes). Purified by% ethyl acetate) and 2- (propa-2-in-1-yloxy) ethanol (3.4 g, as a colorless oil)
Yield 80%) was obtained.

Step 2: 2- (Propa-2-in-1-yloxy) ethyl 4-methylbenzenesulfonate

2- (Propa-2-in-1-yloxy) ethanol (1 g, 10 mmol), triethylamine (3 g, 3 mmol) and N, N-dimethylpyridin-4-amine (20 mg, 1 mmol) dichloromethane (20 ml)
), P-Toluenesulfonic acid (2.9 g, 15 mmol) was added at 0 ° C. The reaction mixture was warmed to room temperature and stirred overnight at room temperature. 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 give a crude residue. Purified by silica gel flash column chromatography (eluent of 10-20% ethyl acetate in hexane), 2- (propa-2-in-1-yloxy) ethyl 4-methylbenzenesulfonate (700 mg, yield) : 40%) was obtained as a bright yellow oil.

Step 3: 2- (2,6-dioxopiperidine-3-yl) -5-(2- (propa-2-in-1-yloxy) ethoxy) isoindoline-1,3-dione

Stirring solution of N, N-dimethylformamide (15 ml) of 2- (propa-2-in-1-yloxy) ethyl 4-methylbenzenesulfonate (700 mg, 2.8 mmol) and potassium carbonate (1.1 g, 8.3 mmol) 2- (2,6-dioxopiperidine-3-yl) -5-hydroxyisoindoline-1,3-dione (755 mg, 2.8 mmol) was added at room temperature. The resulting mixture was stirred at 50 ° C. overnight. TLC showed that the reaction was complete. The mixture 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 mlx2). The organic layers were combined into one, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was subjected to silica gel flash chromatography (0-50 in hexanes). (Elution with% ethyl acetate) to purify as a bright yellow solid 2- (2,6-dioxopiperidine-3-yl) -5-(2- (propa-2-in-1-yloxy) ethoxy) Isoindoline-1,3-
Zeon (290 mg, 30% yield) was obtained.

2- (2,6-dioxopiperidine-3-yl) -5-(2- (propa-2-in-1-yloxy) ethoxy) isoindoline-1,3-dione is described for compound 73. Using the procedure 7-(6-((1r, 3r) -3-((6-iodopyridine-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3- b] React with indole and the title compound 5- (2-((3- (5-((1r, 3r) -3-((5- (5H-pyrid [4,3-b] indole-7-) Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) ethoxy) -2- (2,6-dioxopiperidine-3-yl) Iso Produced indoline-1,3-dione.

¹ H 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.

124, 144 (Compound 102 method), 145, 146, 147 (Compound 94 method), 172 (Compound 73 method), 179, using procedures similar to Compound 110 (Compound 102 method) above. (Method of compound 173), 188 (method of compound 173), 189 (method of compound 73) were prepared.

Exemplary Compound 180 Synthesis Scheme Step 1: (S) -5-Amino-5-oxo-4-(1-oxo-5- (propa-2-in-1-yloxy) isoindoline-2-yl) pentane Tert-butyl acid acid

5-Amino-4- (5-hydroxy-1-oxoisoindoline-2-yl) -5-oxopentanoic acid (S) -tert-butyl (450 mg, 1.35 mmol), and 3-bromopropa-1-in ( 192 mg, 1.62 mmol)
Potassium carbonate (372 mg, 2.69 mmol) in a stirred solution of N, N-dimethylformamide (4 ml).
And potassium iodide (22.4 mg, 0.135 mmol) were added and the mixture was stirred at 50 ° C. overnight under nitrogen. 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 eluted with silica gel flash chromatography (eluted with 50% ethyl acetate in hexanes). Purified with 5% methanol added) and purified as a colorless oil, 5-amino-5-oxo-4-(1-oxo-5- (propa-2-in-1-yloxy) isoindrin-2-yl). ) Pentanoic acid (S) -tert-butyl (489 mg, 97% yield) was obtained.

Step 2: 3- (1-oxo-5- (propa-2-in-1-yloxy) isoindoline-2-yl) piperidine-2,6-dione

5-Amino-5-oxo-4-(1-oxo-5- (propa-2-in-1-yloxy) isoindoline-2-
Ill) Potassium tert-butoxide (1N in THF, 107.7 mg, 0.96 mmol) in a stirred solution of pentanate (S) -tert-butyl (325 mg, 0.873 mmol) in anhydrous tetrahydrofuran (20 ml) under a nitrogen atmosphere. , Dropped at 0 ° C. and added. 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 is collected, washed with water (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is eluted with silica gel flash chromatography (eluted with 50% ethyl acetate in hexanes). 3 (1-oxo-5- (propa-2-in-1-yloxy) isoindrin-2-yl) piperidin-2,6 as a white solid. -Dione (128 mg, 49% yield) was obtained.

Step 3: 3- (5-((3- (5-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) ) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) -1-oxoisoindoline-2-yl) Piperidine-2,6-dione

3- (1-oxo-5- (propa-2-in-1-yloxy) isoindrin-2-yl) piperidin-2,6-dione (50 mg, 0.168 mmol), 7- (6-(((() 1r, 3r) -3-((6-iodopyridine-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b] indol (74 mg, 0.14 mmol) and triethylamine ( Trans-dichlorobis (triphenylphosphine) palladium (II) (4.91 mg, 0.007 mmol) and copper iodide (1.33 mg, 0.007 mmol) in a stirred solution of N, N-dimethylformamide (1 ml) at 70.7 mg, 0.70 mmol). ) Was added at room temperature in a nitrogen atmosphere. The mixture was degassed with nitrogen three times. The resulting mixture was stirred for 12 hours at 65 ° C. TLC showed that the reaction was complete. TLC showed that the reaction was complete. The mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer is collected, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is purified by prep TLC (eluted with 10% methanol in dichloromethane). Then, as a white solid, 3-(5-((3- (5-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indol-7-yl) pyridine) -2-yl) Oxy) Cyclobutoxy)
Pyridine-2-yl) propa-2-in-1-yl) oxy) -1-oxoisoindoline-2-yl) piperidine-2,6-dione (19 mg, 16% yield) was obtained.

¹ HNMR (400 MHz, DMSO-d6): δ .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 = 16.8Hz, 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 = .0 Hz, 1H), 7.29-7.33 (m, 2H), 7.50 (d, J = .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.

Scheme of synthesis of exemplary compound 64
5- (4- (3- (5-((1r, 3r) -3- ((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl))
Oxy) Cyclobutoxy) Pyridine-2-yl) Propyl) Piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione

The title compound was prepared according to the following scheme using the procedures described above for other targets and using universal procedures known to those of skill in the art. Starting material 7- (6-((1r, 3r) -3-((6- (3-hydroxyprop-1-in-1-yl) pyridine-3-yl) oxy) cyclobutoxy) pyridine-3- Ill) -5H-pyrido [4,3-b] indole tert-butyl carboxylic acid was prepared according to the procedure described for compound 117.

5- (4- (3- (5-((1r, 3r) -3- ((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl))
Oxy) Cyclobutoxy) Pyridine-2-yl) Propyl) Piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione
¹ H NMR (400 MHz, CD ₃ OD) δ .42 (s, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.50 (d, J =
6.1 Hz, 1H), 8.38 (d, J = .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 = .3 Hz, 1H), 7.42 (s, 1H), 7.33 (s, 2H), 7.29 (d, J = .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).

Exemplary Compound 67 Synthesis Scheme Step 1: 14-((5-bromo-3- (trifluoromethyl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecane-1-ol

NaH (30 mg, 0.76 mmol) was added to a solution of pentaethylene glycol (330 mg, 1.38 mmol) in THF (5 mL) at 0 ° C. The solution was stirred at room temperature for 1 hour. Then 5-bromo-2-chloro-3- (trifluoromethyl) pyridine (180 mg, 0.69 mmol) was added. 2 of the obtained solution at 80 ° C.
Stir for 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.

Step 2: 14-((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -3,6 , 9,12-Tetraoxatetradecane-1-ol

14-((5-bromo-3- (trifluoromethyl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecane-1-ol,
(180 mg, 0.39 mmol), 5-methyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5H-pyrido [4,3-b] indol (120 mg, 0.39 mmol) Dioxane / H ₂ O of Pd (amphos) Cl ₂ (20 mg, 10%) and CsF (118 mg, 0.78 mmol) [prepared as described in Step 1 of Compound 63]. The mixed solution of (10/1, 5 mL) was stirred 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 under vacuum. The residue was purified by silica gel column chromatography to give the desired compound (85 mg, 47% yield).

Step 3: 2- (2,6-dioxopiperidine-3-yl) -5-((14-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl)) -3- (Trifluoromethyl) Pyridine-2-yl) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) Isoindoline-1,3-dione

14-((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -3,6,9, 12-Tetraoxatetradecane-1-ol (85 mg, 0.15 mmol)
, 2- (2,6-dioxopiperidine-3-yl) -5-hydroxyisoindoline-1,3-dione (41 mg)
, 0.15 mmol), and PPh ₃ (47 mg, 0.18 mmol) in THF to which DIAD (45 mg, 0.22 mmol) was added 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 under vacuum. The residue was purified by silica gel column chromatography to give the title compound (34 mg, 28% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ .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.

The following were prepared using the procedure for compound 67: compound 69, compound 113.
Exemplary Compound 65 Synthesis Scheme Step 1: 4-((1r, 3r) -3- (benzyloxy) cyclobutoxy) Pyridine

Triphenylphosphine (7.06 g, 26.93 mmol, in a solution of pyridine-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). 1.2 eq) and diisopropyl azodicarboxylate (5.45 g, 26.93 mmol, 1.2 eq) were added all at once under nitrogen at 10 ° C. 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 stirred for 1 minute. The aqueous layer was extracted with dichloromethane (50 mLx3). The combined organic layers were washed with brine (50 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: tetrahydrofuran, 20: 1-5: 1). HPLC showed 41% of the product at 254 nm. The residue was purified by flash C18 column chromatography [acetonitrile: water (0.5% ammonium hydroxide) = 5% -50%]. The compound 4- (3-benzyloxycyclobutoxy) pyridine (3.2 g, 12.53 mmol, 55% yield) was obtained as a white solid.

Step 2: 1-Benzyl-4-((1r, 3r) -3- (benzyloxy) cyclobutoxy) Pyridine-1-ium bromide

Benzyl bromide (2.81 g, 16.45 mmol, 1 eq) was added to a solution of 4- (3-benzyloxycyclobutoxy) pyridine (4.2 g, 16.45 mmol, 1 eq) in toluene (65 mL). 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 pulverized with petroleum ether (80 mL). The compound 1-benzyl-4-((1r, 3r) -3- (benzyloxy) cyclobutoxy) pyridin-1-ium bromide (6.5 g, 15.25 mmol, yield 92%) was obtained as a white solid.

Step 3: 1-Benzyl-4-((1r, 3r) -3- (benzyloxy) cyclobutoxy) -1,2,3,6-tetrahydropyridine

Sodium borohydride ((1r, 3r) -3- (benzyloxy) cyclobutoxy) pyridin-1-ium bromide (6.5 g, 15.25 mmol, 1 eq) in ethanol (120 mL) solution of 1-benzyl-4-((1r, 3r) -3- (benzyloxy) cyclobutoxy) 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 mLx2). The combined organic layers were washed with saturated brine (40 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The compound 1-benzyl-4- (3-benzyloxycyclobutoxy) -3,6-dihydro-2H-pyridine (4.5 g, 12.88 mmol, 84% yield) was obtained as a colorless oil.

Step 4: (1r, 3r) -3-((1-benzylpiperidine-4-yl) oxy) cyclobutane-1-ol

Palladium activity in 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 carbon catalyst (0.5 g, purity 10%) was added under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred at 25 ° C. for 24 hours under hydrogen (50Psi). LCMS showed that the reaction was not complete. The mixture was then stirred for 12 hours at 35 ° C. 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 3-[(1-benzyl-4-piperidyl) oxy] cyclobutanol (2.8 g, 10.71 mmol, 83% yield) was obtained as a colorless oil.

Step 5: 4-((1r, 3r) -3-hydroxycyclobutoxy) piperidine-1-carboxylate tert-butyl

3-[(1-benzyl-4-piperidyl) oxy] cyclobutanol (1.1 g, 4.21 mmol, 1 eq) in a methanol (10 mL) solution with palladium hydroxide (591 mg) and di-tert-butyl carbonate (1.84 g). , 8.42 mmol, 2 eq) was added under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred at 25 ° C. for 12 hours under hydrogen (50Psi). The reaction mixture was filtered and the filter was concentrated. Silica gel chromatography (petroleum ether: ethyl acetate = 20: 1)
Purified according to ~ 2: 1). The compound 4- (3-hydroxycyclobutoxy) piperidine-1-carboxylate tert-butyl (820 mg, 3.02 mmol, 71% yield) was obtained as a colorless oil.

Step 6: 4-((1r, 3r) -3-((5-bromopyridin-2-yl) oxy) cyclobutoxy) piperidine-1-carboxylate tert-butyl

Dimethylformamide of 4- (3-hydroxycyclobutoxy) piperidin-1-carboxylate tert-butyl (400 mg, 1.47 mmol, 1 eq) and 5-bromo-2-fluoro-pyridine (285 mg, 1.62 mmol, 1.1 eq) To a mixed solution of (8 mL), cesium carbonate (960 mg, 2.95 mmol, 2 eq) was added at a time 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 layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (30 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether / ethyl acetate, 200: 1-20: 1). The product 4- [3-[(5-bromo-2-pyridyl) oxy] cyclobutoxy] piperidine-1-carboxylate tert-butyl (560 mg, 1.30 mmol, 88% yield) as a colorless oil. Obtained.

Step 7: 4-((1r, 3r) -3-((5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl))
Pyridine-2-yl) oxy) cyclobutoxy) piperidine-1-carboxylate tert-butyl

4- [3-[(5-Bromo-2-pyridyl) oxy] cyclobutoxy] piperidine-1-carboxylic acid tert-
Butyl (560 mg, 1.31 mmol, 1 eq), 4,4,4', 4', 5,5,5', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) ( In a suspension of 432 mg, <U> 1.70 mmol, 1.3 eq), and potassium acetate (257 mg, 2.62 mmol, 2 eq, dioxane (20 mL), [1,1'-bis (diphenylphosphino) ferrocene] dichloro Palladium (II) (95 mg, 0.13 mmol, 0.1 eq) was added. The mixture was degassed in vacuum and purged 3 times with nitrogen. 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: 1-10: 1). 4- [3- [. [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-pyridyl] oxy] cyclobutoxy] piperidine-1-carboxylate tert-butyl (500 mg) , 1.05 mmol, yield 80%) was obtained as a colorless oil.

Step 8: 4-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidine- Tert-Butyl 1-carboxylate

4- [3-[[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -2-pyridyl] oxy] cyclobutoxy] piperidin-1-carboxylic acid tert -Butyl (240 mg, 0.50 mmol, 1 eq), 7-bromo-5H-pyrido [4,3-b] indol (125 mg, 0.50 mmol, 1 eq), and potassium carbonate (140 mg, 1.01 mmol, 2 eq) ), To a mixed solution of dimethylformamide (8 mL) and water (2 mL), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (37 mg, 0.05 mmol, 0.1 equivalent) was added. 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 brine and then extracted with ethyl acetate (50 mLx2). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 20: 1). 4- [3-[[5- (5H-pyrido [4,3-b] indole-7-yl) -2-pyridyl] oxy] cyclobutoxy] piperidine-1-carboxylate tert-butyl (175 mg, 0.34 mmol (67% yield) was obtained as an off-white solid.

Step 9: 7-(6-((1r, 3r) -3- (piperidine-4-yloxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b] indole

4- [3-[[5- (5H-pyrido [4,3-b] indol-7-yl) -2-pyridyl] oxy] cyclobutoxy] piperidine-1-carboxylate tert-butyl (170 mg, 0.33) A solution of mmol (1 equivalent) in hydrochloric acid (4 M in dioxane, 8 mL, 100 eq) was stirred at 25 ° C. for 10 minutes. The mixture was concentrated in vacuo. Product 7- [6- [3- (4-piperidyloxy) cyclobutoxy] -3-pyridyl] -5H-pyrid [4,3-b] indole (190 mg, crude, hydrochloride) brown solid And used directly in the next step without further purification.

Step 10: 5-((5,5-dimethoxypentyl) oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

2- (2,6-dioxopiperidine-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) to a mixed solution 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 aqueous hydrochloric acid solution and then extracted with ethyl acetate (50 mLx2). The combined organic layers were washed with brine (50 mLx3), 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-dioxopiperidine-3-yl) isoindoline-1,3-dione (120 mg, 0.30 mmol, yield 14%) Obtained as a colorless oil.

Step 11: 5-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) oxy) pentanal

Mixing 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 aqueous solution, 7 mL, 50 eq) was added to the solution at one time at 25 ° C. under a nitrogen atmosphere. The mixture was stirred at 70 ° C. for 1 hour. The aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (20 mLx2), then with brine (20 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo 5-Product. [2- (2,6-dioxo-3-piperidyl) -1,3-dioxo-isoindoline-5-yl] oxypentanal (93 mg, crude) was obtained as a bright yellow solid.

Step 12: 5-((5- (4-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy)) Cyclobutoxy) piperidine-1-yl) pentyl) oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

7- [6- [3- (4-piperidyloxy) cyclobutoxy] -3-pyridyl] -5H-pyrid [4,3-b] indol (110 mg, 0.24 mmol, 1 eq, hydrochloride) dichloromethane ( Sodium acetate (40 mg, 0.49 mmol, 2 eq) was added to the mixture of 2 mL) and methanol (5 mL) at a time at 20 ° C. The mixture was stirred for 10 minutes at 20 ° C. 5- [2- (2,6-dioxo-3-piperidyl) -1,3-dioxo-isoindoline-5-yl] oxypentanal (88 mg, 0.24 mmol, 1 eq) was added. The mixture was stirred at 20 ° C. for 10 minutes. Acetic acid (0.02 mL) and sodium cyanoborohydride (31 mg, 0.49 mmol, 2 eq) were then added at once. 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 by half-reverse phase HPLC (column: Phenomenex Synergi C18 150 * 25 * 10um; mobile phase: [water (0.225% formic acid) -acetonitrile]; B%: 3% -33%, 10 minutes). Product 2- (2,6-dioxo-3-piperidyl) -5- [5- [4- [3- [[5- (5H-pyrido [4,3-b] indole-7-yl)- 2-Pyridyl] oxy] cyclobutoxy] -1-piperidyl] pentoxy] Isoindoline-1,3-dione trivalentate (50.2 mg, 0.05 mmol, 21% yield) was obtained as an off-white solid.

¹ H 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 --. 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
The following were prepared using a procedure similar to the above: Compounds 82, 123 (described in Compounds 65 and 67, and detailed in the scheme below).

Synthesis scheme of exemplary compound 66
5- (4- (2- (4-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl))
Oxy) Cyclobutoxy) Piperidine-1-yl) Ethyl) Piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione

Step 1: Benzyl 4- (2,2-diethoxyethyl) piperazine-1-carboxylate

K ₂ CO ₃ (1.25 g, 9.0 mmol) and 2-bromo-1,1-diethoxyethane (1.0 g, 4.54 mmol) in a DMF (20 mL) solution of piperazine-1-carboxylate benzyl (1.0, 4.54 mmol). ) Was added. The obtained mixture was stirred for 20 hours at 80 ° C. The reaction mixture was then diluted with water (50 ml) and extracted with EA. The organic layer was washed with brine, dried over DDL ₄ and concentrated. The residue was purified by chromatography (silica gel, PE: EA1: 1) to give the desired compound, benzyl 4- (2,2-diethoxyethyl) piperazine-1-carboxylate (1.55 g), as a colorless oil. Obtained.

Step 2: 1- (2,2-diethoxyethyl) piperazine

4- (2,2-diethoxyethyl) piperazine-1-carboxylate benzyl (1.55 g, 4.6 mmol) MeOH
Pd (OH) ₂ / C (0.3 g, 20%) was added to the (30 mL) solution. The obtained mixture was stirred for 3 hours at 30 ° C. 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 could be followed without further purification. Used in the process of.

Step 3: 5- (4- (2,2-diethoxyethyl) piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

DIEA (2.3 g, 17.8 mmol) and 2- (2,6-dioxopiperidine-3-yl) in a solution of 1- (2,2-diethoxyethyl) piperazine (0.9 g, 4.45 mmol) in NMP (15 mL). ) -5-Fluoroisoindoline-1,3-dione (1.35 g, 4.9 mmol) was added. The obtained mixture was stirred for 20 hours at 90 ° C. The reaction mixture was then diluted with water (50 mL) and extracted with DCM / MeOH (10/1). The organic layer was washed with brine, dried over DDL ₄ and concentrated. The residue was purified by chromatography (silica gel, DCM: MeOH (20: 1)) to give the desired compound (1.4 g) as a yellow solid.

Step 4: 2- (4- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) piperazine-1-yl) acetaldehyde

5- (4- (2,2-diethoxyethyl) piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (300 mg, 0.65 mmol) ), A solution of HCl (5 mL aqueous solution, 2.5 mol / L) was stirred for 20 hours at 50 ° C. The mixture was basified with NaHCO ₃ (20 mL) and extracted with EA. The solution was washed with brine, dried over DDL 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.

Step 5: 5- (4- (2- (4-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl)) Oxy) Cyclobutoxy) Piperidine-1-yl) Ethyl) Piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione
2- (4- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) piperazine-1-yl) acetaldehyde (180 mg, 0.41 mmol) MeOH In a solution of / DMSO (8 mL, 1/1), 7-(6-((1r, 3r) -3- (piperidine-4-yloxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4, 3-b] Indole (97 mg, 0.24 mmol) [prepared as described in Compound 65], AcOH (1 drop), and NaBH ₃ CN (60 mg, 0.94 mmol) were added. The resulting mixture was stirred for 2 hours at 10 ° C. The reaction mixture was then diluted with water (10 ml) and extracted with EA. The organic phase was washed with brine, filtered and the crude material was purified by prep-HPLC to give the title compound (21.2 mg) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): 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 = .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 = .5 Hz, 1H), 5.34 (s, 1H), 5.08 ( d, J = .7 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.

Synthesis scheme of exemplary compound 171
5-((4,4-difluoro-5-(4-((1r,3r) -3-((5-(5-methyl-5H-pyrid [4,3-b] indole-7-yl) pyridine) -2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) Pentyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione

Step 1: O5-tert-butyl O1-ethyl 2,2-difluoropentanedioate

Tert-butyl propa-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). A mixed solution of tetrahydrofuran (100 mL) of equivalent) was heated to 55 ° C. with strong 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. A 10% aqueous solution of ammonium chloride (100 mL) and ethyl acetate (500 mL) were added. The resulting mixture was stirred at room temperature for 0.5 hours and filtered through Celite. The organic layer was washed with a further ammonium chloride solution (100 mLx5) to remove the remaining copper complex (blue). The solution was dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 500/1, 100/1) to yield O5-tert-butyl O1-ethyl 2,2-difluoropentanedioate (18.6 g, 73.74 mmol). Rate 95%) was obtained as a yellow oil.

Step 2: tert-butyl 4,4-difluoro-5-hydroxy-pentanoate

A suspension of ethanol (100 mL) of sodium borohydride (3.24 g, 85.63 mmol, 1.20 equivalents) was cooled to 0 ° C. in an ice bath and O5-tert-butyl O1-ethyl 2,2-difluoropentanedioate. A solution of ethanol (100 mL) (18 g, 71.36 mmol, 1.00 equivalent) was added dropwise from an addition funnel with vigorous stirring. The dropping rate was carefully controlled to maintain the temperature of the reaction mixture at 0-15 ° C. The mixture was then stirred for 1 hour at 15 ° C. The reaction mixture was quenched by dropping and adding a 5% aqueous citric acid solution (40 mL) while cooling. The aqueous layer was extracted with ethyl acetate (200 mLx3). The combined organic layers were washed with brine (200 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20/1, 10/1) to tert-butyl 4,4-difluoro-5-hydroxy-pentanoate (14.2 g, 67.55 mmol, yield). 95%) was obtained as a colorless oil.

Step 3: tert-butyl 4,4-difluoro-5-tetrahydropyran-2-yloxypentanoate

In a mixture of tert-butyl 4,4-difluoro-5-hydroxy-pentanoate (14.2 g, 67.55 mmol, 1.00 equivalent) and 4-methylbenzenesulfonic acid (642 mg, 3.38 mmol, 0.05 equivalent) in dichloromethane (50 mL). , Under nitrogen, -10 ° C, 3,4-dihydro-2H-pyran (17.05 g, 202.65 mmol, 3)
.00 equivalent) was added. The mixture was then heated to 25 ° C. and stirred for 16 hours. The reaction is quenched with saturated sodium bicarbonate solution (50 mL) and then dichloromethane (50 mL x 3).
Extracted with. The combined organic layers were washed with brine (50 mLx3), 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 tert-butyl 4,4-difluoro-5-tetrahydropyran-2-yloxypentanoate (17.2 g,). Crude) was obtained as a colorless oil.

Step 4: 4,4-difluoro-5-tetrahydropyran-2-yloxy-pentan-1-ol

In a solution of lithium aluminum hydride (2.66 g, 70.12 mmol, 1.20 eq) in tetrahydrofuran (300 mL), 4,4-difluoro-5-tetrahydropyran-2-yloxy-pentanoate tert-
A solution of butyl (17.2 g, 58.44 mmol, 1.00 eq) in tetrahydrofuran (60 mL) was added dropwise under nitrogen at 0 ° C., while the temperature was maintained below 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hour. The reaction was quenched at 0 ° C. with water (2.6 mL), aqueous sodium hydroxide solution (15%, 5.2 mL), and water (8 mL). The suspension was filtered through a Celite bed. The cake was washed with ethyl acetate (500 mL). The combined organic layers were washed with brine (200 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 20: 1-10: 1). 4,4-difluoro-5-tetrahydropyran-2-yloxy-pentan-1-ol (10.9 g, 48.61 mmol, yield 83%)
Was obtained as a colorless oil.

Step 5: (4,4-difluoro-5-tetrahydropyran-2-yloxy-pentyl) 4-methylbenzenesulfonate

4,4-difluoro-5-tetrahydropyran-2-yloxy-pentane- 1 -ol (10.9 g, 48.61 mmol, 1.00 eq) and p-toluenesulfonyl chloride (13.90 g, 72.91 mmol, 1.50 eq) Triethylamine (9.84 g, 97.22 mmol, 2.00 eq) was added to the mixed solution of dichloromethane (100 mL) at a time at 0 ° C. under nitrogen. 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 layer was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20/1, 10/1) and (4,4-difluoro-5-tetrahydropyran-2-yloxy-pentyl) 4-methylbenzenesulfonic acid. A salt (16.6 g, 43.87 mmol, 90% yield) was obtained as a colorless oil.

Step 6: Dimethyl 4- (4,4-difluoro-5-hydroxy-pentoxy) benzene-1,2-dicarboxylate

Cesium carbonate in a solution of N, N-dimethylformamide (6 mL) of 4-methylbenzenesulfonate (1 g, 2.64 mmol, 1 eq) (4,4-difluoro-5-tetrahydropyran-2-yloxy-pentyl) (1.72 g, 5.28 mmol, 2 eq) and dimethyl 4-hydroxybenzene-1,2-dicarboxylate (555 mg, 2.64 mmol, 1 eq) were added. The mixture was stirred at 50 ° C. for 12 hours. LCMS showed that the starting material was consumed and the desired compound was present. The mixture was filtered, poured into hydrochloric acid (1N, 30 mL) and the aqueous layer was extracted with dichloromethane (20 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 20/1 to 5/1). Dimethyl 4- (4,4-difluoro-5-hydroxy-pentoxy) benzene-1,2-dicarboxylate (700 mg, 2.11 mmol, 79% yield) was obtained as a colorless oil.

Step 7: 4- [4,4-difluoro-5- (trifluoromethylsulfonyloxy) pentoxy] benzene-1,2-dicarboxylate dimethyl

2,6-Dimethylpyridine in a solution of dimethyl 4- (4,4-difluoro-5-hydroxy-pentoxy) benzene-1,2-dicarboxylate (600 mg, 1.81 mmol, 1 eq) in dichloromethane (10 mL). (580 mg, 5.42 mmol, 3 eq) was added dropwise at 0 ° C. After the addition, the mixture was stirred at this temperature for 10 minutes, then trifluoromethylsulfonyl trifluoromethanesulfonate (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 present. The mixture was concentrated in vacuo. The residue was further purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 4: 1). 4- [4,4-Difluoro-5- (trifluoromethylsulfonyloxy) pentoxy] benzene-1,2-dicarboxylic acid dimethyl (600 mg , 1.29 mmol, 71% yield) was obtained as a white solid.

Step 8: 4- [4,4-difluoro-5- [4- [3-[[5- (5-methylpyrido [4,3-b] indole-7-yl) -2-pyridyl] oxy] cyclobutoxy ] -1-piperidole] pentoxy] benzene-1,2-dicarboxylate dimethyl

4- [4,4-Difluoro-5- (trifluoromethylsulfonyloxy) pentoxy] Benzene-1,2-dicarboxylate dimethyl (150 mg, 0.3 mmol, 1 eq) acetonitrile (1 mL) and dimethyl sulfoxide (0.5 mL) ) Into the solution of potassium carbonate (133 mg, 1 mmol, 3 eq) and 5-methyl-7- [6- [3- (4-piperidyloxy) cyclobutoxy] -3-pyridyl] pyrido [4,3-b]. Indol (138 mg, 0.3 mmol, 1 eq) [prepared as described in Compound 82] was added. The mixture was stirred at 50 ° C. for 16 hours. LCMS showed that the starting material had almost disappeared and the desired compound was present. The mixture was poured into water (20 mL) and the aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was further purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 4: 1). 4- [4,4-Difluoro-5- [4- [3-[[5- (5-methylpyrido [4,3-b] indole-7-yl) -2-pyridyl] oxy] cyclobutoxy] -1 -Ciperidole] pentoxy] Benzene-1,2-dicarboxylic acid dimethyl (160 mg, 0.2 mmol, yield 66%) was obtained as a yellow oil.

Step 9: 4- [4,4-difluoro-5- [4- [3-[[5- (5-methylpyrido [4,3-b] indole-7-yl) -2-pyridyl] oxy] cyclobutoxy ] -1-piperidole] pentoxy] phthalic acid

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 a solution of methanol (3 mL) and water (1.5 mL), potassium hydroxide (36 mg, 0.6 mmol, 4) Equivalent) was added. The mixture was stirred for 2 hours at 55 ° C. LCMS showed that the starting material was consumed and the desired compound was present. The reaction mixture was adjusted to pH = (7) with hydrochloric acid (1M) and concentrated under reduced pressure to remove methanol and water. The residue was used directly in the next step without further purification. 4- [4,4-difluoro-5- [4- [3-[[5- (5-methylpyrido [4,3-b] indole-7-yl) -2-pyridyl] oxy] cyclobutoxy] -1 -Piperidole] pentoxy] phthalic acid (110 mg, 0.1 mmol, 95% yield) was obtained as a yellow solid.

Step 10: 5- [4,4-difluoro-5- [4- [3-[[5- (5-methylpyrido [4,3-b] indole-7-yl) -2-pyridyl] oxy] cyclobutoxy ] -1-piperidole] pentoxy] -2- (2,6-dioxo-3-)
Piperidine) Isoindoline-1,3-dione

4- [4,4-difluoro-5- [4- [3-[[5- (5-methylpyrido [4,3-b] indol-7-yl) -2-pyridyl] oxy] cyclobutoxy] -1 -Piperidil] pentoxy] Sodium acetate (37 mg, 0.5 mmol, 3 eq) is added to a solution of phthalic acid (110 mg, 0.2 mmol, 1 eq) in acetic acid (2 mL), and the mixture is stirred for 1 hour at 25 ° C. did. Then 3-aminopiperidine-2,6-dione (30 mg, 0.2 mmol, 1.2 eq, hydrochloric acid) was added to the mixture, heated to 120 ° C., and stirred for another 11 hours. LCMS showed that the starting material was consumed and the desired compound was present. The mixture was concentrated in vacuo. The residue was purified by preparative infarction liquid chromatography column: Phenomenex Synergi C18 150 * 25 * 10um; mobile phase: [water (0.225% formic acid) -acetonitrile]; B%: 14% -35%, 7 minutes. .. 5- [4,4-difluoro-5- [4- [3-[[5- (5-methylpyrido [4,3-b] indole-7-yl) -2-pyridyl] oxy] cyclobutoxy] -1 -Piperidyl] pentoxy] -2- (2,6-dioxo-3-piperidyl) isoindoline-1,3-dione (67 mg, 0.08 mmol, yield 50%, purity 98%, formic acid) is obtained as a gray solid. rice field.

¹ H NMR: (400MHz, DMSO-d ₆ ) δ = 11.11 (s, 1H), δ = 9.35 (s, 1H) δ = 8.64 (s,
1H), 8.49 --8.84 (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 --5.59 (m, 1H) , 5.12 --5.510 (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.

Exemplary Compound 164 Synthetic Scheme Step 1: Benzyl 6- (tosyloxy) hexaneate

4-Toluene sulfonyl chloride (1.88 g, 9.90 mmol) was added 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) at 0 ° C. .. The mixture was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. 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 subjected to silica gel flash chromatography (in hexane). , Elution with 30-50% ethyl acetate) to give benzyl 6- (tosyloxy) hexaneate (960 mg, 54% yield) as a colorless oil.

Step 2: Benzyl 6- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yloxy) hexaneate

Benzyl 6- (tosyloxy) hexanoate (200 mg, 0.53 mmol) and 2- (2,6-dioxopiperidine-3-yl) -5-hydroxyisoindoline-1,3-dione (146 mg, 0.53 mmol), carbonate A mixture of potassium (147 mg, 1.06 mmol) and potassium iodide (9 mg, 0.05 mmol) in N, N-dimethylformamide (3 ml) was stirred for 12 hours at 50 ° C. TLC showed that the reaction was complete. The reaction mixture was partitioned between water (15 mL) and ethyl acetate (15 mL). The organic layer is collected, washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is subjected to silica gel flash chromatography (2-5% methanol in dichloromethane). Purify by elution) and as a yellow solid, benzyl 6- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yloxy) benzyl hexanoate (100 mg, 40) %) Was obtained.

Step 3: 6- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yloxy) caproic acid

6-(2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yloxy)
A mixture of benzyl hexanoate (100 mg, 0.21 mmol) and palladium activated carbon (20%, 50 mg) in methanol (2 ml) was stirred at room temperature for 1 hour under a hydrogen atmosphere (hydrogen balloon). TLC showed that the reaction was complete. The reaction mixture is filtered and concentrated under reduced pressure to a 6- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yloxy) hexanoic acid (70). mg, yield 86%) was obtained as a yellow oil, which was used directly in the next step without further purification.

Step 4: 5- (6- (4-(((1r, 3r) -3- (5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yloxy) cyclobutoxy) piperidine -1-yl) -6-oxohexyloxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

6-(2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-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 in Compound 65], and triethylamine (56 mg, 0.56 mmol) in a mixture of N, N-dimethylformamide (2 ml), (2- (7-). Aza-1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) (212 mg, 0.56 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. 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 subjected to silica gel flash chromatography (in dichloromethane). , 2-5% elution with methanol) to give the title compound (6.6 mg, 5% yield) as a white solid.

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 = .8Hz, 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 = .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).

Synthesis schemes for exemplary compounds 198 and 205
2- (2,6-dioxopiperidine-3-yl) -5-((3- (3- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido)] 4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-
Il) Phenyl) Propa-2-in-1-yl) Oxy) Isoindoline-1,3-dione

2- (2,6-dioxopiperidine-3-yl) -5-(3-(3-(4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido]] , 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-
Il) Phenyl) Propoxy) Isoindoline-1,3-dione

Compounds 198 and 205 were prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 68
2- (2,6-dioxopiperidine-3-yl) -5-(4- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,3-) b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pentyl) Piperazine-1-yl) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

¹ H 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 = .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 = .0 Hz, 1H) ), 5.07 (dd, J = 12.0 Hz, 8.0Hz, 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
Scheme of synthesis of exemplary compound 70
2- (2,6-dioxopiperidine-3-yl) -5-(2-(2-(2-((1r, 3r) -3-((5- (5-methyl-5H-) Pyrido [4,3-b] indole-7-yl) pyrididine-2-yl) oxy) cyclobutoxy) ethoxy) ethoxy) ethoxy) ethoxy) isoindoline-1,3-dione

Step 1: 2-((1r, 3r) -3- (benzyloxy) cyclobutoxy) -5-bromopyridine

DMF (15 mL) of (1r, 3r) -3- (benzyloxy) cyclobutane-1-ol (500 mg, 2.8 mmol)
NaH (336 mg, 8.4 mmol, 60%) was added to the solution at 0 ° C. The solution was stirred for 30 minutes at 0 ° C. A solution of 5-bromo-2-fluoropyridine (1.0 g, 5.6 mmol) in DMF (3 mL) was added. 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 layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE: EA = 100: 1) to give the desired compound (630 mg, 67% yield) as a colorless oil.

Step 2: (1r, 3r) -3-((5-bromopyridin-2-yl) oxy) cyclobutane-1-ol

2-((1r, 3r) -3- (benzyloxy) cyclobutoxy) -5-bromopyridine (630 mg, 1.88 mmol) in a solution of DCM (15 mL) with BBr ₃ (1.42 g, 5.65 mmol)- Added at 78 ° C. The resulting solution was stirred at −78 ° C. for 0.5 hours. The solution was quenched with י ₃ . The layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined and concentrated to give the desired compound (390 mg, crude) as a yellow solid, which was used directly in the next step without further purification.

Step 3: 5-bromo-2-((1r, 3r) -3-((1-phenyl-2,5,8,11-tetraoxatridecane-13-)
Il) Oxy) Cyclobutoxy) Pyridine

NaH (262 mg, 60%) in a solution of (1r, 3r) -3-((5-bromopyridin-2-yl) oxy) cyclobutane-1-ol (390 mg, 1.64 mmol) in THF (15 mL). Was added at 0 ° C. The solution was stirred at 10 ° C. for 0.5 hours, 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 column chromatography on PE: EA (1: 1) silica gel to give the desired compound (350 mg) as a yellow solid.
Got

5-bromo-2-((1r, 3r) -3-((1-phenyl-2,5,8,11-tetraoxatridecane-13-yl) oxy) cyclobutoxy) pyridine was added according to the following scheme. The final compound 2- (2,6-dioxopiperidine-3-yl) -5- (2- (2- (2-( 2- (2-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) Ethoxy) ethoxy) ethoxy) ethoxy) Isoindoline -1,3-dione was converted.

Compound 70: ¹ H 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 = .0 Hz, 2H), 7.43 (s, 1H), 7.35 (d, J =
.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.

Synthesis scheme of exemplary compound 71
2- (2,6-dioxopiperidine-3-yl) -5-((15-(5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) Ill) -3,6,9,12-Tetraoxapentadeca-14-in-1-yl) Oxy) Isoindoline-1,3-dione

Step 1: 15- (5-bromopyridin-2-yl) -3,6,9,12-tetraoxapentadeca-14-in-1-ol

Anhydrous THF of 3,6,9,12-tetraoxapentadeca-14-in-1-ol (570 mg, 2.45 mmol)
A solution of (10 mL) followed by 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) in an N ₂ atmosphere. Below, added at 15 ° C. 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 EtOAc.
Extracted with (10 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography to give the desired compound (530 mg, 56% yield) as a yellow oil.

15- (5-bromopyridin-2-yl) -3,6,9,12-tetraoxapentadeca-14-in-1-ol to the above procedure and those skilled in the art according to the scheme below. Using known universal procedures, the final compound 2- (2,6-dioxopiperidine-3-yl) -5-((15- (5- (5-methyl-5H-pyrido] [4,, 3-b] Indole-7-yl) Pyridine-2-yl) -3,6,9,12-Tetraoxapentadeca-14-
In-1-yl) Oxy) Isoindoline -1,3-Dione was converted.

Compound 71: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ .39 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H),
8.30 (d, J = 2.0 Hz, 1H), 8.28 (d, J = .0 Hz, 1H), 8.11 (s, 1 H), 7.80 (d, J = .4 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.63-7.68 (m, 2H), 7.44 (d, J = .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.

Synthesis scheme of exemplary compound 74
2- (2,6-dioxopiperidine-3-yl) -5-((15-(5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) Il) -3,6,9,12-tetraoxapentadecyl) oxy) isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 74: ¹ H NMR (400 MHz, CDCl ₃ ): 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 =. 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.

Synthesis scheme of exemplary compound 72
5-((14-((5- (5H-pyrid [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecyl) oxy) ) -2- (2,6-dioxopiperidine-3-yl) -4,6,7-trifluoroisoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

2- (2,6-dioxopiperidine-3-yl) -4,5,7-trifluoro-6-hydroxyisoindoline-1,3-dione was prepared as described below.

Step 1: 3,4,6-trifluoro-5-hydroxyphthalic acid

Potassium hydroxide (2.24 g, 40 mmol, 8 eq) was added to an aqueous solution (20 mL) of 3,4,5,6-tetrafluorophthalic acid (1.18 g, 5 mmol). The resulting solution was heated at 90 ° C. for 9 hours. The reaction was then cooled to room temperature and neutralized with HCl (1N). The resulting solution was extracted with ethyl acetate (50 mLx3). The organic layers were combined into one, washed with brine (20 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum to give the desired crude product (1.15 g) as a white solid, which was obtained. It was used in the next step without further purification.

Step 2: 2- (2,6-dioxopiperidine-3-yl) -4,5,7-trifluoro-6-hydroxyisoindoline-1,3-dione

AcONa (209 mg, 2.54) in an AcOH solution of 3,4,6-trifluoro-5-hydroxyphthalic acid (500 mg, 2.12 mmol) and 3-aminopiperidine-2,6-dione (383 mg, 2.33 mmol). mmol) was added. The resulting solution was stirred at 120 ° C. for 4 hours. After cooling to room temperature, the solvent was removed under vacuum. It was then quenched with water (30 mL). The resulting solution was extracted with EA (30 mLx3). The combined organic layers were washed with brine (10 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum to 2- (2,6-dioxopiperidine-3-yl) -4,5. , 7-Trifluoro-6-Hydroxyisoindoline-1,3-dione (400 mg, 1.22 mmol, 58%) was obtained.

Compound 72: ¹ H 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.

Synthesis scheme of exemplary compound 81
5-((14-((5- (5H-pyrid [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecyl) oxy) ) -2- (2,6-dioxopiperidine-3-yl) -6-fluoroisoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 81: ¹ H NMR (400 MHz, CDCl ₃ ): 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), .60 (s, 1H), 7.37-7.45 (m, 3H),
6.84 (d, J = .0 Hz, 1H), 4.92-4.95 (m, 1H), 4.53 (t, J = .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.

Scheme of synthesis of exemplary compound 75
2- (2,6-dioxopiperidine-3-yl) -5-(4-(5-((5-((5- (5-methyl-5H-pyrido [4,3-b] indole-7) -Il) Pyridine-2-yl) Oxy) Pentyl) Oxy) Pentyl) Piperidine-1-yl) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 75: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 11.07 (s, 1H), 9.38 --. 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 --6.09 (m, 1H), 5.09 --5.00 (m, 1H), 4.36 --4.99 (m, 2H), 3.95 (s, 5H), 3.34 (s, 4H), 2.87 (s, 2H), 2.99- 2.78 (m, 1H),
2.82 --.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, s, 4H), 1.22 --1.05 (m, 4H). (M ⁺ H) +77 1.6.

Synthesis scheme of exemplary compound 76
2- (2,6-dioxopiperidine-3-yl) -5-(3- (3- (4- (3- (5- (5-methyl-5H-pyrido [4,3-b]]
Indole-7-yl) Pyridine-2-yl) Propa-2-in-1-yl) Piperazine-1-yl) Propoxy) Azetidine-1-yl) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using procedures universal to those skilled in the art.

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 =. 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.

Synthesis scheme of exemplary compound 78
2- (2,6-dioxopiperidine-3-yl) -5-(4- (6-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,3-) b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Hexil) Piperazine-1-yl) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 78: ¹ H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.35 (s, 1H), 8.64 (t, J = 3.9 Hz, 1H), 8.49 (d, J = .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 = .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 = .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.

Synthesis scheme of exemplary compound 85
2- (2,6-dioxopiperidine-3-yl) -5-((1r, 3r) -3-((5-(((5- (5- (5-methyl-5H-pyrido]], 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Pentyl) Oxy) Pentyl) Oxy) Cyclobutoxy) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 85: ¹ H 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 = .0 Hz) , 2H). (M ⁺ H) +77 4.6.

Synthesis scheme of exemplary compound 79
2- (2,6-dioxopiperidine-3-yl) -5-((5-((5-((5- (5-methyl-5H-pyrido [4,3-b]]
Indole-7-yl) Pyridine-2-yl) Oxy) Pentyl) Oxy) Pentyl) Oxy) Azetidine-1-yl) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 79: ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.35 (s, 1H), 8.59 (d, J = .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 = .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 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 = .4 Hz, 2H), 1.79-1.89 (m, 3H), 1.44-1.70 (m, 10H). (M ⁺ H) +759.6.

Exemplary compound 80 synthesis scheme
2- (2,6-dioxopiperidine-3-yl) -5-((1- (5-((5-((5- (5-methyl-5H-pyrido [4,3-b]]
Indole-7-yl) Pyridine-2-yl) Oxy) Pentyl) Oxy) Pentyl) Azetidine-3-
Il) Oxy) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

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 = .6, 2.5 Hz, 1H), 7.96 (s, 1H), 7.80 (d, J = .8 Hz, 1H), 7.60 (d) , J = 6.8 Hz, 2H), 7.23 (d, J = 7.2 Hz, 2H), 6.93 (d, J = .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.

Synthesis scheme of exemplary compound 84
2- (2,6-dioxopiperidine-3-yl) -5-((6- (3-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,3) -b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Phenoxy) Hexil) Oxy) Isoindoline-1,3-dione

Step 1: 2-((6- (3- (benzyloxy) phenoxy) hexyl) oxy) tetrahydro-2H-pyran

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). ) A solution of acetone (30 mL) was stirred 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 mLx3) and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified to give the desired product (PE: EA = 20: 1) (1.2 g, 83% yield) as a colorless oil.

Step 2: 3-((6-((Tetrahydro-2H-pyran-2-yl) oxy) hexyl) oxy) phenol

Add Pd / C (200 mg) to a solution of 2-((6- (3- (benzyloxy) phenoxy) hexyl) oxy) tetrahydro-2H-pyran (1.2 g, 3.13 mmol) in MeOH (30 mL) at room temperature. rice field. The resulting solution was stirred under 1 atm H ₂ at room temperature overnight. The mixture was filtered and the filtrate was concentrated under vacuum to give the desired crude product as a bright yellow oil (900 mg), which was used directly in the next step.

Step 3: 2-((6- (3-((1r, 3r) -3- (benzyloxy) cyclobutoxy) phenoxy) hexyl) oxy) tetrahydro-2H-pyran

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 a solution of THF (5.0 mL) was added DIAD (206 mg, 1.02 mmol) at 40 ° C. under a nitrogen atmosphere. The resulting mixture was heated to 80 ° C. overnight. After cooling to room temperature, the reaction was quenched with water. The mixture was extracted with EA (50 mL), the organic layer was washed with water (20 mLx3), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified to give the desired product (PE: EA = 5: 1) (130 mg, 84% yield) as a colorless oil.

2-((6- (3-((1r, 3r) -3- (benzyloxy) cyclobutoxy) phenoxy) oxy) oxy) tetrahydro-2H-pyran is known to those skilled in the art with the above procedure. The final compound 2- (2,6-dioxopiperidine-3-yl) -5-((6- (3-((1r, 3r)) -3-((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) phenoxy) hexyl) oxy) isoindoline-1, 3-Converted to Zeon.

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.

Exemplary compound 86 synthesis scheme
4-((14-(4- (5H-Piridine [4,3-b] indole-7-yl) phenoxy) -3,6,9,12-tetraoxatetradecyl) amino) -2- (2, 6-dioxopiperidine-3-yl) isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 86: ¹ H 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.

Synthesis schedule for exemplary compound 87
6-((14-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecyl) oxy) ) -2- (2,6-dioxopiperidine-3-yl) -1H-pyrrolo [3,4-c] pyridin-1,3 (2H) -dione

Step 1: 6-((14-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy)-3,6,9,12-tetraoxatetra Decyl) Oxy) Pyridine-3,4-dicarboxylic acid

14-((5- (5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) oxy) -3,6,9,12-tetraoxatetradecane-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) to which sodium hydride (162.0 mg, 4.2 mmol) was added. The resulting solution was stirred with MW for 2 hours in an N ₂ atmosphere at 100 ° C. 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 mLx2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography to give the desired compound (50 mg, 0.077 mmol, 9% yield).

Step 2: 6-((14-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy)-3,6,9,12-tetraoxatetra Decyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) -1H-pyrrolo [3,4-c] pyridin-1,3 (2H) -dione

6-((14-((5- (5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecyl) oxy) ) NaOAc (6 mg, 0.092 mmol) in a solution of AcOH (6 mL) of pyridine-3,4-dicarboxylic acid (50 mg, 0.077 mmol) and 3-aminopiperidin-2,6-dione (12 mg, 0.092 mmol). added. The resulting solution was stirred at 120 ° C. for 16 hours. After cooling to room temperature, the reaction was quenched by the addition of water (20 mL). This mixture was extracted with EA (20 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by prep-TLC with DCM / CH ₃ OH (10: 1) to give the title compound ( 4.0 mg, 0.005 mmol, 7% yield).

Compound 87: ¹ H NMR (400 MHz, CDCl ₃ ): 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 Hz, 1H), 4.94-4.99 (m, 1H), 4.54 (t, J)
= .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.

Synthesis scheme of exemplary compound 88
2- (2,6-dioxopiperidine-3-yl) -5-((14-((5- (5- (2,2,2-trifluoroethyl) -5H-pyrido] [4,3-b ] Indole-7-yl) Pyridine-2-yl) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 88: ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.35 (s, 1H), 8.63 (d, J = .6 Hz, 1H), 8.45 (s, 1H), 8.21 (d, J = .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 = .4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.87-4.92 (m, 3H), 4.55 (t, J = .8 Hz, 2H), 4.24
(t, J = 4.8 Hz, 2H), 3.90 (t, J = 4.4 Hz, 3H), 3.66-3.73 (m, 12 H), 2.76-2.87 (m, 3H), 2.09-2.16 (m, 1H) .. (M + H) ⁺ 820.5
Synthesis scheme of exemplary compound 89
2- (2,6-dioxopiperidine-3-yl) -5-(4- (3,3,3-trifluoro-2-yl)-((5-((5- (5-methyl-5H) -Pyrid [4,3-b] indole-7-yl) pyridin-2-yl) oxy) pentyl) oxy) ethoxy) propyl) piperidine-1-yl) isoindoline-1,3-dione

Step 1: 2- (5-benzyloxypentoxy) acetate

Ethyl 2-diazoacetate (704 mg, 6.18 mmol, 1.2 eq) and dilodium tetraacetate (11 mg, 0.03 mmol) in a solution of 5-benzyloxypentan-1-ol (1 g, 5.15 mmol, 1.0 eq) in dichloromethane (20 mL). ) Was added. The mixture was stirred at 20 ° C. for 0.5 hours. The mixture was quenched with ethyl alcohol (10 mL) and then concentrated. Residues are silica column chromatographed (
Purification with petroleum ether : ethyl acetate = 50: 1 to 4: 1) gave ethyl 2- (5-benzyloxypentoxy) acetate (700 mg, 2.50 mmol, 49% yield) as a yellow oil.

Step 2: 2- (5-benzyloxypentoxy) ethanol

Tetrahydrofuran (4 mL) solution of LiAlH ₄ (189 mg, 4.99 mmol, 2.0 eq) in tetrahydrofuran (10 mL) of ethyl 2- (5-benzyloxypentoxy) acetate (700 mg, 2.50 mmol, 1.0 eq). The solution was added at 0 ° C. The mixture was then stirred for 2 hours at 20 ° C. The mixture was quenched with water (0.2 mL), aqueous sodium hydroxide solution (1 M, 0.2 mL), and more water (0.8 mL). It was then filtered and concentrated. The residue is purified by silica column chromatography (petroleum ether; ethyl acetate = 30: 1-10: 1) to give 2- (5-benzyloxypentoxy) ethanol (400 mg, 1.68 mmol, 67% yield). Obtained as a white oil.

Step 3: 2- (5-benzyloxypentoxy) ethyl 4-methylbenzenesulfonic acid

Potassium hydroxide (2.83) 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). g, 50.35 mmol, 30.0 eq) was added. The mixture was stirred at 20 ° C. for 0.5 hours. 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 column chromatography (petroleum ether : ethyl acetate = 30: 1-10: 1) to 2- (5-benzyloxypentoxy) ethyl 4-methylbenzenesulfonic acid (570 mg, 1.45 mmol, (Yield 86%) was obtained as a white oil.

Step 4: 4- (3,3,3-trifluoro-2-hydroxy-propyl) piperidine-1-carboxylate tert-butyl

4- (2-oxoethyl) piperidine-1-carboxylate tert-butyl (1.9 g, 8.36 mmol, 1.0 eq)
Tetrabutylammonium fluoride (1M, 0.1 mL) was added at 0 ° C. to a mixture of tetrahydrofuran (20 mL) of trimethyl (trifluoromethyl) silane (1.43 g, 10.03 mmol, 1.2 eq). The mixture was then stirred for 1 hour at 20 ° C. Hydrochloric acid (1M, 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 column chromatography (petroleum ether: ethyl acetate = 100: 1-10: 1) and 4- (3,3,3-trifluoro-2-hydroxy-propyl) piperidin-1-carboxylic acid. tert - Butyl (2.0 g, 6.73 mmol, 80% yield) was obtained as a white solid.

Step 5: 4- [2- [2- (5-benzyloxypentoxy) ethoxy] -3,3,3-trifluoro-propyl] piperidine-1-carboxylate tert-butyl

Sodium hydride in a solution of dimethylformamide (2 mL) of 4- (3,3,3-trifluoro-2-hydroxy-propyl) piperidin-1-carboxylate tert-butyl (216 mg, 0.73 mmol, 1.0 eq) (58 mg, 1.46 mmol, 60% in mineral oil, 2.0 eq) was added at 15 ° C. Then the mixture is heated to 15 ° C.
Was stirred under nitrogen for 0.5 hours. 2- (5-benzyloxypentoxy) ethyl 4-methylbenzenesulfonic acid (200 mg, 0.51 mmol, 0.7 eq) was added to this mixture and stirred at 50 ° C. for an additional 2.5 hours. The mixture was diluted with water (5 mL), extracted with ethyl acetate (20 mLx2), washed with brine (20 mL), dried over anhydrous sodium sulfate and then concentrated. The mixture was purified by silica column chromatography (petroleum ether: ethyl acetate = 200: 1-10: 1) and 4- [2- [2- (5-benzyloxypentoxy) ethoxy] -3,3,3. -Trifluoro-propyl] piperidin-1-carboxylate tert-butyl (300 mg, 0.58 mmol, yield 80%) was obtained as a white oil.

4- [2- [2- (5-benzyloxypentoxy) ethoxy] -3,3,3-trifluoro-propyl] piperidine-1-carboxylate tert-butyl to the above procedure and to those skilled in the art. Using known universal procedures, the title compound 2- (2,6-dioxopiperidine-3-yl) -5- (4- (3,3,3-trifluoro) is according to the following synthetic scheme. -2- (2-((5-((5- (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) pentyl) oxy) ethoxy) propyl ) Piperidine-1-yl) Converted to isoindrin-1,3-dione.

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.

Scheme of synthesis of exemplary compound 90
2- (2,6-dioxopiperidine-3-yl) -5-(4-((4-(((5- (5-methyl-5H-pyrido [4,3-b] indole-7) -Il) Pyridine-2-yl) Oxy) Buta-2-in-1-yl) Oxy) Butoxy) Butoxy) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 90: ¹ HNMR (400 MHz, CDCl ₃ ): 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 = .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.

Synthesis scheme of exemplary compound 91
2- (2,6-dioxopiperidine-3-yl) -5-(4- (8-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,3-) b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Octyl) Piperazine-1-yl) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

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.

Synthesis scheme of exemplary compound 92
5-((14-((3-Chloro-5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy)-3,6,9, 12-Tetraoxatetradecyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 92: ¹ H NMR (400 MHz, CDCl ₃ ): 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, 78 8.5.

Synthesis scheme of exemplary compound 93
5-((6-((5- (2,2-difluoro-2- (5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) ethoxy) ) Pentyl) Oxy) Hexil) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 93: ¹ H NMR (400 MHz, CDCl ₃ ): 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 = .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.

Scheme of synthesis of exemplary compound 96
2- (2,6-dioxopiperidine-3-yl) -5-(4- (6-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,3-) b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Hexil) -3- (Trifluoromethyl) Piperazine-1-yl) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 96: ¹ H 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 --.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.

Exemplary compound 99 synthesis scheme
2- (2,6-dioxopiperidine-3-yl) -5-((1- (3- (3-((1r, 3r) -3-((5- (5-methyl-5H-pyrido)] 4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Propoxy) Propyl) Azetidine-3-yl) Oxy) Isoindoline-1,3-dione

Step 1: 2- (3-Bromopropoxy) Tetrahydro-2H-Pyran

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 tetrahydrofuran (80 ml) is stirred overnight at room temperature. did. The reaction mixture was quenched with aqueous sodium bicarbonate solution (saturated, 10 mL) and extracted with tert-butyl methyl ether (50 mLx3). The organic layers were combined into one, washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue.
This was purified by silica gel flash chromatography (eluted with 10% ethyl acetate in hexanes) to obtain 2- (3-bromopropoxy) tetrahydro-2H-pyran (6.4 g, 72% yield) as a colorless oil. ..

Step 2: 3- (3-((Tetrahydro-2H-pyran-2-yl) oxy) propoxy) propan-1-ol

Sodium hydride (60% in mineral oil) (0.88 g, 222 mmol) was added to a solution of propane-1,3-diol (4.6 g, 60 mmol) in N, N-dimethylformamide (50 mL) at 0 ° C. The obtained mixed solution 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 obtained 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 mLx2). The organic layers were combined into one, washed with brine (50 mlx2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel flash chromatography (30% ethyl acetate in hexanes). Purified by (eluting with) and 3-(3-((tetrahydro-2H-pyran-2-yl)) as a colorless oil.
Oxy) propoxy) propan-1-ol (0.9 g, yield 45%) was obtained.

Step 3: 4-Methylbenzenesulfonic acid 3- (3-((Tetrahydro-2H-pyran-2-yl) oxy))
Propoxy) Propyl

Stirring 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) To sil chloride (0.94 g, 4.95 mmol) and 4-dimethylaminopyridine (50 mg, 0.4 mmol) were added at 0 ° C. The resulting solution was warmed 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 organic layers are grouped together, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is subjected to silica gel flash chromatography (10-20 in hexanes). Purified by% ethyl acetate), 4-methylbenzenesulfonic acid 3-(((tetrahydro-2H-pyran-2-yl) oxy) propoxy) propyl (1.2 g, 78% yield) as a colorless oil. ) Was obtained.

Step 4: 2- (3-(3-((1r, 3r) -3- (benzyloxy) cyclobutoxy) propoxy) propoxy) tetrahydro-2H-pyran

Sodium hydride (60% in mineral oil) (63 mg, 1.57 mmol) in a solution of (1r, 3r) -3- (benzyloxy) cyclobutanol (200 mg, 1.12 mmol) in N, N-dimethylformamide (6 ml). )
Was added at 0 ° C., and the obtained mixture was stirred at room temperature for 30 minutes. 4-Methylbenzenesulfonic acid 3- (3-((tetrahydro-2H-pyran-2-yl) oxy) propoxy) propyl (501 mg, 1.34 mmol) was added, and the obtained 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 mLx2). The organic layers were combined into one, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel flash chromatography (30% ethyl acetate in hexanes). Purified by (eluting with), and as a colorless oil, 2- (3- (3-((1r, 3r) -3- (benzyloxy) cyclobutoxy) propoxy) propoxy) tetrahydro-2H-pyran (234 g, yield 47) %) Was obtained.

Step 5: (1r, 3r) -3- (3- (3-hydroxypropoxy) propoxy) cyclobutanol

2- (3- (3-((1r, 3r) -3- (benzyloxy) cyclobutoxy) propoxy) propoxy) tetrahydro-2H-pyran (468g, 1.23 mmol), palladium carbon (10%, 60mg) methanol The mixture (30 ml) was stirred under a hydrogen atmosphere (hydrogen balloon) overnight at room temperature. Palladium on carbon was removed by filtration and washed with methanol (5 mlx2). The filtrates are combined and concentrated under reduced pressure to give (1r, 3r) -3- (3- (3-hydroxypropoxy) propoxy) cyclobutanol (240 mg, yield: 95%) a colorless oil. Got as.

Step 6: 3-(3-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) Cyclobutoxy) Propoxy) Propan-1-ol

Sodium hydride (60 in mineral oil, 60) in a solution of (1r, 3r) -3- (3- (3-hydroxypropoxy) propoxy) cyclobutanol (100 mg, 0.49 mmol) in N, N-dimethylformamide (3 ml). %) (28 mg, 0.69 mmol) was added 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 obtained 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 mLx2). 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 subjected to silica gel flash chromatography (5% methanol in dichloromethane). Purified by elution) and used as a white solid 3-(3-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine) -2-yl) Oxy) Cyclobutoxy) Propoxy) Propane-1-ol (75 mg)
, Yield 34%) was obtained.

Step 7: 3-(3-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) Cyclobutoxy) Propoxy) Propanal

3- (3-(((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) Dess-Martin peryodinane (129 mg, 0.3 mmol) 0 in a stirred solution of dichloromethane (5 ml) of propoxy) propoxy-1-ol (70 mg, 0.15 mmol)
Added at ° C. The resulting reaction mixture was heated to room temperature and stirred at this temperature for an additional 30 minutes. The reaction mixture is quenched with aqueous sodium bicarbonate solution (10 ml), extracted with dichloromethane (20 mlx2), washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to form a white solid. Crude 3- (3-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) oxy) cyclobutoxy) ) Propoxy) Propanal (80 mg, crude) was obtained and used in the next step without further purification.

Step 8: 2- (2,6-dioxopiperidine-3-yl) -5-((1- (3- (3-((1r, 3r) -3-((5- (5-methyl-5H) -Pirido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) propyl) azetidine-3-yl) oxy) isoindoline-1,3-dione

5- (Azetidine-3-yloxy) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione hydrochloride (70 mg, 0.17 mmol) [Procedures described above and the art. Prepared as shown in the scheme below using universal procedures known to those of skill in the art], N-ethyl-N-isopropylpropane-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)) A solution of cyclobutoxy) propoxy) propanal (80 mg, 0.17 mmol) in methanol (5 ml) at room temperature 30
Stir for minutes, then sodium cyonobrohydriole (22 mg, 0.35 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture is quenched with aqueous sodium bicarbonate solution (saturated, 10 ml), extracted with ethyl acetate (20 ml), washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and crude. Residues are obtained and purified by preparative TLC (eluting with 10% methanol in dichloromethane) to 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) ) Pryc) azetidine-3-yl) oxy) isoindrin-1,3-dione (20 mg, yield: 15%) was obtained as a white solid.

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 = .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.

Scheme of synthesis of exemplary compound 100
2- (2,6-dioxopiperidine-3-yl) -5-(6-(4-(4-((5- (5- (5-methyl-5H-pyrido [4,3-b] indole-7-) Il) Pyridine-2-yl) Oxy) Butoxy) Butoxy) -2-Azaspiro [3.3] Heptane-2-yl) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 100: ¹ H 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 = .6 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 6 Hz, 1H), 7.50 (d, J = .0 Hz, 1H), 7.56 (s, 1H), 7.61 (d, J = .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 = .4 Hz, 1H), 8.60 (d, J = 5.6 Hz, 1H), 9.34 (s, 1H). (M ⁺ H) +77 1.6.

Synthesis scheme of exemplary compound 101
5-((1- (3- (3-((1r, 3r) -3-((5- (5H-pyridine [4, 3-b] indole-7-yl) -3- (trifluoromethyl)) Pyridine-2-yl) Oxy) Cyclobutoxy) Propoxy) Propyl) Azetidine-3-yl) Oxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

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.

The following were prepared using a similar procedure: Compound 105.
Synthesis scheme of exemplary compound 103
5-((14-((5- (8,9-difluoro-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl))
Oxy) -3,6,9,12-tetraoxatetradecyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

Step 1: 5-bromo-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecane-16-yl) oxy) pyridine

1-Phenyl-2,5,8,11,14-pentaoxahexadecane-16-ol (2.6 g, 7 ) in a solution of compound 5-bromo-2-fluoropyridine (2.0 g, 9.5 mmol) in DMF (20 mL). .91 mmol) and NaH (950 mg, 24 mmol, 60%) were added at 0 ° C. The obtained mixture was stirred for 18 hours at 20 ° C. TLC (PE: EA = 1: 1, Rf = 0.5) showed that 5-bromo-2-fluoropyridine was consumed. The mixture was diluted with EA (30 mL) and washed with water (3 * 30 mL) and brine (30 mL). The organic layer is dried and concentrated to give a crude product, which is purified by column chromatography on PE: EA (1: 1) silica gel to give the desired product (3.6 g) as a colorless oil. ) Was obtained.

Step 2: 2-((1-Phenyl-2,5,8,11,14-pentaoxahexadecane-16-yl) oxy) -5- (4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl) Pyridine

5-bromo-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecane-16-yl) oxy) Pyridine (3.6 g, 7.22 mmol) in a dioxane (50 mL) solution, 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) were added. The resulting solution was stirred at 90 ° C. for 18 hours. The mixture was filtered and concentrated. The crude product was purified by column chromatography on silica gel with PE: EA (1: 1) to give the desired product (3.0 g, yield = 78%) as a yellow oil.

Step 3: 5- (4-bromo-2,3-difluorophenyl) -2-((1-phenyl-2,5,8,11,14-pentaoxahexadecane-16-yl) oxy) pyridine

2-((1-Phenyl-2,5,8,11,14-pentaoxahexadecane-16-yl) oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl) In a solution of pyridine (2.8 g, 5.27 mmol) in dioxane / H ₂ O (55 mL, 10/1, v / v), 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) were added. The resulting solution was stirred under N ₂ at 90 ° C. for 18 hours. 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 product was purified by column chromatography on silica gel with PE: EA (1: 1) to give the desired product (1.5 g, yield = 48%) as a brown oil.

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-Pentaoxahexadecane-16-yl) Oxy) Pyridine

5- (4-bromo-2,3-difluorophenyl) -2-((1-phenyl-2,5,8,11,14-pentaoxahexadecane-16-yl) oxy) pyridine (1.0 g, 1.68 mmol) ) In a dioxane (20 mL) solution, 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) were added. The resulting solution was stirred at 90 ° C. for 18 hours. LCMS is completely 5- (4-bromo-2,3-difluorophenyl) -2-((1-phenyl-2,5,8,11,14-pentaoxahexadecane-16-yl) oxy) pyridine Shown that it was consumed. The mixture was filtered and concentrated. The crude product was purified by column chromatography on silica gel with PE: EA (3: 2) to give the desired product (660 mg, yield = 95%) as a brown oil.

Step 5: 5- (2,3-difluoro-4- (4-nitropyridin-3-yl) phenyl) -2-((1-phenyl-2,5,8,11,14-pentaoxahexadecane-16) -Il) Oxy) Pyridine

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-Pentaoxahexadecane-16-yl) Oxy) In a solution of pyridine (350 mg, 0.544 mmol) in dioxane / H ₂ O (11 mL, 10/1, v / v), 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) were added. The mixture was stirred at 110 ° C. for 1 hour under N ₂ . After 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 residue was purified by column chromatography on silica gel with PE / EA (1: 3) to give the desired product (170 mg) as a yellow oil.

Step 6: 8,9-difluoro-7-(6-((1-phenyl-2,5,8,11,14-pentaoxahexadecane-16-yl) oxy) pyridin-3-yl) -5H-pyrido [4,3-b] Indole

5- (2,3-difluoro-4- (4-nitropyridin-3-yl) phenyl) -2-((1-phenyl-2,5,8,11,14-pentaoxahexadecane-16-yl)) A solution of P ( Oet ) ₃ (3 mL) of oxy) pyridine (340 mg, 0.53 mmol) was stirred at 110 ° C. for 3 hours. After the reaction, the mixture was purified by column chromatography on silica gel with DCM / MeOH (30: 1) to give the desired product (205 mg) as a brown solid.

8,9-Difluoro-7-(6-((1-phenyl-2,5,8,11,14-pentaoxahexadecane-16-yl) oxy) Pyridine-3-yl) -5H-pyrido [4, 3-b] Indole was added to the final compound 5-((14-((5- (- 8,9-Difluoro-5H-pyrido [4,3-b] indole-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] Indole-7-yl) Pyridine-2-yl) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) -2- (2,6-dioxopiperidine-3) -Il) Isoindoline-1,3-dione (Compound 112) was converted.

Compound 103: ¹ H 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 = .8 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.61 (d, J = .8 Hz, 1H), 7.29 (s, 1H), 7.23 (d, J = .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.

Compound 112: ¹ HNMR (400 MHz, CDCl ₃ ): 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 = .4 Hz, 1H), 5.08-5.13 (m, 1H), 4.46 (d, J = .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.

Synthesis scheme of exemplary compound 104
2- (2,6-dioxopiperidine-3-yl) -5-(3- (3-(3-((1r, 3r) -3-((5- (5-methyl-5H-pyrido]] , 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Propoxy) Propoxy) Azetidine-1-yl) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 104: ¹ H 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 = .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.

The following compounds were prepared using procedures similar to those described above: 125 (procedures described in Compound 67 are also used), 148 (procedures described in Compound 67 are also used), Compound 170.

Synthetic Scheme of Exemplary Compound 106 Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 106: ¹ H 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.

Synthesis scheme of exemplary compound 107
2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (6-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-) Il) Pyridine-2-yl) Oxy) -2-Azaspiro [3.3] Heptane-2-yl) Butoxy) Butoxy) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

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 = .4 Hz, 1H), 7.56 (s, 1H), 7.78 (d, J = .4 Hz, 1H), 7.90-7.93 (m, 1H), 8.21 (d, J = .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) +77 1.6.

Synthesis scheme of exemplary compound 108
2- (2,6-dioxopiperidine-3-yl) -5-((6-((6-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,, 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl)
Oxy) Hexil) Oxy) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 108: ¹ H NMR (400 MHz, DMSOd-6): 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, 1H), 6.34-6.37
2H), 6.98 (d, J = .4 Hz, 1H), 7.24-7.26 (m, 1H), 7.33 (d, J = .0 Hz, 1H), 7.59-7.65 (m, 3H), 7.72 (d) , J = .0 Hz, 1H), 7.97 (s, 1H), 8.17-8.21 (m, 1H), 8.31 (d, J = .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.

Synthesis scheme of exemplary compound 109
2- (2,6-dioxopiperidine-3-yl) -5-((6-((4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,, 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl)
Oxy) Hexil) Oxy) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 109: ¹ H NMR (400 MHz, DMSOd-6): 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 = .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 = .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.

Synthesis scheme of exemplary compound 111
2- (2,6-dioxopiperidine-3-yl) -5-(3-((3- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido]] 4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Azetidine-1-yl) Isoindoline- 1,3-Zeon

Step 1: 3- (propa-2-in-1-yloxy) azetidine-1-carboxylate tert-butyl

Sodium hydride (60% in mineral oil) (60% in mineral oil) in a stirred solution of N, N-dimethylformamide (10 mL) of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.0 g, 12.2 mmol) at 0 ° C. 255mg,
6.36 mmol) was added, and the obtained mixture was stirred at 0 ° C. for 30 minutes. The resulting mixture was warmed to room temperature and stirred for an additional 30 minutes, then 3-bromoprop-1-in (818 mg, 6.94 mmol) was added and the resulting reaction mixture was stirred overnight at 50 ° C. LCMS showed that the reaction was complete. The reaction mixture was quenched with water (10 mL) at 0 ° C. and extracted with ethyl acetate (30 mLx2). The organic layers were combined into one, washed with brine (30 mlx2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel flash chromatography (10% ethyl acetate in hexanes). As a colorless oil, tert-butyl 3- (propa-2-in-1-yloxy) azetidine-1-carboxylate (1.03 g, yield 84%) was obtained.

Step 2: 3-((3- (5-Hydroxypyridin-2-yl) propa-2-in-1-yl) oxy) azetidine-1-carboxylate tert-butyl

Stirring of acetonitrile (10 ml) of 3- (propa-2-in-1-yloxy) azetidine-1-carboxylate tert-butyl (900 mg, 4.27 mmol) and 6-bromopyridine-3-ol (734 mg, 4.27 mmol) Triethylamine (863 mg, 8.54 mmol) was added to the solution at room temperature and in a nitrogen atmosphere, followed by bis (triphenylphosphine) palladium (II) chloride (150 mg, 0.214 mmol) and cuprous iodide (41 mg, 0.214 mmol). ) Was added. The mixture was degassed with nitrogen three times. The reaction mixture was heated to 65 ° C. and stirred overnight. TLC showed that the reaction was complete. 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 subjected to silica gel flash column chromatography (eluted with 100% ethyl acetate in hexanes). Purified as a brown oil, 3-((3- (5-hydroxypyridin-2-yl) propa-2-in-1-yl) oxy) azetidine-1-carboxylate tert-butyl (550 mg, yield 42) %) Was obtained.

Step 3: 3-((3- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) Il) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Azetidine-1-carboxylate tert-butyl

3-((3- (5-Hydroxypyridine-2-yl) propa-2-in-1-yl) oxy) azetidine-1-carboxylate tert-butyl (100 mg, 0.325 mmol), (1s, 3s)- 3-((5- (5-Mole-5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) oxy) cyclobutyl methanesulfonate (137 mg, 0.325 mmol) and cesium carbonate ( A solution of 211 mg, 0.65 mmol) anhydrous N, N-dimethylformamide (2 ml) was stirred for 36 hours at 70 ° C. TLC showed that the reaction was complete. The mixture was partitioned between ethyl acetate (50 ml) and water (25 ml). The organic layer is collected, washed with brine (25 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is eluted with silica gel flash column chromatography (eluting with 3% methanol in dichloromethane). ) As a white solid 3-((3- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7) -Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Azetidine-1-carboxylate tert-butyl (60 mg, 29% yield) Obtained.

Using the procedures described above and universal procedures known to those of skill in the art, 3-((3- (5-((1r, 3r) -3-((5-) (5-Methyl-5H-pyrido [4,3-b] indole-7-
Il) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Azetidine-1-carboxylate tert-butyl is used as the final compound 2- (2, 2, 6-Dioxopiperidine-3-yl) -5-(3-((3- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] 4,3-b ] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Azetidine-1-yl) Isoindoline-1,3-dione Converted to.

Compound 111: ¹ HNMR (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.

The following exemplary compounds were prepared using a similar procedure: 194.
Synthesis scheme of exemplary compound 114
2- (2,6-dioxopiperidine-3-yl) -5-((5- (4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,3) -b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Butoxy) Pentyl) Oxy) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 114: ¹ H 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 = 5.2,12.0Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = .0, 8.0Hz, 1H), 7.32 (d) , J = 1.6 Hz, 1H), 7.44 (d, J = 6.0 Hz, 1H), 7.54 (d, J = .0 Hz, 1H), 7.60 (s, 1H), 7.75 (d, J = .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 = .2 Hz, 1H), 9.34 (s, 1H). (M ⁺ H) +760.5.

Using a procedure similar to that for compound 140, the following was prepared: compound 115.
Synthesis scheme of exemplary compound 116
2- (2,6-dioxopiperidine-3-yl) -5-((2- (4- (4-((5- (5-methyl-5H-pyrido [4,3-b] indole-7) -Il) Pyridine-2-yl) Oxy) Butoxy) Butyl) -2-Azaspiro [3.3] Heptane-6-Il) Oxy) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

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, 3H) 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 = .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) +77 1.6.

Synthesis scheme of compound 118:
2- (2,6-dioxopiperidine-3-yl) -5-(3-((3- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido]] 4,3-b] indole-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propa-2-in-1-yl) oxy) azetidine -1-yl) Isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 118: ¹ H 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.

Synthesis scheme of exemplary compound 121
(2S, 4R) -1-((S) -20-((5- (5H-pyrido [4,3-b] indole-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-methylthiazole-5-yl) phenyl) ) Ethyl) Pyrrolidine-2-carboxamide

Step 1: 14-((5-bromopyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecane-1-ol

Sodium hydride (60% in mineral oil, 60% in mineral oil) in a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (20 g, 83.93 mmol) in N, N-dimethylformamide (100 mL) at 0 ° C. ) (1.36g, 34
.09 mmol) was added, and the obtained 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 showed that the reaction was complete. The reaction mixture was quenched with water (150 mL) at 0 ° C. and extracted with ethyl acetate (150 mLx2). The organic layers were combined into one, washed with brine (200 mlx2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was subjected to silica gel flash chromatography (2% methanol in dichloromethane). Purified by (elution with), 14-((5-bromopyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecane-1-ol (8 g, yield 72%) as a colorless oil. Got

Step 2: 17-((5-bromopyridin-2-yl) oxy) -3,6,9,12,15-pentaoxaheptadecane-1-oate tert-butyl

14-((5-bromopyridine-2-yl) oxy)-3,6,9,12- tetraoxatetradecane -1-ol (2.00 g, 5.07 mmol) and ammonium chloride tetrabutyl (1.41 g, 5.07 mmol) ), A stirred solution of dichloromethane (20 ml) and sodium hydroxide (20 ml, 35% aqueous solution) was added tert-butyl 2-bromoacetate (2.97 g, 15.22 mmol) at 0 ° C. The reaction mixture was then warmed to room temperature and stirred overnight at room temperature. The organic layer was collected and the aqueous layer was extracted with dichloromethane (20 ml). The organic layers were combined into one, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was subjected to silica gel flash column chromatography (50% in hexanes). Purified by (eluting with ethyl acetate) and as a colorless oil, 17-((5-bromopyridin-2-yl) oxy) -3,6,9,12,15-pentaoxaheptadecane-1-oate tert-butyl (1.64 g, yield 64%) was obtained.

Step 3: 17-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12,15-pentaoxaheptadecane- 1-Oate tert-butyl

7-bromo-5H-pyrido [4,3-b] indol (300 mg, 1.22 mmol), 4,4,4', 4', 5,5,5', 5'-octamethyl-2,2'- 1,1'-Bis (diphenylphosphino) ferrocene palladium in a stirred solution of bi (1,3,2-dioxaborolane) (620 mg, 2.44 mmol) and potassium acetate (239 mg, 2.44 mmol) in dioxane (5 ml). (II) Dichloride (176 mg, 0.24 mmol) was added at room temperature in a nitrogen atmosphere, and the mixed solution was degassed with nitrogen three times. The resulting mixture was stirred at 90 ° C. overnight. LCMS showed that the reaction was complete. In the reaction mixture, 14-((5-bromopyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecane- 1 -ol (930 mg, 1.83 mmol), sodium carbonate aqueous solution (2N) , 3.2 ml), and tetrakis (triphenylphosphine) palladium (70 mg, 0.06 mmol) was added. The mixture was degassed with nitrogen three times. The obtained 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 organic layers were combined into one, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was subjected to silica gel flash chromatography (2% methanol in dichloromethane). Dissolved in)
Purified with 17-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12,15- as a gray oil. Pentaoxaheptadecane-1-oate tert-butyl (260 mg, yield 36%) was obtained.

Step 4: 17-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12,15-pentaoxaheptadecane- 1-Oic acid

17-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12,15-pentaoxaheptadecane-1-oate A mixture of tert-butyl (130 mg, 0.22 mmol) and dichloromethane (1 ml) of 2,2,2-trifluoroacetic acid (2 ml) was stirred at room temperature for 1 hour. The volatile components are evaporated under reduced pressure to form a brown solid 17-((5- (5H-pyrido [4,3-b] indole-7-).
Ill) Pyridine-2-yl) Oxy) -3,6,9,12,15-Pentaoxaheptadecane-1-oxyic acid (120 mg, crude) is obtained and the next step without further purification. Used directly in.

Step 5: (2S, 4R) -1-((S) -20-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -2- (tert-butyl) -4-oxo-6,9,12,15,18-pentaoxa-3-azaikosan-1-
Oil) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide

17-((5- (5H-Pyrrolidine [4,3-b] Indole-7-yl) Pyridine-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-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide hydrochloride (105 mg, 0.22 mmol), and N-ethyl-N-
HATU (2- (7-aza-1H-benzotriazole-1-yl) -1,1 in a stirred solution of anhydrous N, N-dimethylformamide (3 ml) of isopropylpropane-2-amine (142 mg, 1.10 mmol) , 3,3-Tetramethyluronium hexafluorophosphate) (167 mg, 0.44 mmol) was added at room temperature and stirred for 20 minutes. The mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer is collected, washed with brine (20 mlx2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is eluted by preparative TLC (eluted with 10% methanol in dichloromethane). Purify and
As a white solid, (2S, 4R) -1-((S) -20-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -2 -(tert-Butyl) -4-oxo-6,9,12,15,18-pentaoxa-3-azaicosan-1-oil) -4-hydroxy-N-((S) -1- (4- (4) -Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (28 mg, yield 13%) was obtained.

¹ H NMR (400 MHz, DMSOd-6): δ .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 = 7.6 Hz, 1H), 5.12 (s, 1H), 6.97 (d, J = .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 = .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.

The following were prepared using a similar procedure: compound 1, compound 5, compound 6, compound 120, and compound 122.

Synthesis scheme for exemplary compound 119
(2S, 4R) -1-((S) -17-((5- (5H-pyrido [4,3-b] indole-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-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 119: ¹ H NMR (400 MHz, DMSO-d ₆ ): 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 =. 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 = .2 Hz, 1H), 7.90 (s, 1H), 8.35 (d, J = .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.

Synthesis scheme of exemplary compound 126
2- (2,6-dioxopiperidine-3-yl) -5-((5- (6- (methyl ((1r, 3r) -3-((5- (5-methyl-5H-pyrido]] , 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutyl) Amino) -2-
Azaspir [3.3] heptane-2-yl) pentyl) oxy) isoindoline-1,3-dione

Step 1: (1r, 3r) -3- (methylamino) cyclobutanol

Lithium aluminum hydride (1.6 g, 42.7 mmol) was added to a solution of tert-butyl carbamic acid (2 g, 10.7 mmol) in tetrahydrofuran (30 ml) at 0 ° C. ((1r, 3r) -3-hydroxycyclobutyl). .. The mixture was stirred at 65 ° C. for 2 hours. TLC showed that the reaction was complete. The mixture was quenched at 0 ° C. with water (1.6 ml), sodium hydroxide (1.6 ml, 15% aqueous solution), and water (4.8 ml). The mixture was stirred at room temperature for 15 minutes and filtered. The filtrate is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude (1r, 3r) -3- (methylamino) cyclobutanol (1.3 g) as a colorless oil for further purification. Used for the next step without doing.

Step 2: ((1r, 3r) -3-hydroxycyclobutyl) (methyl) tert-butyl carbamic acid

Di-tert-butyl carbonate (4.2 g) in 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) at room temperature.
, 19.28 mmol) was added. The mixture was stirred at room temperature for 12 hours. TLC showed that the reaction was complete. The mixture was diluted with dichloromethane (10 ml) and washed with aqueous hydrochloric acid solution (1N, 10 ml). The organic layer is collected, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is subjected to silica gel flash column chromatography (33-50% ethyl acetate in hexanes). (Elution with) to give ((1r, 3r) -3-hydroxycyclobutyl) (methyl) tert-butyl carbamate (1.2 g, 56% in two steps) as a colorless oil.

Step 3: Methyl ((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutyl) carbamic acid tert-butyl

7- (6-fluoropyridin-3-yl) -5-methyl-5H-pyrido [4,3-b] indol (300 mg, 1.1 mmol) and ((1r, 3r) -3-hydroxycyclobutyl (methyl) ) Sodium hydride (60% in mineral oil) was added to a solution of 1-methylpyrrolidin-2-one (3 ml) of tert-butyl carbamate (218 mg, 1.1 mmol) at 0 ° C. The mixture was added. The mixture was cooled to room temperature and stirred for 30 minutes at room temperature. LC-MS showed that the reaction was complete. The mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was separated. Collected, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is subjected to silica gel flash chromatography (eluting with 1-2% methanol in dichloromethane). Methyl ((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) as a bright yellow oil after purification ) Cyclobutyl) tert-butyl carbamate (450 mg, 91%) was obtained.

Step 4: 6- (Methyl ((1r, 3r) -3-((5- (5-Methyl-5H-pyrido [4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutyl ) Amino) -2-Azaspiro [3.3] Obtains tert-butyl heptane-2-carboxylate

Methyl ((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl)
A mixture of tert-butyl (450 mg, 0.98 mmol) tert-butyl carbamate (yl) oxy) cyclobutyl) and dichloromethane (2 ml) of 2,2,2-trifluoroacetic acid (2 ml) was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. Volatiles were evaporated under reduced pressure. The residue was dissolved in methanol (5 ml), then N-ethyl-N-isopropylpropane-2-amine (380 mg, 2.94 mmol), 6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-. Butyl (207 mg, 0.98 mmol) and acetic acid (71 mg, 1.18 mmol) were added sequentially 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 showed that the reaction was complete. The mixture was concentrated and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer is collected, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is subjected to silica gel flash chromatography (2-5% methanol in dichloromethane). Purified by elution) and used as a white solid 6- (methyl ((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine- 2-Il) oxy) cyclobutyl) amino) -2-azaspiro [3.3] heptane-2-carboxylate tert-butyl (240 mg, 44% in two steps) was obtained.

Step 5: N-Methyl-N-((1r, 3r) -3-((5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl))
Pyridine-2-yl) Oxy) Cyclobutyl) -2-Azaspiro [3.3] Heptane-6-amine

6-(Methyl ((1r, 3r) -3-((5- (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) oxy) cyclobutyl) amino) A mixture of tert-butyl -2-azaspiro [3.3] heptane-2-carboxylate (100 mg, 0.18 mmol) and anhydrous dichloromethane ( 0.5 ml) of 2,2,2-trifluoroacetic acid (0.5 ml), The mixture was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure to crude N-methyl-N-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl)). Pyridine-2-yl) oxy) cyclobutyl) -2-azaspiro [3.3] heptane-6-amine (100 mg) was obtained and used in the next step without further purification.

Step 6: 2- (2,6-dioxopiperidine-3-yl) -5-((5- (6- (methyl ((1r, 3r) -3-((5- (5-methyl-5H-) Pyrido [4,3-b] indole-7-yl) pyrididine-2-yl) oxy) cyclobutyl) amino) -2-azaspiro [3.3] heptane-2-yl) pentyl) oxy) isoindoline-1,3- Zeon

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] Heptane-6-amine (100 mg, crude) and N-ethyl-N-isopropylpropan-2-amine (70 mg, 0.54 mmol) in a solution of 5-((2-) (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline-5-yl) Oxy) Pentanol (65 mg, 0.18 mmol) and acetic acid (13 mg, 0.21 mmol) were added at 0 ° C. .. The mixture was stirred at room temperature for 30 minutes, then sodium cyanoborohydride (23 mg, 0.36 mmol) was added. The mixture was stirred at room temperature for 16 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure to give a crude residue, which was purified by HPLC and used as a white solid 2- (2,6-dioxopiperidine-3-yl) -5-((5- (6). -(Methyl ((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutyl) amino)- 2-Azaspiro [3.3
] Heptane-2-yl) pentyl) oxy) Isoindoline-1,3-dione (57.3 mg, 40% in two steps) was obtained.

¹ H NMR (400 MHz, DMSO-d6): δ .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.

Synthesis scheme of exemplary compound 127
3- (5-(4-((1- (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) piperidine-4-yl) methyl) Piperazine-1-yl) -1-oxoisoindoline-2-yl) piperidine-2,6-dione

Step 1: (1- (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) piperidine-4-yl) methanol

7- (6-Fluoropyridin-3-yl) -5-methyl-5H-pyrido [4,3-b] indole (200 mg, 0.72 mmol), and piperidine-4-ylmethanol (108 mg, 0.93 mmol) Potassium carbonate (298 mg, 2.16 mmol) was added to the mixed solution of 1-methylpyrrolidine-2-one (5 ml), and the temperature was 100 ° C. under a nitrogen atmosphere.
Stird overnight. The cooled reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer is collected, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is subjected to silica gel flash chromatography (2-5% methanol in dichloromethane). Purified by elution) as a bright yellow solid (1- (5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) piperidin-4-yl) Methanol (205 mg, yield 76%) was obtained.

Step 2: 1- (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) piperidine-4-carbaldehyde

In a solution of Dess-Martin peryodinan (136 mg, 0.32 mmol) in dichloromethane (3 ml),
(1- (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) piperidine-4-yl) Methanol (60 mg, 0.16 mmol) was added. The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction mixture was partitioned between dichloromethane (20 ml) and water (20 ml). The organic layer is collected, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is purified by prep TLC (eluted with 3% methanol in dichloromethane). And as a white solid (1- (5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) piperidin-4-yl) carboaldehyde (58 mg, Yield 97%) was obtained.

Step 3: 4- (1-oxo-3H-isobenzofuran-5-yl) piperazine-1-carboxylate tert-butyl

In a solution of 5-bromo-3H-isobenzofuran-1-one (45 g, 211.24 mmol, 1.00 eq) and tert-butyl piperazin-1-carboxylate (39.34 g, 211.24 mmol, 1.00 eq) in dioxane (500 mL), Tris (dibenzilidenacetone) 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) were added. Mixture
Was heated at 100 ° C. for 16 hours under nitrogen protection. The mixture was filtered through a cerite bed and the filtrate was concentrated in vacuo. The residue was pulverized with ethyl acetate: petroleum ether (500 mL, v / v = 1: 2). 4- (1-oxo-3H-isobenzofuran-5-yl) piperazine-1-carboxylate tert-butyl (50 g, 122.5 mmol, 58% yield, 78% purity) was obtained as a yellow solid.

Step 4: 4- (4-tert-Butoxycarbonylpiperazin-1-yl) -2- (hydroxymethyl) benzoic acid

4- (1-oxo-3H-isobenzofuran-5-yl) piperazine-1-carboxylate tert-butyl (47.8 g, 150.14 mmol, 1.00 eq) hydroxide (150 mL), methanol (150 mL) and water (150 mL) Sodium hydroxide (24 g, 600 mmol, 4.00 eq) was added to the mixture. The mixture was stirred at 25 ° C. for 1 hour. The solution was adjusted to pH = 4-5 with hydrochloric acid solution (1M) and extracted with ethyl acetate (100mLx5). The organic layer was concentrated under vacuum. The crude product was pulverized in ethyl acetate: petroleum ether (450 mL, v: v = 1: 2). 4- (4-tert-Butoxycarbonylpiperazine-1-
Il) -2- (hydroxymethyl) benzoic acid (40 g, 118.91 mmol, 79% yield) was obtained as a yellow solid.

Step 5: 4- [3- (Hydroxymethyl) -4-methoxycarbonyl-phenyl] piperazine-1-carboxylate tert-butyl

TMS- in a solution of 4- (4-tert-butoxycarbonylpiperazine-1-yl) -2- (hydroxymethyl) benzoic acid (20 g, 59.46 mmol, 1.00 eq) in methanol (100 mL) and ethyl acetate (100 mL). Diazomethane (2M, 89 mL, 3.00 eq) was added at -10 ° C. The solution was stirred at -10 ° C for 0.25 hours. The solution was quenched with water (300 mL) and extracted with ethyl acetate (150 mLx3). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated. 4- [3- (Hydroxymethyl) -4-methoxycarbonyl-phenyl] piperazine-1-carboxylate tert-butyl (20.84 g, crude) was obtained as a brown oil.

Step 6: 4- [3- (bromomethyl) -4-methoxycarbonyl-phenyl] piperazine-1-carboxylate tert-butyl

In a solution of 4- [3- (hydroxymethyl) -4-methoxycarbonyl-phenyl] piperazine-1-carboxylate tert-butyl (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 mLx2). 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). 4- [3- (Bromomethyl) -4-methoxycarbonyl-phenyl] piperazine-1-carboxylate tert-butyl (12 g, 29.03 mmol, 49% yield) was obtained as a pale yellow oil.

Step 7: 4- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindoline-5-yl] piperazine-1-carboxylate tert-butyl

3-Aminopiperidin-2, in a solution of acetonitrile (300 mL) of 4- [3- (bromomethyl) -4-methoxycarbonyl-phenyl] piperazin-1-carboxylate tert-butyl (12 g, 29.03 mmol, 1.00 eq) 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) were added. The solution was stirred at 80 ° C. for 16 hours. LCMS showed that the reaction was almost complete. The reaction mixture was cooled to 20 ° C. and filtered. The solid was washed with acetonitrile (30 mL). 4- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindoline-5-yl] piperazine-1-carboxylate tert-butyl (6 g, 14 mmol, yield 48%) as a white solid I got it as a thing.

Step 8: 3- (1-oxo-5-piperazine-1-yl-isoindoline-2-yl) piperidine-2,6-
Zeon

4- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindoline-5-yl] piperazine-1-
Hydrochloride / dioxane (4 M, 100 mL, 28.57 eq) was added to a solution of tert-butyl carboxylate (6 g, 14 mmol, 1.00 eq) in dioxane (70 mL). 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 solids were collected. 3- (1-oxo-5-piperazine-1-yl-isoindoline-2-yl) piperidine-2,6-dione (5 g, 13.71 mmol, yield 98%, hydrochloride) was obtained as a white solid. ..

Step 9: 3- (5-(4-((1- (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl)
Ill) piperidine-4-yl) methyl) piperazine-1-yl) -1-oxoisoindoline-2-yl)
Piperidine-2,6-Zeon

1-(5- (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) piperidine-4-carbaldehyde (58 mg, 0.15 mmol), N-ethyl-N -Isopropylpropane-2-amine (32 mg, 0.23 mmol), 3- (1-oxo-5- (piperazine-1-yl) isoindoline-2-yl) piperidine-2,6-dione (51 mg, 0.15) A mixture of mmol) and acetic acid (0.5 ml) in methanol (4 ml) was stirred at room temperature for 30 minutes. Then, sodium cyanoborohydride (21 mg, 2.10 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 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 prep TLC (10% in dichloromethane). Purified by (eluting with methanol) to form a bright yellow solid 3-(4-((1- (5- (5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl)) Pyridine-2-yl)
Piperidine-4-yl) methyl) piperazine-1-yl) -1-oxoisoindoline-2-yl) piperidine-2,6-dione (57 mg, 53% yield) was obtained.

¹ H NMR (400 MHz, DMSO-d6): δ .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 = .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 = .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.

Scheme of synthesis of exemplary compound 128
3- (5- (4- (2- (1- (5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl))
Piperidine-4-yl) ethyl) piperazine-1-yl) -1-oxoisoindoline-2-yl) piperidine-2,6-dione

It was prepared according to the following synthetic scheme using the procedures described for compound 127.

Compound 128: ¹ H 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, 2.2 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.48 (d, J = 5.8 Hz) , 1H), 8.62 (d, J = .0 Hz, 1H), 9.33 (s, 1H), 10.95 (s, 1H). (M ⁺ H) +697.6.

Synthesis scheme of exemplary compound 130
2- (2,6-dioxopiperidine-3-yl) -5-(3- (3- (3- (4-((5- (5-methyl-5H-pyrido [4,3-b] indole) indole -7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) piperidine-1-yl) propoxy) propoxy) azetidine-1-yl) isoindoline-1,3-dione

Prepared according to the following synthetic schemes using the procedures described above and using universal procedures known to those of skill in the art.

Compound 130: ¹ H 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, 3 H), 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.

Synthesis scheme of exemplary compound 129
2- (2,6-dioxopiperidine-3-yl) -5-((1,1,1-trifluoro-6-)-(2-(2-((5- (5-methyl-5H) -Pirido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) ethoxy) ethoxy) ethoxy) hexane-2-yl) oxy) isoindoline-1,3-dione

Step 1: 6- (2- (2- (2- (5-bromopyridin-2-yloxy) ethoxy) ethoxy) ethoxy) -1,1,1-trifluorohexane-2-ol

5- (2- (2- (2- (5-bromopyridin-2-yloxy) ethoxy) ethoxy) ethoxy) pentanal (575 mg, 1.47 mmol) [Procedures described above and universally known to those of skill in the art. Prepared according to the following scheme using the procedure] and CF ₃ Si (CH ₃ ) ₃ (320 mg, 2.21 mmol) in THF was added with TBAF (1M, 2.2 mL, 2.20 mmol) at room temperature. The reaction was stirred at room temperature for 3 hours. After quenching with 1N HCl (3 mL), the mixture was extracted with EA (30 mL) and washed with brine. The organic layer was dried and concentrated under vacuum. The residue is purified by silica gel (PE: EA = 2: 1) and 6- (2- (2- (2- (5-bromopyridin-2-yloxy) ethoxy) ethoxy) ethoxy) -1,1,1 -Trifluorohexane-2-ol (400 mg, yield 60%) was obtained.

Step 2: 6- (2- (2- (2- (5-bromopyridin-2-yloxy) ethoxy) ethoxy) ethoxy) -1,1,1-trifluorohexane-2-yltrifluoromethanesulfonate

6-(2- (2- (2- (5-bromopyridin-2-yloxy) ethoxy) ethoxy) ethoxy) -1,1,1-
Tf ₂ ( O120 mg, 0.42 mmol) was added to a DCM solution of trifluorohexane-2-ol (130 mg, 0.28 mmol) and pyridine (67 mg, 0.85 mmol) at 0 ° C. The resulting solution was warmed to room temperature for 1 hour. The reaction mixture is diluted with DCM (10 mL), washed with water and brine, concentrated under vacuum, and 6- (2- (2- (2- (5-bromopyridin-2-yloxy) ethoxy) ethoxy). Ethoxy) -1,1,1-trifluorohexane-2-yltrifluoromethanesulfonate (160 mg, 96%) was obtained.

Compound 129: ¹ HNMR (400 MHz, CDCl ₃ ): 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.

Scheme of synthesis of exemplary compound 131
2- (2,6-dioxopiperidine-3-yl) -5-((17-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine-2) -Il) Oxy) -3,6,9,12,15-Pentaoxaheptadecyl) Oxy) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Using a procedure similar to that for compound 131, the following was prepared: compound 132.
Synthesis scheme of exemplary compound 133
2- (2,6-dioxopiperidine-3-yl) -5-(3-(6-((5-((5- (5- (5-methyl-5H-pyrido [4,3-b] indole-7) -Il) Pyridine-2-yl) Oxy) Pentyl) Oxy) Oxy) Hexil) Azetidine-1-yl) Isoindoline-1,3-dione

Step 1: (6- (benzyloxy) hexyl) Magnesium bromide

2 suspensions of anhydrous tetrahydrofuran (100 ml) of (((6-bromohexyl) oxy) methyl) benzene (10 g, 0.037 mol), magnesium (1.33 g, 0.055 mol) and iodine (200 mg).
Stir at 50 ° C. for hours. Iodine disappeared and the mixture was stirred for an additional hour to give (6- (benzyloxy) hexyl) magnesium bromide (crude), which was used in the next step without further purification.

Step 2: 3- (6- (benzyloxy) hexyl) -3-hydroxyazetidine-1-carboxylate tert-butyl

Magnesium bromide (6- (benzyloxy) hexyl) was added to a solution of anhydrous tetrahydrofuran (50 ml) of tert-butyl 3-oxoazetidine-1-carboxylate (5.2 g, 0.031 mol) at 0 ° C. The obtained mixture was heated 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 is collected, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is subjected to silica gel flash column chromatography (33-50% ethyl acetate in hexanes). As a colorless oil, tert-butyl 3- (6- (benzyloxy) hexyl) -3-hydroxyazetidine-1-carboxylate (1.7 g, 12% in two steps) was obtained.

Step 3: 3- (6- (benzyloxy) hexylidene) azetidine-1-carboxylate tert-butyl

1-methoxy-N-triethylammoni in a stirred solution of 3- (6- (benzyloxy) hexyl) -3-hydroxyazetidine-1-carboxylate tert-butyl (800 mg, 2.2 mmol) in toluene (10 ml). Osulfonyl-methaneimide salt (Burges reagent) (1.57 g, 6.6 mmol) was added. The resulting solution was heated to 90 ° C. and stirred at this temperature for 2 hours. Pour the mixture into water (20 mL) and pour
Extracted with ethyl acetate (20 mLx2). The organic layers were combined into one, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was subjected to silica gel flash column chromatography (30% in hexane). Purification by (eluting with ethyl acetate) gave tert-butyl 3- (6- (benzyloxy) hexylidene) azetidine-1-carboxylate (125 mg, yield 16%) as a colorless oil.

Step 4: 3- (6-Hydroxyhexyl) azetidine-1-carboxylate tert-butyl

A mixture of tert-butyl 3- (6- (benzyloxy) hexylidene) azetidine-1-carboxylate (125 mg, 0.36 mmol) and palladium carbon (10%, 50 mg) in methanol (30 ml) was added under a hydrogen atmosphere (hydrogen). Balloon), stirred for 3 hours at room temperature. TLC showed that the reaction was complete. Palladium on carbon was removed by filtration and washed with methanol (5 mlx2). The filtrates were combined and concentrated under reduced pressure to give tert-butyl 3- (6-hydroxyhexyl) azetidine-1-carboxylate (88 mg, yield: 95%) as a colorless oil.

Using tert-butyl 3- (6-hydroxyhexyl) azetidine-1-carboxylate, the above procedure and universal procedures known to those of skill in the art, the final compound 2- (2,6-dioxopiperidine-3-yl) -5-(3-(6-((5-((5- (5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) ) Pyridine-2-yl) Oxy) Pentyl) Oxy) Hexil) Azetidine-1-yl) Isoindoline-1,3-Dione was converted.

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.

Synthesis scheme of exemplary compound 134
2- (2,6-dioxopiperidine-3-yl) -5-((6- (6-(((1r, 3r) -3-((5- (5-methyl-5H-pyridone] 4,3 -b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridazine-3-yl) Hexa-5-in-1-yl) Oxy) Isoindoline-1,3-dione

Step 1: 3,6-diiodopyridazine

A mixture of 3,6-dichloropyridazine (5.0 g, 34.0 mmol) and sodium iodide (50 g, 0.68 mol) in acetone (50 ml) was stirred at 65 ° C. for 3 hours. The reaction mixture was quenched with water (100 ml) and extracted with ethyl acetate (200 mlx2). The organic layers were combined into one, washed with brine (200 mlx2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel flash column chromatography (40% acetate in hexanes). Purified by (eluting with ethyl), 3,6-diiodopyridazine as a brown solid (5.4 g, 4.9 mmol, 48% yield)
Got

Step 2: 3-Fluoro-6-iodopyridazine

A mixture of 3,6-dichloropyridazine (1 g, 3.0 mmol) and cesium fluoride (413 mg, 0.9 mol) in dimethyl sulfoxide (10 ml) was stirred at 140 ° C. overnight. Water (50 mL) the reaction mixture
And ethyl acetate (100 mL). The organic layer is collected, washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which is eluted with silica gel flash column chromatography (eluting with 20% ethyl acetate in hexanes). ) To obtain 3-fluoro-6-iodopyridazine (840 mg).

Step 3: 7-(6-((1r, 3r) -3-((6-iodopyridazine-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5-methyl-5H-pyrido [4, 3-b] Indole

(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) solution with sodium hydride (60% in mineral oil) (110 mg, 2.7 mmol) 0 Added at ° 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 mLx3). The organic layers were combined into one, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was subjected to silica gel flash chromatography (20% methanol in dichloromethane). Purified by (elution with), and as a brown solid, 7- (6-((1r, 3r) -3-((6-iodopyridazine-3-yl) oxy) cyclobutoxy) pyridine-3-yl) -5- Methyl-5H-pyrid [4,3-b] indol (70 mg, 0.13 mmol, 44% yield) was obtained.

7-(6-((1r, 3r) -3-((6-iodopyridazine-3-yl) oxy) cyclobutoxy) pyridine-3-
Il) -5-methyl-5H-pyrid [4,3-b] indole to the final compound 2- according to the following scheme using the above procedure (step 6 of compound 73 and step 1 of compound 180). (2,6-dioxopiperidine-3-yl) -5-((6- (6-(((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,3-b ] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridazine-3-yl) Hexa-5-in-1-yl) Oxy) Isoindoline-1,3-dione was converted.

Compound 134: ¹ HNMR (400 MHz, DMSO-d ₆ ): 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 = .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.

In addition, compound 149 was prepared from compound 134 using the hydrogenation procedure described above for the conversion of compounds 102-110.

Synthesis scheme of exemplary compound 145
2- (2,6-dioxopiperidine-3-yl) -5-(((2-((((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,, 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutyl) Methyl) -2-Azaspiro [3.3] Heptane-6-yl) Oxy) Butoxy) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Compound 135: ¹ H NMR (400 MHz, DMSO-d ₆ ): 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.

Synthesis scheme of exemplary compound 136
2- (2,6-dioxopiperidine-3-yl) -5-(((2-((1s, 3s) -3-((5- (5-methyl-5H-pyrido] [4,3) -b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutane-1-carbonyl) -2-azaspiro [3.3] Heptane-6-yl) Oxy) Butoxy) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Compound 136: 1H NMR (400 MHz, DMSO-d ₆ ): 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 = .8 Hz, 1H), 9.37 (s, 1H), 11.12 (s, 1H). (M + H) ⁺ 797.5.

Scheme of synthesis of exemplary compound 137
2- (2,6-dioxopiperidine-3-yl) -5-((5- (6- (methyl ((1r, 3r) -3-((5- (5-methyl-5H-pyrido]] , 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutyl) Amino) -2-
Azaspir [3.3] heptane-2-yl) -5-oxopentyl) oxy) isoindoline-1,3-dione

Step 1: Benzyl 5-hydroxypinate

Tetrahydro-2H-pyran-2-one (1 g, 10 mmol) and sodium hydroxide (400 mg, 10 mmol)
) Was stirred at 70 ° C. for 16 hours. The mixture is concentrated under reduced pressure to give a crude residue, which is dissolved in acetone (20 ml), followed by tetrabutylammonium bromide (161 mg, 0.5 mmol) and benzyl bromide (2 g, 12 mmol). It was added continuously at room temperature. The mixture was stirred at 60 ° C. for 4 hours. TLC showed that the reaction was complete. The mixture was concentrated and the residue was partitioned between ethyl acetate (30 ml) and water (50 ml). The organic layer is collected, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is subjected to silica gel flash chromatography (33-50% ethyl acetate in hexanes). (Elution with) was purified to obtain benzyl 5-hydroxypinate (500 mg, 24%) as a bright yellow solid.

Benzyl 5-hydroxypinate was added to the final compound 2- (2,6-dioxopiperidine-3-) according to the following scheme using the above procedure and universal procedures known to those of skill in the art. Il) -5-((5- (6- (methyl ((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine- 2-yl) oxy) cyclobutyl) amino) -2-azaspirio [3.3] heptane-2-yl) -5-oxopentyl) oxy) Isoindoline-1,3-dione was converted.

Compound 137: ¹ H 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.

Synthesis scheme of exemplary compound 138
5-((14-((5- (5- (difluoromethyl) -5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12 -Tetraoxatetradecyl) oxy) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione

Step 1: 5- (difluoromethyl) -7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b] indole

Sodium hydride (mineral oil) in an anhydrous N, N-dimethylformamide (6 ml) solution of 7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b] indole (500 mg, 1.90 mmol). Medium, 60%) (380 mg, 9.50 mmol) was added at 0 ° C. and the resulting mixture was stirred at room temperature for 30 minutes. Then 2-chloro-2,2-sodium difluoroacetate (580 mg, 3.80 mmol) was added, and the obtained 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 organic layers were combined into one, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel flash chromatography (50% ethyl acetate in hexanes). 5- (Difluoromethyl) -7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b] indol (35 mg, 6% yield) as a yellow solid.
) Was obtained.

5- (Difluoromethyl) -7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b] indole to the above procedure and universal procedures known to those of skill in the art. Using the following scheme, the final compound 5-((14-((5- (5- (difluoromethyl) -5H-pyrido [4,3-b] indole-7-yl) pyridin-2- Il) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) -2- (2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione was converted.

Compound 138: ¹ H 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.

Synthesis scheme of exemplary compound 139
2- (2,6-dioxopiperidine-3-yl) -5-((14-((3-fluoro-5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) ) Pyridine-2-yl) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 140
2- (2,6-dioxopiperidine-3-yl) -5-((14-((3-Methyl-5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) ) Pyridine-2-yl) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) Isoindoline-1,3-dione

Step 1: 2-Fluoro-5-iodo-3-methylpyridine

Potassium iodide (395 mg, 2.4 mmol) and iodine (306 g, 1.2 mmol) in a mixture of N, N-dimethylacetamide (10 ml) of 6-fluoro-5-methylpyridine-3-amine (300 mg, 2.4 mmol).
, Copper (I) iodide (137 mg, 0.72 mmol), and tert-butyl nitrite (1.7 g, 14.4 mmol) were added and stirred at 90 ° C. for 2 hours. Quench the reaction mixture with water (30 ml) and ethyl acetate (20 ml).
). The organic layers were combined into one, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel flash chromatography (10% ethyl acetate in hexanes). 2-Fluoro-5-iodo-3-methylpyridine (350 mg, yield 62%) was obtained as a white solid.

2-Fluoro-5-iodo-3-methylpyridine is added to the final compound 2- (2,6-, 6- Dioxopiperidine-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 was converted.

Synthesis scheme of exemplary compound 141
2- (2,6-dioxopiperidine-3-yl) -5-((6- (5-((1r, 3r) -3-((5- (5-methyl-5H-pyridole] 4,3 -b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyrimidine-2-yl) Hexa-5-in-1-yl) Oxy) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

In addition, compound 151 was prepared from compound 141 using the hydrogenation procedure described above for the conversion of compounds 102 to 110.

Synthesis scheme of exemplary compound 142
2- (2,6-dioxopiperidine-3-yl) -5-((1- (3-(5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido]] 4,3-b] Indole-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propa-2-in-1-yl) azetidine-3 -Il) Oxy) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 143
2- (2,6-dioxopiperidine-3-yl) -5-((14-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl)-6- (Trifluoromethyl) Pyridine-2-yl) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) Isoindoline-1,3-dione

Step 1: 6-Chloro-3-iodo-2- (trifluoromethyl) pyridine

Lithium diisopropylamide (2M in THF, 3.03 mmol) in THF (15 ml)
), A solution of 2-chloro-6- (trifluoromethyl) pyridine (500 mg, 2.75 mmol) in tetrahydrofuran (5 ml) was added at -65 ° C. under a nitrogen atmosphere. Dark brown solution for 30 minutes at -65 ° C
Was stirred with. A solution of iodine (0.7 g, 2.75 mmol) in tetrahydrofuran (5 ml) was added to the reaction mixture at −65 ° C. within 20 minutes. After stirring at the same temperature for another 20 minutes, the reaction mixture was quenched with hydrochloric acid (2M, 6 ml) at 0 ° C. and stirred for 20 minutes. The reaction mixture was extracted with ethyl acetate (30 mL). The organic layers were combined into one, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel flash chromatography (1% ethyl acetate in hexanes). 6-Chloro-3-iodo-2- (trifluoromethyl) pyridine (316 mg, 37% yield) was obtained as a brown solid.

6-Chloro-3-iodo-2- (trifluoromethyl) pyridine, using the above procedure and universal procedures known to those of skill in the art, according to the following scheme, the final compound 2- ( 2,6-dioxopiperidine-3-yl) -5-((14-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) -6- (trifluoro) Methyl) Pyridine-2-yl) Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) Isoindoline -1,3-Dione was converted.

Synthesis scheme of exemplary compound 146
2- (2,6-dioxopiperidine-3-yl) -5-((6- (6-(3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7) -Il) Pyridine-2-yl) Oxy) Propoxy) Pyridine-3-yl) Hexa-5-in-1-yl) Oxy) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 152
2- (2,6-dioxopiperidine-3-yl) -5-((1- (3-(5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido]] 4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Azetidine-3-yl) Oxy) Isoindoline- 1,3-Zeon

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Exemplary Compound 150 Synthesis Scheme Step 1: 2- [5- (3-benzyloxycyclobutoxy) -2,2-difluoro-pentoxy] tetrahydropyran

Sodium hydride (581 mg, 14.53 mmol, in mineral oil, 60%, 1.10 equivalent) in a solution of 3-benzyloxycyclobutanol (2.59 g, 14.53 mmol, 1.10 equivalent) in N, N-dimethylformamide (100 mL). Was added under nitrogen at 0 ° C. The mixture was stirred at 0 ° C. for 0.5 hours, (4,4-difluoro-5-tetrahydropyran-2-yloxy-pentyl) 4-methylbenzenesulfonate (5.0 g, 13.21 mmol, 1.00 equivalent) [for compound 171. A solution of N, N-dimethylformamide (20 mL) prepared as described] was added dropwise at 0 ° C. The reaction mixture was stirred for 6 hours at 60 ° C. The mixture was cooled to 25 ° C., poured into ice water (w / w = 1/1) (30 mL) and stirred for 15 minutes. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1/0, 20/1) and 2- [5- (3-benzyloxycyclobutoxy) -2,2-difluoro-pentoxy] tetrahydropyran. (1.75 g, 4.21 mmol, yield 32%, purity 92%) was obtained as a colorless oil.

Step 2: 3- (4,4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy) cyclobutanol

2- [5- (3-benzyloxycyclobutoxy) -2,2-difluoro-pentoxy] Tetrahydropyran (1.75 g, 4.55 mmol, 1.00 equivalent) in a solution of methanol (30 ml) in a palladium activated carbon catalyst (1.0 g, Purity 10%) was added under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 25 ° C. for 16 hours under hydrogen (15 psi). The reaction mixture was filtered and the filter was concentrated. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10: 1 to 1: 1) and 3- (4,4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy) cyclobutanol (1.2). g, .08 mmol, 90% yield) was obtained as a colorless oil.

Step 3: 5-bromo-2- [3- (4,4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy) cyclobutoxy] pyridine

3- (4,4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy) cyclobutanol (1.2 g, 4.08 mmol, 1.00 eq) and 5 -bromopyridine-2-ol (1.06 g, 6.12 mmol, 1.50) 1,1'-(azodicarbonyl) dipiperidine (1.54 g, 6.12 mmol, 1.50 equivalents) and tributylphosphine (1.24 g, 6.12 mmol, 1.50 equivalents) under nitrogen in a mixture of toluene (60 mL) (equivalent). , Added at 0 ° C at once. The mixture was stirred at 110 ° C. for 16 hours. The mixture was cooled to 25 ° C and concentrated at 45 ° C under reduced pressure. The residue was poured into ice water (w / w = 1/1) (30 mL) and stirred for 15 minutes. The aqueous layer was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100/1 to 50/1). 5-Bromo-2- [3- (4,4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy) cyclobutoxy] Pyridine (1.36 g, 3.02 mmol, 74.0% yield) was obtained as a yellow oil. ..

Step 4: 5- [3-[(5-bromo-2-pyridyl) oxy] cyclobutoxy] -2,2-difluoro-pentan-1-ol

5-bromo-2- [3- (4,4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy) cyclobutoxy] In a mixture of pyridine (1.1 g, 2.44 mmol, 1.00 eq) in tetrahydrofuran (25 mL) Hydrochloride (4M, 10 mL, 16.38 eq) was added at once under nitrogen. The mixture was stirred at 25 ° C. for 1 hour. The mixture was poured into saturated aqueous sodium hydrogen carbonate solution (20 mL) and stirred for 15 minutes. The aqueous layer was extracted with ethyl acetate (50 mL x 3). Brine (50mLx3) of organic layers combined into one
Washed with, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10/1, 5/1) to 5- [3-[(5-bromo-2-pyridyl) oxy] cyclobutoxy] -2,2. -Difluoro-pentane-1-ol (700 mg, 1.91 mmol, 78% yield) was obtained as a colorless oil.

Step 5: [5- [3-[(5-bromo-2-pyridyl) oxy] cyclobutoxy] -2,2-difluoro-pentyl] trifluoromethanesulfonate

5- [3-[(5-bromo-2-pyridyl) oxy] cyclobutoxy] -2,2-difluoro-pentane-1-ol (400 mg, 1.09 mmol, 1.00 eq) and triethylamine (552 mg, 5.46 mmol). , 5.00 eq) of dichloromethane (10 mL) was added trifluoromethanesulfonyl chloride (368 mg, 2.18 mmol, 2.00 eq) under nitrogen at 0 ° C. After completion of the addition, 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 [5- [3-[(5-bromo-2-pyridyl) oxy] cyclobutoxy] -2,2-difluoro-. Pentil] trifluoromethanesulfonate (465 mg, 0.93 mmol, 85% yield) was obtained as a colorless oil.

Step 6: 6- [2- (2,6-dioxo-3-piperidyl) -1,3-dioxo-isoindoline-5-yl] -2,6-diazaspiro [3.3] heptane-2-carboxylic acid tert- Butyl

2- (2,6-dioxo-3-piperidyl) -5-fluoro-isoindrin-1,3-dione (300 mg, 1.09 mmol, 1.00 eq) and 2,6-diazaspiro [3.3] heptane-2-carboxylic acid Nitrogen tert-butyl acid; N, N-diisopropylethylamine (561 mg, 4.34 mmol, 4.00 eq) in a mixture of oxalic acid (317 mg, 0.65 mmol, 0.60 eq) (methylsulfinyl) methane ( 5 mL). Below, added at once. 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 layer was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is pulverized with petroleum ether: ethyl acetate (1: 1, 50 mL) and 6- [2- (2,6-dioxo-3-piperidyl) -1,3-dioxo-isoindoline-5-yl]. Tert-butyl -2,6-diazaspiro [3.3] heptane-2-carboxylate (420 mg, 0.92 mmol, 85% yield) was obtained as a yellow solid.

Step 7: 5- (2,6-diazaspiro [3.3] heptane-2-yl) -2- (2,6-dioxo-3-piperidyl)
Isoindoline-1,3-dione

6- [2- (2,6-dioxo-3-piperidyl) -1,3-dioxo-isoindoline-5-yl] -2,6- diazaspiro [3.3 ] heptane-2 A mixture of trifluoroacetic acid (1 mL) and dichloromethane (10 mL) of tert-butyl carboxylate (420 mg, 0.92 mmol, 1.00 eq) was stirred at 25 ° C. for 1 hour under nitrogen. TLC showed that the reaction was complete. The mixture was concentrated at 45 ° C. under reduced pressure. Half-taken reverse phase HPLC (column: Phenomenex Synergi Max-RP 250 * 50mm * 10um; mobile phase: [water (0.225% FA) -ACN]; B%: 5ACN% -30ACN%, 15 minutes; 50 % Minimum), 5- (2,6-diazaspiro [3.3] heptan-2-yl) -2- (2,6-dioxo-3-piperidyl) isoindoline-1,3-dionelate ( 260 mg, 0.64 mmol, 70% yield) was obtained as a yellow solid.

Step 8: 5- [6- [5- [3-[(5-bromo-2-pyridyl) oxy] cyclobutoxy] -2,2-difluoro-pentyl] -2,6-diazaspiro [3.3] heptane-2 -Il] -2- (2,6-dioxo-3-piperidyl) isoindoline-1,3-dione

[5- [3-[(5-Bromo-2-pyridyl) oxy] cyclobutoxy] -2,2-difluoro-pentyl] trifluoromethanesulfonate (460 mg, 0.92 mmol, 1.00 eq) and 5- (2, 6-Diazaspiro [3.3] heptane-2-yl) -2- (2,6-dioxo-3-piperidyl) isoindoline-1,3-
Potassium carbonate (255 mg, 1.85 mmol, 2.00 eq) in a mixture of acetonitrile (25 mL) of dione salt (443 mg, 1.11 mmol, 1.20 eq) and (methylsulfinyl) methane (5 mL) once under nitrogen at 25 ° C. In addition to. The mixture was stirred at 25 ° C. for 10 hours. LC-MS showed that [5- [3-[(5-bromo-2-pyridyl) oxy] cyclobutoxy] -2,2-difluoro-pentyl] trifluoromethanesulfonate was completely consumed, and desired. It was shown that one main peak of MS was detected. 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 over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (petroleum ether / ethyl acetate = 1/1, 1/3) to form a yellow solid 5- [6- [5- [3-[(5-bromo-2-)). Pyridyl) oxy] cyclobutoxy] -2,2-difluoro-pentyl] -2,6-diazaspiro [3.3] heptane-2-yl] -2- (2,6-dioxo-3-piperidyl) isoindoline-1, 3-Dione (320 mg, 0.45 mmol, 49% yield) was obtained.

Step 9: 5- [6- [2,2-difluoro-5- [3-[[5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2" -Pyridil] Oxy] Cyclobutoxy] Pentil]-2.6-Diazaspiro [3.3]
Heptane-2-yl] -2- (2,6-dioxo-3-piperidyl) isoindoline-1,3-dione

5- [6- [5- [3-[(5-bromo-2-pyridyl) oxy] cyclobutoxy] -2,2-difluoro-pentyl] -2,6-diazaspiro [3.3] heptane-2-yl] -2- (2,6-dioxo-3-piperidyl) isoindrin-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 -dioxaborolan (86 mg, 0.34 mmol, 1.20 eq), potassium acetate (55 mg, 0.56 mmol, 2.00 eq), and Degas a solution of 1,1'-bis (diphenylphosphino) ferrocene-palladium (ii) dichloride dichloromethane complex (23 mg, 0.02 mmol, 0.10 eq) in dioxane (10 mL), then under nitrogen for 2 hours at 90 ° C. The heated reaction mixture was filtered and the filter was concentrated. The crude product was purified by prep-TLC (dichloromethane: methanol = 20: 1) and 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] heptane 2-Il] -2- (2,6-dioxo-3-piperidyl) isoindrin-1,3-dione (200 mg, 0.26 mmol, 94% yield) was obtained as a yellow oil.

Step 10: 5- [6- [2,2-difluoro-5- [3-[[5- (5-methylpyrido [4,3-b] indole-7-yl) -2-pyridyl] oxy] cyclobutoxy ] Pentil] -2,6-diazaspiro [3.3] heptane-2-yl] -2- (2,6-dioxo-3-piperidyl) isoindoline-1,3-dione

5- [6- [2,2-Difluoro-5- [3-[[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-"
Il) -2-pyridyl] oxy] cyclobutoxy] pentyl] -2.6-diazaspiro [3.3] heptane-2-yl] -2- (2,6-dioxo-3-piperidyl) isoindrin-1,3-dione (200 mg) , 0.26 mmol, 1.00 equivalent), 7-bromo- 5 -methyl-pyrido [4,3-b] indol (69 mg, 0.26 mmol, 1.00 equivalent), sodium carbonate (56 mg, 0.53 mmol, 2.00 equivalent), and 1 Degas a solution of N, N-dimethylformamide (5 mL) and water (0.5 mL) of a 1'-bis (diphenylphosphino) ferrocene-palladium (ii) dichloride dichloromethane complex (21 mg, 0.02 mmol, 0.10 equivalent). Then, it was heated to 90 ° C. under nitrogen for 2 hours. LCMS showed that the reaction was complete. 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 and concentrated in vacuo. The mixture was purified by half-taken reverse phase HPLC (18-48% acetonitrile + 0.225% aqueous formic acid solution, 10 minutes or longer). The collected fractions were then concentrated to remove most of acetonitrile. The solution was lyophilized. 5- [6- [2,2-difluoro-5- [3-[[5- (5-methylpyrido [4,3-b] indole-7-yl) -2-pyridyl] oxy] cyclobutoxy] pentyl] -2,6- diazaspiro [3.3] heptane-2-yl] -2- (2,6-dioxo-3-piperidyl) isoindoline-1,3-dione formate (21.6 mg, 0.02 mmol, yield 9) %, Purity 95%) was obtained as a yellow solid.

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 = .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 = .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.

Synthesis scheme of exemplary compound 153
2- (2,6-dioxopiperidine-3-yl) -5-(3- (3,3,3-trifluoro-2-yl) ((5-((1r, 3r) -3-((5-) (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pentyl) oxy) propyl) azetidine-1-yl) isoindoline-1,3 -Zeon

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

The following was prepared using the procedure for compound 153: compound 154.
Synthesis scheme of exemplary compound 155
2- (2,6-dioxopiperidine-3-yl) -5-((5-(2-((1r, 3r) -3-((5- (5-methyl-5H-pyrido]] 4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) ethoxy) Pyridine-2-yl) Oxy) Azetidine-1-yl) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 156
2- (2,6-dioxopiperidine-3-yl) -5-(3- (3-(5-((1r, 3r) -3-((5- (5-methyl-5H-pyrido]] , 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propoxy) Azetidine-1-yl) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 157
2- (2,6-dioxopiperidine-3-yl) -5-(((2-((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,3) -b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutane-1-carbonyl) -2-azaspiro [3.3] Heptane-6-yl) Oxy) Butoxy) Isoindoline-1,3-dione

Step 1: (1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutane carboxylic acid

(1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutanecarbaldehyde (70 mg, 0.20 mmol) Sodium chloride (62 mg, 0.63 mmol), sodium dihydrogen phosphate anhydride (168 mg, 1.08 mmol) and 2-methylbut-2-ene (233 mg, 3.33 mmol) in a solution of tetrahydrofuran (1 ml) and water (1 ml). Was added, and then the mixture was stirred at room temperature overnight. TLC showed that the reaction was complete. The reaction mixture is diluted with dichloromethane (20 ml), washed with water (10 mlx3), brine (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure and crude (1r, 3r) -3- ( (5- (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine-2-yl) oxy) Cyclobutanecarboxylic acid was obtained as a yellow solid.

(1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutanecarboxylic acid, described above for compound 153. 2- (2,6-dioxopiperidine-3-yl) -5-(4-((2-((1r, 3r) -3-(( 5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutane-1-carbonyl) -2-azaspiro [3.3] heptane-6-yl) Oxy) Butoxy) Isoindoline -1,3-Dione was converted to dione.

Synthesis scheme of exemplary compound 158
2- (2,6-dioxopiperidine-3-yl) -5-((6-(4-((1r, 3r) -3-((5- (5-methyl-5H-pyridone] 4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Piperidine-1-yl) Pyridazine-4-yl) Oxy) ethoxy) Isoindoline-1,3-dione

Step 1: 5- (2- (benzyloxy) ethoxy) -3-chloropyridazine

Sodium hydride (5 ml) in a stirred solution of 2- (benzyloxy) ethanol (440 mg, 2.895 mmol) and 3,5-dichloropyridazine (428 mg, 2.895 mmol) 1-methyl-2-pyrrolidinone (5 ml).
In oil, 60%) (347 mg, 8.68 mmol) was added at 0 ° C. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was quenched with an aqueous ammonium chloride solution (15 mL) at 0 ° C. and extracted with ethyl acetate (20 mLx3). The organic layer was washed with brine (20 mlx2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was silica gel flash column chromatography (eluted with 15% ethyl acetate in hexanes). Purified by 5- (2) as a light brown oil
-(Benzyloxy) ethoxy) -3-chloropyridazine (680 mg, 89% yield) was obtained.

Step 2: (1r, 3r) -3-((1- (5- (2- (benzyloxy) ethoxy) pyridazine-3-yl) piperidine-4-yl) oxy) cyclobutanol

5- (2- (benzyloxy) ethoxy) -3-chloropyridazine (240 mg, 0.910 mmol), and (1r, 3r) -3- (piperidin-4-yloxy) cyclobutanol (155 mg, 0.910 mmol) [ As described in Step 5 of Compound 65, but without the use of di-tert-butyl carbonate, (1r, 3r) -3-((1-benzylpiperidin-4-yl) oxy) cyclobutane-1- Prepared via hydrogenation of all] in a mixture of 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 cesium carbonate (739 mg, 2.27 mmol) were added under nitrogen. The mixture was then heated to 90 ° C. overnight. TLC showed that the reaction was complete. The reaction mixture was extracted with ethyl acetate (30 mLx3). The organic layer was washed with brine (10 mlx2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was silica gel flash column chromatography (eluted with 8% ethyl acetate in hexanes). (1r, 3r) -3-((1- (5- (2- (benzyloxy) ethoxy) pyridazine-3-yl) piperidin-4-yl) oxy) cyclobutanol ( 135 mg, yield 38%) was obtained.

(1r, 3r) -3-((1- (5- (2- (benzyloxy) ethoxy) pyridazine-3-yl) piperidine-4-yl) oxy) cyclobutanol can be used in the above procedure and in the art. Using universal procedures known to those of skill in the art, the final compound 2- (2,6-dioxopiperidine-3-yl) -5-(2-((6- (4- (4-( (1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidine-1- It was converted to yl) pyridazine-4-yl) oxy) ethoxy) isoindoline-1,3-dione.

Synthesis schemes for exemplary compound 159 and exemplary compound 160
2- (2,6-dioxopiperidine-3-yl) -5-((3- (5-((1s, 3s) -3-((5- (5-methyl-5H-pyrido]] 4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Azetidine-1-yl) Isoindoline- 1,3-Zeon

2- (2,6-dioxopiperidine-3-yl) -5-(3-(3-(5-((1s, 3s) -3-((5- (5-methyl-5H-pyrido]] , 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Pyridine-2-yl) Propoxy) Azetidine-1-yl) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 161
2- (2,6-dioxopiperidine-3-yl) -5-(3-(2-(2-(((1r, 3r) -3- ((5- (5-methyl-5H-) Pyrido [4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) ethoxy) ethoxy) ethoxy) Azetidine-1-yl) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

The following additional compounds were prepared based on the schematic method of compound 163 and using universal procedures known to those of skill in the art: 162, 165, 178, 181, and 182.

Synthesis schemes for exemplary compounds 165 and 166
5-((5- (1-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutane-1 -Carbonyl) piperidine-4-yl) oxy) pentyl) oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

5-((5- (1-((1s, 3s) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutane-1 -Carbonyl) piperidine-4-yl) oxy) pentyl) oxy) -2- (
2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis schemes for exemplary compounds 167 and 168
2- (2,6-dioxopiperidine-3-yl) -5-(3-((3- (5- (3-((5- (5-methyl-5H-pyrido [4,3-b]] Indole-7-yl) Pyridine-2-yl) Oxy) Propoxy) Pyridine-2-yl) Propa-2-in-1-yl) Oxy) Azetidine-1-yl) Isoindoline-1,3-dione

2- (2,6-dioxopiperidine-3-yl) -5-(3-(3-(3-((5- (5-methyl-5H-pyrido [4,3-b] indole) -7-Il) Pyridine-2-yl) Oxy) Propoxy) Pyridine-2-yl) Propoxy) Azetidine-1-yl) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 169
2- (2,6-dioxopiperidine-3-yl) -5-(3-((3-((((1r, 3r) -3-((5- (5-methyl-5H-pyrido)) [4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Methyl) Oxetane-3-yl) Methoxy) Propoxy) Azetidine-1-yl) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 174
2- (2,6-dioxopiperidine-3-yl) -5-(((3-((((1r, 3r) -3-((5- (5-methyl-5H-pyrido] [4,, 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Methyl) Bicyclo [1.1.1] Pentane-1-yl) Methoxy) Butoxy) Isoindoline-1,3-dione

Step 1: Bicyclo [1.1.1] Pentane-1,3-diyldimethanol

Lithium aluminum hydride (419 mg, 10.87 mmol) was added to a solution of dimethyl bicyclo [1.1.1] pentane-1,3-dicarboxylate (500 mg, 2,72 mmol) in tetrahydrofuran (5 ml) at 0 ° C. to obtain the product. The resulting mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction mixture was quenched with water (1 ml), sodium hydroxide (2 ml, 10% aqueous solution), and water (1 ml). The solids are removed by filtration, the filtrate is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give bicyclo [1.1.1] pentane-1,3-diyldimethanol (256 mg, crude, 70% yield). Obtained as a light yellow oil.

Bicyclo [1.1.1] pentane-1,3-diyldimethanol was added to the final compound 2- (2) according to the following scheme using the above procedure and universal procedures known to those of skill in the art. , 6-dioxopiperidine-3-yl) -5-(((3-((((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b]] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Methyl) Bicyclo [1.1.1] Pentane-1-yl) Methanol) Butoxy) Isoindoline-1,3-dione was converted.

Synthesis scheme of exemplary compound 175
2- (2,6-dioxopiperidine-3-yl) -5-((5-((3- (3-((5- (5-methyl-5H-pyrido [4,3-b]]
Indole-7-yl) Pyridine-2-yl) Oxy) Azetidine-1-carbonyl) Bicyclo [1.1.1] Pentane-1-yl) Methoxy) Pentyl) Oxy) Isoindoline-1,3-dione

Step 1: 3- (Hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylate

Lithium borohydride (120 mg, 5.43 mmol) was added to a solution of bicyclo [1.1.1] pentane-1,3-dicarboxylic acid dimethyl (1 g, 5.43 mmol) in tetrahydrofuran (10 ml) at 0 ° C. under nitrogen. .. The mixture was heated to room temperature and stirred at room temperature for 5 hours. The mixture was quenched with aqueous hydrochloric acid (1N) to pH 3-4 and extracted with dichloromethane (10 mlx2). The organic layers are grouped together, washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give a crude residue, which is subjected to silica gel flash chromatography (20-33% in hexanes). Purification by elution with ethyl acetate) gave methyl 3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylate (400 mg, 47%) as a colorless oil.

3- (Hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylate of the final compound according to the following scheme using the above procedure and universal procedures known to those of skill in the art. 2- (2,6-dioxopiperidin-3-yl) -5-((5-((3- (3-((5- (5-methyl-5H-pyrido [4,3-b] indol- 7-yl) Pyridine-2-yl) Oxy) Azetidine-1-carbonyl) Bicyclo [1.1.1
] Pentane-1-yl) methoxy) pentyl) oxy) Isoindoline-1,3-dione was converted.

Synthesis scheme of exemplary compound 176
5- (3- (3- (3-((1r, 3r) -3-((5- (8,9-difluoro-5-methyl-5H-pyridine [4,3-b] indole-7-yl) ) Pyridine-2-yl) Oxy) Cyclobutoxy) Propoxy) Propoxy) Azetidine-1-yl) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above for compound 104 (in modified order) and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 177
3- (5- (3- (3- (3- ((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine- 2-yl) oxy) cyclobutoxy) propoxy) propoxy) azetidine-1-yl) -1-oxoisoindoline-2-yl) piperidine-2,6-dione

Step 1: 5- (3-(3-(3-((1r, 3r) -3-((5- (5H-pyrido [4,3-b] indole-7-yl) -3- (trifluoro) Methyl) Pyridine-2-yl) Oxy) Cyclobutoxy) Propoxy) Propoxy) Azetidine-1-yl) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione

7-(6-((1r, 3r) -3- (3- (3- (azetidine-3-yloxy) propoxy) propoxy) cyclobutoxy) pyridin-3-yl) -5-methyl-5H-pyrido [4 , 3-b] Indol (crude, 0.390 mmol) [prepared as described for compound 104], N-ethyl-N-isopropylpropane-2-amine (86 mg, 1.17 mmol) and 2-cyano- A mixture of 1-methyl-2-pyrrolidinone (3 ml) of methyl 4-fluorobenzoate (90 mg, 0.468 mmol) was stirred for 16 hours at 90 ° C. TLC showed that the reaction was complete. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (30 ml). The organic layer is collected, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which is subjected to silica gel flash column chromatography (2-4% methanol in dichloromethane). Purified by (elution with) to form a bright yellow oil 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) azetidine-1-yl) -2- (2,6-dioxopiperidine-3-yl) iso Indoline-1,3-dione (160 mg, 61% yield) was obtained.

Step 2: 2-formyl-4- (3-(3-(3-((1r, 3r) -3-((5- (5-methyl-5H-pyridine [4,3-b] indole-7- Ill) Pyridine-2-yl) Oxy) Cyclobutoxy) Propoxy) Propoxy) Azetidine-1-yl) Methyl benzoate

2-cyano-4-(3-(3-(3-((1r,3r) -3-((5-(5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridine) -2-yl) Oxy) Cyclobutoxy) Propoxy) Propoxy) Azetidine-1-yl) Methyl benzoate (160 mg, 0.237 mmol) in a mixture of pyridine (3 ml) -water (1.5 ml) -acetic acid (1.5 ml) , Sodium diphosphate (125 mg, 1.179 mmol) and lane nickel (85% aqueous solution) (300 mg) were added at room temperature. The resulting mixture was stirred for 2 hours at 50 ° C. The mixture is diluted with ethyl acetate (30 ml), washed with water (30 mlx2), dilute hydrochloric acid solution (1N, 30 ml), brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the crude residue. It was obtained and purified by silica gel flash chromatography (eluting with 2-5% methanol in dichloromethane) to give 2-formyl-4- (3- (3-(3- ((1r, 3r)) as a brown oil. ) -3- ((5- (5-Methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) propoxy) azetidine-1-yl) Methyl benzoate (90 mg, 56% yield) was obtained.

Step 3: 3- (5-(3- (3- (3-((1r, 3r) -3-((5- (5-methyl-5H-pyridine [4,3-b] indole-7-yl) ) Pyridine-2-yl) Oxy) Cyclobutoxy) Propoxy) Propoxy) Azetidine-1-yl) -1-oxoisoindoline-2-yl) Piperidine-2,6-dione

3-Aminopiperidin-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 2-formyl-4- (3) -(3-(3-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indol-7-yl) pyridin-2-yl) oxy) cyclo A mixture of butoxy) propoxy) propoxy) azetidine-1-yl) methyl benzoate (90 mg, 0.133 mmol) in methanol (5 ml) was stirred at room temperature for 15 minutes. Sodium cyanoborohydride (16 mg, 0.400 mmol) was then added and stirred overnight at room temperature. TLC showed that the reaction was complete. 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, concentrated under reduced pressure and crude residual. The product was obtained and purified by Prep-HPLC (8% methanol in ethyl acetate) to give the title compound as a white solid (50 mg, 50% yield).

¹ H NMR (400 MHz, DMSO-d6): δ .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 = .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.

Synthesis scheme of exemplary compound 184
2- (2,6-dioxopiperidine-3-yl) -5-((7-(3-((5-(5-methyl-5H-pyrido [4,3-b] indole-7) -Il) Pyridine-2-yl) Oxy) Azetidine-1-carbonyl) Bicyclo [1.1.1
] Pentane-1-yl) heptyl) oxy) isoindoline-1,3-dione

Step 1: (6- (benzyloxy) hexyl) triphenylphosphonium bromide

A mixture of (((6-bromohexyl) oxy) methyl) benzene (2.7 g, 10 mmol) and triphenylphosphine (2.6 g, 10 mmol) in acetonitrile (10 ml) was stirred at reflux for 40 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give (6- (benzyloxy) hexyl) triphenylphosphonium bromide (5 g, 94% yield) as a colorless oil.

Step 2: Methyl 3-formylbicyclo [1.1.1] pentane-1-carboxylate

Methyl 3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylate (156 mg, 1 mmol)
Dess-Martin peryodinan (840 mg, 2.0 mmo) in a stirred solution of dichloromethane (10 ml).
l) was added at 0 ° C. The resulting reaction mixture was heated to room temperature and stirred at this temperature for an additional hour. The reaction mixture is quenched with aqueous sodium sulfite solution (10 ml), extracted with dichloromethane (20 mlx2), washed with brine (20 mlx2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue. , This was purified by silica gel flash chromatography (eluted with 20% ethyl acetate in hexane), and as a colorless oil, 3-formylbicyclo [1.1.1] methyl 3-formylbicyclo [1.1.1] pentane-1-carboxylate (110 mg, 70% yield). Got

Step 3: Methyl 3- (7- (benzyloxy) hepta-1-en-1-yl) bicyclo [1.1.1] pentane-1-carboxylate

(6- (benzyloxy) hexyl) Triphenylphosphonium bromide (373 mg, 0.70 mmol) in anhydrous tetrahydrofuran (6 ml) solution with n-butyllithium (2.5 M hexane solution) (0.28 mL, 0.7 mmol) -20 The mixture was added dropwise at ° C, and the obtained mixed solution was stirred at the same temperature for 30 minutes. A solution of methyl 3-formylbicyclo [1.1.1] pentane-1-carboxylate (90 mg, 0.58 mmol) in anhydrous tetrahydrofuran (1 ml) was added dropwise. The obtained reaction mixture was gradually 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 mlx2). The organic layers were combined into one, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel flash chromatography (10% ethyl acetate in hexanes). Purified by (eluting with), and as a colorless oil, 3- (7- (benzyloxy) hepta-1-en-1-yl) bicyclo [1.1.1] pentane-1-carboxylate methyl (56 mg, yield 29%) ) Was obtained.

Methyl 3- (7- (benzyloxy) hepta-1-en-1-yl) bicyclo [1.1.1] pentane-1-carboxylate, described above and universally known to those of skill in the art. The final compound 2- (2,6-dioxopiperidine-3-yl) -5-((7- (3- (3- ((5- (5- (5- (5- (5- (5- (5- (5- (5- (5-) 5-)
Methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) azetidine-1-carbonyl) bicyclo [1.1.1] pentane-1-yl) heptyl) oxy) isoindoline -1,3-Converted to Zeon.

Synthesis scheme of exemplary compound 185
(2S, 4R) -N- (2-(2-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) ethoxy) -4- (4) -Methylthiazole-5-yl) benzyl) -4-hydroxy-1-((S) -3-methyl-2- (1-oxoisoindoline-2-yl) butanoyl) pyrrolidine-2-carboxamide

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Using a procedure similar to that for compound 185, the following were prepared: compounds 186, 187:
, 196, 201.

Synthesis scheme of exemplary compound 193
2- (2,6-dioxopiperidine-3-yl) -5-(3- (3- (2- (6-((5- (5-methyl-5H-pyrido [4,3-b] indole) -7-Il) Pyridine-2-yl) Oxy) -2-azaspiro [3.3] Heptane-2-yl) -2-oxoethoxy) Propoxy) Azetidine-1-yl) Isoindoline-1,3-dione

Using the procedures described above, and using universal procedures known to those of skill in the art,
Prepared according to the following scheme.

Synthesis scheme of exemplary compound 195
5-((14-((5- (4-Chloro-5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy)-3,6,9, 12-Tetraoxatetradecyl) Oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

Step 1: 3-bromo-5-chloropyridin-4-amine

N-Bromosuccinimide (14.5 g, 81.67 mmol) was added to a solution of 3-chloropyridin-4-amine (10 g, 77.78 mmol) in acetonitrile (100 ml) at room temperature, and the resulting mixture was subjected to overnight under nitrogen. The mixture was stirred at 60 ° C. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (50 mlx2). The organic layers are combined, washed with brine (50 mlx2), dried over anhydrous sodium sulfate and concentrated to give a residue, which is subjected to silica gel flash chromatography (in hexanes, 20-50% ethyl acetate). Purified by elution) and used as a white solid 3-bromo-5-
Chloropyridin-4-amine (8.8 g, 54% yield) was obtained.

Step 2: 3- (4-Bromophenyl) -5-chloropyridin-4-amine

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 (diphenylphos). A mixture of dioxane (100 ml) of fino) ferrocene palladium (II) dichloride (3.5 g, 4.82 mmol) was stirred under nitrogen at 90 ° C. overnight. TLC showed that the reaction was complete. To this mixture are 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 mixed solution was stirred under nitrogen at 90 ° C. overnight. The reaction mixture is filtered, the filtrate is partitioned between ethyl acetate (100 ml) and water (100 ml), the organic layer is washed with brine (20 mlx2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was obtained and purified by silica gel flash chromatography (eluted with 20-50% ethyl acetate in hexane) as a yellow solid 3- (4-bromophenyl) -5-chloropyridin-4. -Amine (2.3 g, 34% yield) was obtained.

Step 3: 4-Azido-3- (4-bromophenyl) -5-chloropyrididine

Sodium nitrite (1.5 g, 22.0) in a solution of 2,2,2-trifluoroacetic acid (10 ml) of 3- (4-bromophenyl) -5-chloropyridin-4-amine (2.5 g, 8.8 mmol). mmol) was added at 0 ° C. for 20 minutes, 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 warmed to room temperature and stirred overnight. The reaction mixture was basicized with sodium carbonate to pH 8 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 mlx2). The organic layers were combined into one, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was subjected to silica gel flash chromatography (30% acetate in hexanes). Purification by (eluting with ethyl) gave 4-azido-3- (4-bromophenyl) -5-chloropyridine (850 mg, yield 31%) as a yellow solid.

Process 4:

Decalin (10) of 4-azido-3- (4-bromophenyl) -5-chloropyridine (850 mg, 2.75 mmol)
The mixture of ml) was stirred for 10 hours in a closed tube at 150 ° C. After cooling to room temperature, the reaction mixture was pulverized 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. It was used directly in the next step without further purification.

7-bromo-4-chloro-5H-pyridole [4,3-b] indole of the final compound according to the following scheme using the above procedure and universal procedures known to those of skill in the art. 5-((14-((5- (4-Chloro-5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy)-3,6,9, It was converted to 12-tetraoxatetradecyl) oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione.

Synthesis scheme of exemplary compound 197
5-(6-((2,2-difluoro-5-((1r,3r) -3-((5-(5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridine) -2-yl) oxy) cyclobutoxy) pentyl) oxy) -2-azaspiro [3.3] heptane-2-yl) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 199
3-((4-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) oxy) butoxy) methyl) -N-methyl-N- ((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutyl) bicyclo [1..1 ] Pentan-1-carboxamide

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 202
2-((1- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) azetidine-3-yl) methoxy) -N-methyl-N -(3-((1r, 3r) -3-((5- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propyl ) Acetamide

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 203
2-((14-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl))
Oxy) -3,6,9,12-Tetraoxatetradecyl) Oxy) -5- (5-Methyl-5H-pyrido [4,3-b] indole-7-yl) nicotinonitrile

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 207
5-((14-((5- (Benzodiazepine [4,5] imidazole [1,2-a] pyrimidine-2-yl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxa Tetradecyl) oxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

Step 1: (E) -1,1,1-trichloro-4-ethoxy-but-3-en-2-one

Ethyl vinyl ether (25 g, 346.71 mmol, 33 mL, 2 eq) was added dropwise at 0 ° C. to a solution of 2,2,2-trichloroacetyl chloride (31.52 g, 173.36 mmol, 19 mL, 1 eq). After addition
The mixture was stirred at this temperature for 5 hours, then the mixture was heated to 25 ° C. for 16 hours. The mixture was stirred under reduced pressure at 130 ° C. and the gas (hydrogen chloride) was evaporated to form a dark black solution. This process took an hour or waited until the gas was exhausted. The residue was concentrated under reduced pressure. The crude product (E) -1,1,1-trichloro-4-ethoxy-but-3-en-2-one (39.3 g, crude) was obtained as a black oil.

Step 2: 2- (Trichloromethyl) pyrimid [1,2-a] benzimidazole

(E) -1,1,1-trichloro-4-ethoxy-but-3-en-2-one (39.2 g, 180.25 mmol, 1.09 eq) and 1H-benzimidazol-2-amine (22 g, 165.23 mmol,) To a mixture of 1 equivalent) of toluene (500 mL) was added triethylamine (20.06 g, 198.27 mmol, 27 mL, 1.2 equivalent) at a time at 25 ° C. under nitrogen. The mixture was stirred at 120 ° C. for 4 hours. The mixture was cooled to 25 ° C and concentrated at 55 ° C under reduced pressure. The crude product 2- (trichloromethyl) pyrimido [1,2-a] benzimidazole (56.3 g, crude) was obtained as a brown solid.

Step 3: Pyrimid [1,2-a] benzimidazol-2-ol

2- (Trichloromethyl) pyrimido [1,2-a] benzimidazole (55.2 g, 192.64 mmol, 1 eq) in a mixture of acetonitrile (950 mL) with sodium hydroxide (10.2 g, 255.02 mmol, 1.32 eq) Aqueous solution (246 mL) was added all at once under nitrogen at 20 ° C. The mixture was stirred at 100 ° C. for 2 hours. The mixture was cooled to 25 ° C and concentrated at 55 ° C under reduced pressure. Ice was added to the resulting residue and the pH of the solution was adjusted to 8 with hydrochloric acid (1N, 130 mL). The solid was filtered and dried under high vacuum. The filter was cooled to 10 ° C. to form some precipitates, the cake was collected by filtration and concentrated under reduced pressure to give a residue. The compound pyrimido [1,2-a] benzimidazol-2-ol (9.3 g, 50.22 mmol, yield 26%) was obtained as a yellow solid to give a crude product (about 7.3 g).

Step 4: 2-bromopyrimid [1,2-a] benzimidazole

Phosphoryl in a solution of 1,1-dichloroethane (18 mL) of pyrimido [1,2-a] benzimidazol-2-ol (0.5 g, 2.70 mmol, 1 eq) and N, N-dimethylformamide (0.18 mL). Tribromid (1.55 g, 5.40 mmol, 2 eq) was added all at once under nitrogen at 20 ° C. The mixture was stirred at 100 ° C. for 6 hours. The mixture was cooled to 25 ° C and concentrated at 45 ° C under reduced pressure. The residue was poured into ice water (w / w = 1/1, 30 mL) and stirred for 10 minutes. The aqueous layer was adjusted to pH = 8 with a saturated aqueous solution of sodium bicarbonate. During this time, some precipitates were formed. The cakes were collected by filtration and dried under high vacuum. The crude product 2-bromopyrimid [1,2-a] benzimidazole (0.65 g, crude) was obtained as a yellow solid.

2-bromopyrimidin [1,2-a] benzimidazole was added to the final compound 5-((14-(14-( (5- (Benza [4,5] imidazole [1,2-a] pyrimidin-2-yl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecyl) oxy) -2 -(2,6-dioxopiperidine-3-yl) isoindoline-1,3-
Converted to Zeon.

Synthesis scheme of exemplary compound 208
2- (2,6-dioxopiperidine-3-yl) -5-(2-(2-(2-((1- (5- (5-methyl-5H-pyrido] [4,3-) b] Indole-7-yl) Pyridine-2-yl) Azetidine-3-yl) Oxy) ethoxy) ethoxy) ethoxy) ethoxy) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 209
2- (2,6-dioxopiperidine-3-yl) -5-(2-((3-((((1r, 3r) -3-((5- (5-methyl-5H-pyrido)) [4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Methyl) Bicyclo [1.1.1] Pentane-1-yl) Methoxy) ethoxy) ethoxy) Isoindoline-1,3 -Zeon

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Scheme of synthesis of exemplary compound 210
2- (2,6-dioxopiperidine-3-yl) -5-((15-(4- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) piperazine-1-) Il) -3,6,9,12-tetraoxapentadecyl) oxy) isoindoline-1,3-dione

Step 1: 4- (5-Methylpyrido [4,3-b] indole-7-yl) piperazine-1-carboxylate tert-butyl

7-bromo-5-methyl-pyrido [4,3-b] indole (1 g, 3.83 mmol, 1 eq) and piperazine-1-
In a solution of dioxane (20 mL) of tert-butyl carboxylate (2.14 g, 11.49 mmol, 3 eq) under nitrogen, (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthalene. (71 mg, 0.11 mmol, 0.03 eq), cesium carbonate (3.74 g, 11.49 mmol, 3 eq) and palladium (II) acetate (86 mg, 0.38 mmol, 0.1 eq) are added, then degassed under vacuum and nitrogen. Purged 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 mLx3). The combined organic layers were washed with 30 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1 to dichloromethane / methanol = 10/1) to obtain a crude product, and the crude product was subjected to half-taken reverse phase HPLC. (Column: Phenomenex luna C18 250 * 50mm * 10um; Mobile phase: [Water (0.225% FA) -ACN]; B%: 27% -52%, 3
Purified by 0; 79% minimum). 4- (5-Methylpyrido [4,3-b] indole-7-yl) piperazine-1-carboxylate tert-butyl (700 mg, .91 mmol, 49% yield) was obtained as a white solid.

Step 2: 5-Methyl-7-piperazine-1-yl-pyrido [4,3-b] indole

Hydrochloric acid / dioxane (700 mg, 1.91 mmol, 1 eq) in 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). 4M, 8 mL, 16.75 eq) was added and then stirred at 25 ° C. for 1 hour. TLC (dichloromethane / methanol = 10/1) showed that the starting material was completely consumed. The reaction mixture was concentrated to obtain a residue. 5-Methyl-7-piperazine-1-yl-pyrido [4,3-b] indole (580 mg, crude, HCl) was obtained as a white solid without purification.

Process 3:
5-Methyl-7-piperazin-1-yl-pyrido [4,3-b] indol (366 mg, 1.21 mmol, 1 eq, HCl) and 4- [2- [2- [2- [2- [3-] (p-tolylsulfonyloxy) propoxy] ethoxy] ethoxy] ethoxy] ethoxy] benzene-1,2-dicarboxylate dimethyl (725 mg, 1.21 mmol, 1 eq) [according to the scheme below, the procedure described above and those skilled in the art. N, N-diisopropylethylamine (626 mg, 4.84 mmol, 0.8 mL, 4 eq) was added to a solution of N, N-dimethylformamide (10 mL) prepared using universal procedures known to those of skill in the art. The mixture was stirred at 80 ° C. for 16 hours. The reaction mixture was concentrated to obtain a residue. Half-retaining reverse phase HPLC (column: Phenomenex luna C18 250 * 50mm * 10um; mobile phase: [water (0.225% formic acid) -ACN]; B%: 10% -40%, 30 minutes, 40% minimum ). 4- [2- [2- [2- [2- [3- [4- (5-methylpyrido [4,3-b] indole-7-yl) piperazine-1-yl] propoxy] ethoxy] ethoxy] ethoxy ] Ethoxy] Benzene-1,2-dicarboxylic acid dimethyl (131 mg, 0.19 mmol, yield 15%, purity 100%) was obtained as a brown oil.

Step 4: 2- (2,6-dioxopiperidine-3-yl) -5-((15- (4- (5-methyl-5H-pyrido [4,3-b]]
Indole-7-il) Piperazine-1-yl) -3,6,9,12-Tetraoxapentadecyl) Oxy) Isoindoline-1,3-dione

4- [2- [2- [2- [2- [3- [4- (5-methylpyridin [4,3-b] indol-7-yl) piperazine-1-yl] propoxy] ethoxy] ethoxy] ethoxy ] Ethoxy] Benzene-1,2-dicarboxylate dimethyl (120 mg, 0.17 mmol, 1 eq), 3-aminopiperidin-2,6-dione (142 mg, 0.86 mmol, 5 eq, HCl), and lithium iodide (347 mg). , 2.60 mmol, 15 eq) was dissolved in a microwave tube with pyridine (4 mL). The sealed tube was heated with microwaves for 2 hours at 120 ° C. The reaction mixture was concentrated to obtain a residue. Half-taken reverse phase HPLC (8-38% acetonitrile + 0.225)
Purification with aqueous% formic acid (10 minutes or longer), then the collected fractions were concentrated to remove most of acetonitrile and then lyophilized to give the crude product. The crude product was then prep-TLC (dichloromethane / methanol = 10/1), 10 mL of water and 0.2 mL of 1M hydrochloric acid, and then lyophilized to give the product. 2- (2,6-dioxopiperidine-3-yl) -5-((15-(4- (5-methyl-5H-pyrido [4,3-b] indole-7-yl) piperazine-1-) Il) -3,6,9,12-tetraoxapentadecyl) oxy) Isoindoline-1,3-dione (20 mg, 0.02 mmol, 14% yield) was obtained as an off-white solid.

¹ H 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.

Synthesis scheme of exemplary compound 211
2- (2,6-dioxopiperidine-3-yl) -5-(3- (3- (2- (6-((5- (5-methyl-5H-pyrido [4,3-b] indole) -7-Il) Pyridine-2-yl) Oxy) -2-azaspiro [3.3] Heptane-2-yl) ethoxy) Propoxy) Azetidine-1-yl) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 212
2- (2,6-dioxopiperidine-3-yl) -5-(3-(((4-((1r, 3r) -3-((5- (5-methyl-5H-pyrido)] 4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Buta-2-in-1-
Il) Oxy) ethoxy) Azetidine-1-yl) Isoindoline-1,3-dione

Step 1: tert-butyl 3- (2-ethoxy-2-oxo-ethoxy) azetidine-1-carboxylate

2-Diazo in 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 acetate (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 was not consumed. The reaction was then stirred at 25 ° C. for an additional 16 hours. Acetic acid was added to the reaction solution. The reaction was then extracted with dichloromethane (30 mLx3) and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1-8: 1) to obtain a product. Tert-butyl 3- (2-ethoxy-2-oxo-ethoxy) azetidine-1-carboxylate (2.24 g, 8.64 mmol, 50% yield) was obtained as a bright yellow oil.

Step 2: 3- (2-Hydroxyethoxy) azetidine-1-carboxylate tert-butyl

In a suspension of lithium aluminum hydride (229.51 mg, 6.05 mmol, 0.7 eq) in tetrahydrofuran (30 mL), tert-butyl 3- (2-ethoxy-2-oxo-ethoxy) azetidine-1-carboxylate (2.24 g). , 8.64 mmol, 1 eq) in tetrahydrofuran (10 mL) was added at -20 ° C. The reaction mixture was stirred for 0.5 hours at 0 ° C. Water (20 mL) was added to the reaction solution, and the organic layer was extracted with ethyl acetate (40 mLx3). The combined organic layers were then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 200/1 to 1: 1) to obtain a product. 3- (2-Hydroxyethoxy) azetidine-1-carboxylate tert-butyl (828 mg, 3.81 mmol, yield 44)
%) Was obtained as a bright yellow oil.

Step 3: 4-[(4-Methoxyphenyl) methoxy] pig-2-in-1-ol

Sodium hydride (2.32 g, 58.08 mmol, 60% in mineral oil, 60% in mineral oil, in a solution of N, N-dimethylformamide (50 mL) of buta-2-in-1,4-diol (5 g, 58.08 mmol, 1 eq). 1 equivalent) was added at 0 ° C. The mixture was stirred for 0.5 hours at 0 ° C. Then methoxybenzyl chloride (9.55 g, 60.98 mmol, 8.3 mL, 1.05 eq) was 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 solution. The solution was extracted with ethyl acetate (40 mLx3). The combined organic layers were then washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 30/1 to 3: 1) to obtain a product. 4-[(4-Methoxyphenyl) methoxy] pig-2-in-1-ol (2.64 g, 12.80 mmol, 22% yield) was obtained as a bright yellow oil.

Step 4: 1- (4-Bromobut-2-yloxymethyl) -4-methoxybenzene

A solution of 4-[(4-methoxyphenyl) methoxy] buta-2-in-1-ol (1 g, 4.85 mmol, 1 eq) and perbromomethane (1.61 g, 4.85 mmol, 1 eq) in dichloromethane (10 mL). To 3 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 resulting solution was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0-80: 1) to give the product. 1- (4-Bromobut-2-yloxymethyl) -4-methoxy-benzene (1 g, 3.72 mmol, 77% yield) was obtained as a bright yellow oil.

Final compound 2- (2,6-dioxopiperidine-3-yl) -5-(2-((4-(((1r, 3r) -3-((5- (5-methyl-5H-) Pyrido [4,3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) Buta-2-in-1-yl) Oxy) ethoxy) Azetidine-1-yl) Isoindoline-1, 3-Zeon
It was prepared according to the scheme below using the procedures described above and universal procedures known to those of skill in the art.

Synthesis scheme of exemplary compound 213
2- (2,6-dioxopiperidine-3-yl) -5-(6-(2-(2-((1r, 3r) -3-((5- (5-methyl-5H-pyrido) [4 , 3-b] Indole-7-yl) Pyridine-2-yl) Oxy) Cyclobutoxy) ethoxy) ethoxy) -2-azaspirio [3.3] Heptane-2-yl) Isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

Additional examples are expected in the context of the present invention and will be described in detail below. These can be prepared as described in the accompanying scheme, or (if specified) can be prepared using a procedure similar to the procedure described above.

Schemes for the synthesis of exemplary compounds 215 and 217 Can be prepared according to the following schemes using the procedures described above and using universal procedures known to those of skill in the art.

Alternatively, one of ordinary skill in the art will recognize that different process sequences and / or different protecting groups can be used to assemble the linkers of the examples described below. In addition, different sequences for the addition of linkers to PTM and ULM can be used for different embodiments, and optionally different sequences of linker assembly and PTM / ULM addition can be used interchangeably for a given embodiment. It can be (ie PTM addition first, then ULM addition, or ULM addition first, then PTM addition). For example, the linker of compound 216 can be assembled as shown in the scheme below.

Compound 216 can then be synthesized according to the scheme below.

Alternatively, compound 216 can be synthesized using different sequences of PTM and ULM additions according to the scheme below.

Exemplary compound 4 synthesis scheme
4-((14-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetradecyl) amino )-2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

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 = .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).

The following were prepared using the procedures described for compound 4: compound 2, compound 3, and compound 48.

Exemplary compound 7 synthesis scheme
(2S, 4R) -1-((S) -14-(4- (benzo [4,5] imidazo [1,2-a] pyrimidine-2-yl) piperazine-1-yl) -2- (tert -Butyl) -4-oxo-6,9,12-trioxa-3-azatetradecanoyl) -4-hydroxy-N-(4-(4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

¹ H NMR (400MHz, 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).

The following were prepared using the procedures described for compound 7: compound 11, compound 12, compound 15, compound 16, compound 19, compound 20, compound 23, compound 25, compound 26.

Scheme of synthesis of exemplary compound 10
(2S, 4R) -1-((S) -14-(4- (benzo [4,5] imidazo [1,2-a] pyrimidine-2-yl) piperazine-1-yl) -2- (tert -Butyl) -4,14-Dioxo-6,9,12-Trioxa-3-azatetradecanoyl) -4-Hydroxy-N-((S) -1- (4- (4-Methylthiazole-5-) Il) Phenyl) Ethyl) Pyrrolidine-2-Carboxamide

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

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).

Additional compounds were prepared using the procedures described for compound 10: 13, 14, 17, 18, 21, 22, 24, 41, 42.

Synthesis scheme of exemplary compound 43
(2S, 4R) -1-((2S) -2- (tert-butyl) -15-((2- (4- (dimethylamino) phenyl) quinoline-6-yl) oxy) -14-hydroxy-4 -Oxo-6,9,12-trioxa-3-azapentadecanoyl) -4-hydroxy-N-(4-(4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

¹ HNMR (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).

The following were prepared using the procedures described for compound 43: compound 45, compound 46, compound 47.

Exemplary compound 8 synthesis scheme
(2S, 4R) -1-((S) -2- (tert-butyl) -15-((2- (4- (dimethylamino) phenyl) quinoline-6-yl) oxy) -4-oxo-6 , 9,12-Trioxa-3-azapentadecanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

¹ HNMR (400 MHz, CD ₃ OD): δ 1.01, 1.03 (two single lines, 9H), 2.07-2.25 (m, 4H), 2.45, 2.47 (two single lines, 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 single lines, 1H).

The following were prepared using the procedures described for compound 8: compound 9, compound 27, compound 28, compound 29, compound 30, compound 31, compound 32, compound 33, compound 34, compound 35, compound 36, compound 37, compound 38, compound 39, compound 40, compound 44.

Synthesis scheme of exemplary compound 49
3- (4-((14-((5- (5H-pyrido [4,3-b] indole-7-yl) pyridin-2-yl) oxy) -3,6,9,12-tetraoxatetra Decyl) Amino) -1-oxoisoindoline-2-yl) Piperidine-2,6-dione

It was prepared according to the following scheme using the procedures described above and using universal procedures known to those of skill in the art.

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 = .4, 6.4 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J = .0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.03 (d, J = .6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.12 (dd, J = .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 Hz, 2H), 3.62-3.68 (m, 14H), 3.36 ( t, J = .6 Hz, 2H), 2.75-2.95 (m, 2H), 2.35-2.47 (m, 1H), 2.10-2.21 (m, 1H).

Compound 218 can be prepared using a procedure similar to that for compound 195.
Compound 219 can be prepared using a procedure similar to that for compound 73/180/112.

Compound 220 can be prepared using a procedure similar to that for compound 73/173.
Compound 221 can be prepared using a procedure similar to that for compound 111/127.

Compound 222 can be prepared using a procedure similar to that for compound 141/180.

Compound 223 can be prepared using a procedure similar to that for compound 102/180.

Compounds 224 and 225 can be prepared according to the following scheme.

Using the methods described above (including schematics for compounds 73, 173 and 180), compounds 226-234 are similarly prepared by using universal procedures known to those of skill in the art. Can be done.

Further, by combining these methods with the above-mentioned procedures for compounds 138, 139, 140 and 203, compounds 235 to 240 can be prepared.

Compounds 241-247 can be prepared using procedures similar to compounds 82/198 and 180.

Compounds 248-251 can be prepared based on compound 82, followed by additional linker synthesis in a manner similar to those described above and those known to those of skill in the art.

Compounds 252 to 256 can be prepared based on the methods for compounds 104, 99 and 198, and combinations thereof.

Additional Examples of compounds 257-330 can be prepared based on the basic PTM, ULM and linker methods described above and in combination with the synthesis of suitable functional and protecting groups known to those of skill in the art. ..

An exemplary PROTAC of the present disclosure can be prepared from the PTM embodiments of the present disclosure using the method for addition of the linker and E3 ligase binding moiety described above.

The exemplary PROTAC of the present disclosure is represented by the structures of Tables 1 and 2, and the data for the exemplary PROTAC are shown in Tables 2 and 3.

* Each compound was tested at 1000 nM, 300 nM, and 100 nM as described in paragraph [1162].
For each compound, the highest degradation observed at any donation is shown in Table 1 below: A: Tau protein ≤ 50% remaining after 72 hours incubation with the test compound; B: with the test compound. Tau protein remaining after 72 hours of incubation ≤ 80% and>50%; C: Tau protein remaining after 72 hours of incubation with the test compound>80%;

* Each compound was tested at 300 nM, 100 nM, 33 nM, and 11 nM as described in paragraph [1162]. For each compound, the highest degradation observed at any donation is shown in Table 2 below: A: Tau protein ≤ 50% remaining after 72 hours incubation with the test compound; B: With the test compound. Tau protein remaining after 72 hours of incubation ≤ 80% and>50%; C: Tau protein remaining after 72 hours of incubation with the test compound>80%;
Tau Protein In Vitro Degradation Assay To determine the efficacy of PROTAC for tau protein degradation, SK-N-SH cells were seeded in 24-well tissue culture treated plates for at least 18 hours prior to compound addition. Table 1 shows 1000nM, 300nM and 100nM tau PROTAC, while Tables show 300nM, 100nM, 33nM and 11nM.
Tau PROTAC was evaluated for tau degradation by lysing cells in a protease inhibitor-containing lysis buffer after 72 hours of incubation with Tau PROTAC. Cytolysis was run on standard SDS-PAGE gels and tau levels were detected by Western blotting using Abcam's (Cambridge, UK) Tau-13 antibody that binds to all types of human tau. For each compound, the highest degradation observed at any donation is shown in Tables 1 and 2 above.

In vivo degradation of tau protein In Experiment 21, male BI6 wild-type mice were divided into seven groups of three, and vehicle ECP-1 ([pH 7.4 phosphate buffer, 5% EtOH and 5% Cremophore RH40]; A. Group; single treatment by bilateral hippocampal infusion with compound 4 tau PROTAC ([3 μL of 1 mg / mL ECP-1 solution]; groups BG; see Figure 1)). After injecting the test substance or vehicle as shown in Figure 1, all animals were slaughtered at specific time points and brain samples were collected. The hippocampus was resected and total tau levels were measured using the Meso Scale Discovery assay kit. The results are shown in Figure 1.

Specific Embodiments The embodiments of the present disclosure provide a bifunctional compound having the following chemical structure, or a pharmaceutically acceptable salt thereof, a mirror image isomer, a stereoisomer, a solvate, a polymorph or a prodrug. Do: ULM-L-PTM,
During the ceremony:
ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to E3 ubiquitin ligase;
PTM is a tau protein targeting moiety; and
L is the bond or chemical linking moiety that connects ULM and PTM.

In any of the embodiments or embodiments described herein, the E3 ubiquitin ligase binding moiety targets E3 ubiquitin ligase selected from the group consisting of von Hippel-Lindow (VLM) and Cereblon (CLM).

In any embodiment or embodiment described herein, the PTM is represented by the formulas I, II, III, IV, V, VI, VII, VIII, IX, X, or XI:

During the ceremony:
A, B, C, D, E, and F are independently substituted 5- or 6-membered aryl or heteroaryl rings, optionally substituted 4- to 7-membered cycloalkyl or heterocyclo. Selected from alkyl, the contact moieties between the rings indicate ring fusion; and the _LPTM is selected from bond, alkyl, alkenyl or alkynyl, optionally one or more rings (ie cycloalkyl, heterocycloalkyl, Aryl or heteroaryl) or interrupted by one or more functional groups, the functional group being -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) Selected from NH-, -NHC (O) O-, or -OC (O) NH-, in the formula,
The functional group is optionally located at any end of the linker.

In any aspect or embodiment described herein, at least one of A, B, C, F, or a combination thereof, is an optionally substituted 5- or 6-membered aryl ring or heteroaryl ring. Is selected from.

In any of the embodiments or embodiments described herein, the rings A, B, C, D, and E of the PTM (eg, aryl and heteroaryl rings) are alkyl, alkenyl, haloalkyl, halogen, hydroxyl, etc. Optionally substituted with 1-8 substituents independently selected from alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluomethyl, and cyano, the alkyl and alkenyl groups are included in the formula. Is further optionally replaced.

In any embodiment or embodiment described herein, the PTM is Formula I, and:
Rings A, B and C are independently 5- or 6-membered fused aryl or heteroaryl rings;
L _PTM is selected from bound or alkyl; and
D is selected from 6-membered aryl, heteroaryl or heterocycloalkyl,
In the formula, A, B, C and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl, or cyano.

In any embodiment or embodiment described herein, the PTM is Formula I, and:
A and C are phenyl or 6-membered heteroaryl rings;
B is a 5-membered heteroaryl ring;
L _PTM is a bond; and
D is a 6-membered heteroaryl or a 6-membered heterocycloalkyl ring,
In the formula, each of A, B, C and D is optional and is independently substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, trifluoromethyl, or cyano, where A, B, The nitrogen atom of either the C or D ring is not directly attached to the heteroatom or carbon atom, to which another heteroatom is directly added.

In any embodiment or embodiment described herein, the PTM is formula III or IV, and:
A, B and C are 5- or 6-membered fused aryl or heteroaryl rings;
L _PTM is selected from bound or alkyl; and
D and E are 5- or 6-membered fused aryl or heteroaryl rings;
In the formula, A, B, C, D and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl, or cyano.

In any embodiment or embodiment described herein, PTM is represented by a chemical structure selected from the group consisting of:

During the ceremony:
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 is one or two substituents independently selected from H, methyl, ethyl and halogen.

In any embodiment or embodiment described herein, PTM is represented by a chemical structure selected from the group consisting of:

During the ceremony:
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 are selected independently of H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino, trifluoromethyl, or cyano. 1 to 8 substituents.

In any embodiment or embodiment described herein, PTM is represented by a chemical structure selected from the group consisting of:

In any aspect or embodiment described herein, ULM is a von Hippel-Lindow (VHL) ligase binding moiety (VLM) represented by the following structure:

During the ceremony:
X ¹ and X ² are independently selected from the group of binding, O, NR ^Y3 , CR ^Y3 R ^Y4 , C = O, C = S, SO, and SO ₂ ;
R ^Y3 and R ^Y4 are independently selected from the group of H, straight or branched C _1-6 alkyl, which are optionally substituted with one or more halos, C _1-6 alkoxyls;
R ^P are 1, 2 or 3 groups, each independently selected from the group of H, halo, -OH, C _1-3 alkyl;
W ³ is optionally substituted-TN (R ^1a R ^1b ), optionally substituted-TN (R ^1a R ^1b ) X ³ , -T-aryl, optionally substituted-T-heteroaryl, Arbitrarily substituted -T-heterocycle, optionally substituted-NR ¹ -T-aryl, optionally substituted -NR ^{1 -T-heteroaryl, or optionally substituted -NR 1 -T-} Selected from a group of heterocycles;
X ³ is C = O, R ¹ , R ^1a , R ^1b ;
R ¹ , R ^1a , and R ^1b are independent, H, linear or branched C ₁ -C ₆ alkyl groups, R ^{Y 3} C = optionally substituted by one or more halo or -OH groups. 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 ) Selected from the group consisting of SO ₂ ;
T is selected from the group of optionally substituted alkyl,-(CH ₂ ) _n -groups, where each one of the methylene groups in the formula is optional with a halogen, a methyl, one or more halogens or a -OH group. A linear or branched C ₁ -C ₆ alkyl group substituted with, or optionally substituted with one or two substituents selected from the group of optionally substituted amino acid side chains;
n is 0-6;
W ⁴

And;
R _{14a and} R _14b are independently selected from the group of H, haloalkyl, or optionally substituted alkyl;
W ⁵ is selected from the group of phenyl or 5-10 membered heteroaryls; and
R ₁₅ can be replaced with 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 . Alkyl to be substituted, haloalkyl optionally substituted, haloalkoxy optionally substituted; selected from the group of aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl;
In the formula, the dashed line indicates the binding site of the chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM' to ULM.

In any aspect or embodiment described herein, ULM is a von Hippel-Lindow (VHL) ligase binding moiety (VLM) represented by the following structure:

During the ceremony:
W ³ is optionally substituted aryl, optionally substituted heteroaryl, or

Selected from the group of;
R ₉ and R ₁₀ are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or ₉ , R ₁₀ , and the carbon atoms to which they bond form cycloalkyls that are optionally substituted;
R ₁₁ is optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

Selected from the group of;
R ₁₂ is selected from the group of H or optionally substituted alkyl;
R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optional Selected from a group of (heterocyclyl) carbonyls substituted with, or optionally substituted aralkyl;
R _{14a and} R _14b are independently selected from the group of H, haloalkyl, or optionally substituted alkyl;
W ⁵ is selected from the group of phenyl or 5- to 10-membered heteroaryl;
R ₁₅ can be replaced with 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 . Alkyl to be substituted, haloalkyl optionally substituted, haloalkoxy optionally substituted; selected from the group of aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl (each independently and optionally substituted);
R ₁₆ is independently selected from the group of H, halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;
o is 0, 1, 2, 3, or 4;
R ₁₈ is independently selected from the group of halos, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or linkers; and
p is 0, 1, 2, 3, or 4, and in the equation, the dashed line indicates at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM'to ULM. The binding site of the chemical linker moiety to be bound is shown.

In any of the embodiments or embodiments described herein, ULM has a chemical structure selected from the group consisting of:

During the ceremony:
R ₁ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl. , Or haloalkyl;
R _14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;
R ₁₅ is H, halogen, CN, OH, NO _2, optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted halo. Selected from the group consisting of alkoxy, cycloalkyl, or cycloheteroalkyl;
X is C, CH ₂ , or C = O; and
R ₃ is a 5- or 6-membered heteroaryl that is bound or optionally substituted.
In the formula, the dashed line indicates the binding site of the chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM' to ULM.

In any embodiment or embodiment described herein, ULM comprises a group according to the following chemical structure:

During the ceremony:
R _14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;
R ₉ is H;
R ₁₀ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
R ₁₁ is

Or a heteroaryl optionally substituted;
p is 0, 1, 2, 3, or 4;
Each R ₁₈ is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or linker;
R ₁₂ is H, C = O;
R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optional A (heterocyclyl) carbonyl substituted with, or an 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;

In the formula, the dashed line indicates the binding site of the chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM' to ULM.

In any aspect or embodiment described herein, ULM comprises a group selected from the structure consisting of:

Here, the phenyl rings of ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9 are optionally fluorine, lower alkyl, and alkoxy groups. Substituted with, where the dashed line indicates the binding site of the chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM' to ULM-a.

In any aspect or embodiment described herein, ULM is a thalidomide, lenalidomide, pomalidomide, analog thereof, an isostar thereof, or a derivative thereof, a cereblon ligase binding moiety (CLM).

In any aspect or embodiment described herein, the CLM has the chemical structure represented by:

During the ceremony:
W is selected from the group consisting of CH ₂ , CHR, C = O, SO ₂ , NH and N-alkyl;
Each X is selected independently 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-hetaryl, 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 H, alkyl (linear, branched chain optionally substituted with R'), OH, R'OCOOR, R'OCONRR ", optionally substituted with R'CH ₂ -Selected from the group consisting of heterocyclyls, and optionally benzyls substituted with R';
Q ₁ , Q ₂ , Q ₃ and Q ₄ represent carbon C substituted with a group independently selected from R', N or N-oxides;
A is independently selected from the group of H, alkyl, cycloalkyl, Cl and F;
R is -CONR'R ", -OR', -NR'R", -SR', -SO ₂ R', -SO ₂ NR'R ", -CR'R"-, -CR'NR'R "-, -aryl, -hetalyl, -alkyl (optionally substituted linear, branched chain), -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',-
Includes S (C = O) (C = N-R') R ”, -SF ₅ , or -OCF ₃ ;
R'and R'are independent, bonded, H, N, N-oxide, alkyl (straight chain, branched chain), cycloalkyl, aryl, heteroaryl, heterocyclic, -C (= O) R, Or selected from the group consisting of heterocyclyls, each of which is optionally substituted;

Represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and R _n comprises a functional group or atom.
In the formula, n is an integer from 1 to 4, and in the formula,
If n is 1, R _n is modified to be covalently attached to the linker group (L), and
If n is 2, 3, or 4, one R _n is modified to be covalently attached to the linker group (L), and any other R _n is optional with PTM, CLM, CLM. It is modified to be covalently attached to a second CLM, CLM', a second linker, or any plurality or combination thereof having the same chemical structure.

In any aspect or embodiment described herein, the CLM has the chemical structure represented by:

During the ceremony:
W was selected independently from the group consisting of CH2, C = O, NH and N-alkyl;
R is independently selected from H, methyl, alkyl;

Represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific; and Rn contains 1 to 4 independently selected functional groups or atoms, and is optional. One of them is modified to be covalently attached to PTM, chemical linker group (L), CLM (or CLM') or a combination thereof.

In any aspect or embodiment described herein, the CLM has the chemical structure represented by:

The dashed line indicates the linker binding point.
In any embodiment or embodiment described herein, the linker (L) comprises a chemical structural unit represented by the following formula:
-(A) _q- ,
During the ceremony:
A is the group linked to the ULM or PTM moiety; and
q is an integer greater than or equal to 1
In the equation, A is the bond, CR ^L1 R ^L2 , O, S, SO, SO ₂ , NR ^L3 , SO ₂ NR ^L3 , SONR ^L3 , CONR ^L3 , NR ^L3 CONR ^L4 , NR ^L3 SO ₂ NR ^L4 , CO, CR ^L1 = CR ^L2 , C≡C, SiR ^L1 R ^L2 , P (O) R ^L1 , P (O) OR ^L1 , NR ^L3 C (= NCN) NR ^L4 , NR ^L3 C (= NCN), NR ^L3 C (= CNO ₂ ) NR ^L4 , C _3-11 cycloalkyl optionally substituted with 0-6 R ^L1 and / or R ^L2 , with 0-6 R ^L1 and / or R ^L2 Optionally substituted C _3-11 heterocyclyl, optionally substituted with 0-6 R ^L1 and / or R ^L2 , optionally with 0-6 R ^L1 and / or R ^L2 Selected from the group consisting of the heteroaryls to be substituted, in the formula, R ^L1 or R ^L2 are independently and arbitrarily attached to each other, and are optionally substituted with 0 to 4 R ^L5 groups and / or a cycloalkyl moiety. Or form a heterocyclyl moiety;
R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are independently H, halo, C _1-8 alkyl, OC _1-8 alkyl, SC _1-8 alkyl, NHC _1-8 alkyl, N ( C _1-8 alkyl) ₂ , C _3-11 cycloalkyl, aryl, heteroaryl, C _3-11 heterocyclyl, OC _1-8 cycloalkyl, SC _1-8 cycloalkyl, NHC _1-8 cycloalkyl, N (C) _1-8 cycloalkyl) ₂ , N (C _1-8 cycloalkyl) (C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P (O) (OC _1-8 alkyl) ) (C _1-8 alkyl), P (O) (OC _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH = CH (C _1-8 alkyl), C (C _1-8 alkyl) ) = CH (C _1-8 alkyl), C (C _1-8 alkyl) = C (C _1-8 alkyl) ₂ , Si (OH) ₃ , Si (C _1-8 alkyl) ₃ , Si (OH) (C _1-8 alkyl) ₂ , COC _1-8 alkyl, CO ₂ H, halogen, CN, CF ₃ , CHF ₂ , CH ₂ F, NO ₂ , SF ₅ , SO ₂ NHC _1-8 alkyl, SO ₂ N (C _1-8 alkyl) ₂ , SONHC _1-8 alkyl, SON (C _1-8 alkyl) ₂ , CONHC _1-8 alkyl, CON (C _1-8 alkyl) ₂ , N (C _1-8 alkyl) CONH (C _1-8 alkyl), N (C _1-8 alkyl) CON (C _1-8 alkyl) ₂ , NHCONH (C _1-8 alkyl), NHCON (C _1-8 alkyl) ₂ , NHCONH ₂ , N ( C _1-8 alkyl) SO ₂ NH (C _1-8 alkyl), N (C _1-8 alkyl) SO ₂ N (C _1-8 alkyl) ₂ , NH SO ₂ NH (C _1-8 alkyl), NH SO ₂ N (C _1-8 alkyl) ₂ , NH SO ₂ NH ₂ .

In any embodiment or embodiment described herein, the linker (L) comprises a group represented by a general structure selected from the group consisting of:
-N (R)-(CH ₂ ) _m -O (CH ₂ ) _n -O (CH ₂ ) _o -O (CH ₂ ) _p -O (CH ₂ ) _q -O (CH ₂ ) _r -OCH _2- ,
-O- (CH ₂ ) _m -O (CH ₂ ) _n -O (CH ₂ ) _o -O (CH ₂ ) _p -O (CH ₂ ) _q -O (CH ₂ ) _r -OCH _2- ,
-O- (CH ₂ ) _m -O (CH ₂ ) _n -O (CH ₂ ) _o -O (CH ₂ ) _p -O (CH ₂ ) _q -O (CH ₂ ) _r -O- ；
-N (R)-(CH ₂ ) _m -O (CH ₂ ) _n -O (CH ₂ ) _o -O (CH ₂ ) _p -O (CH ₂ ) _q -O (CH ₂ ) _r -O-;
-(CH ₂ ) _m -O (CH ₂ ) _n -O (CH ₂ ) _o -O (CH ₂ ) _p -O (CH ₂ ) _q -O (CH ₂ ) _r -O-;
-(CH ₂ ) _m -O (CH ₂ ) _n -O (CH ₂ ) _o -O (CH ₂ ) _p -O (CH ₂ ) _q -O (CH ₂ ) _r -OCH _2- ;

In the equation, each m, n, o, p, q, and r are 0, 1, 2, 3, 4, 5, and 6, respectively, respectively.
However, if the number is zero and there are no NO or OO bonds, then R is selected from the group H, methyl or ethyl, and X is selected from the group H or F;

In any of the embodiments or embodiments described herein, the linker (L) is selected from the group consisting of:

In any of the embodiments or embodiments described herein, the linker (L) is selected from the group consisting of:

In the equation, each n and m are independently 0, 1, 2, 3, 4, 5, or 6.
In any of the embodiments or embodiments described herein, L comprises the following chemical structures:

During the ceremony:
W ^L1 and W ^L2 are independent and optionally substituted with RQ, with 0-4 heteroatoms 4
It is an 8-membered ring, and each RQ is independently H, halo, OH, CN, CF3, C1-C6 alkyl (optionally substituted straight chain, branched chain), C1-C6 alkoxy (optionally). Is it a straight chain, a branched chain) to be replaced?
Or two RQ groups, together with the atom to which they bind, form a 4- to 8-membered ring system containing 0-4 heteroatoms;
Each Y ^L1 is independently bonded, C1-C6 alkyl (optionally substituted linear, branched chain), and optionally one or more C atoms are O, or C1-C6 alkoxy (optional). Substituted with (straight, branched); and dashed lines indicate the point of attachment to the PTM or ULM moiety.

In any of the embodiments or embodiments described herein, L comprises the following chemical structures:

During the ceremony:
W ^L1 and W ^L2 are independently aryl, heteroaryl, cyclic, heterocyclic, C _1-6 alkyl, bicyclic, biaryl, biheteroaryl, or dihypocyclic, and each is optionally R. Substituted with ^Q , each R ^Q is independently H, halo, OH, CN, CF ₃ , hydroxyl, nitro, _C≡CH , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl (Optionally substituted linear, branched chain), C1 _- C ₆ alkoxy (optionally substituted linear, branched chain), OC _1-3 alkyl (optionally substituted by one or more -Fs) ), OH, NH ₂ , NR ^Y1 R ^Y2 , CN, or 4-8 members in which 2 R ^Q groups contain 0-4 heteroatoms, along with the atoms to which they are attached. Form a ring system;
Y ^L1 is independently coupled, NR ^YL1 , O, S, NR ^YL2 , CR ^YL1 R ^YL2 , C = O, C = S, SO, SO ₂ , C ₁ -C ₆ alkyl (optionally substituted) Straight chain, branched chain), and optionally one or more C atoms are substituted with O, C ₁ -C ₆ alkoxy (optionally substituted straight chain, branched chain);
Q ^L is a 3- to 6-membered alicyclic or aromatic ring with 0 to 4 heteroatoms, optionally crosslinked, optionally replaced by 0 to 6 R ^Q , and each R ^Q. Are independently H, C _1-6 alkyl (linear, branched, optionally substituted with one or more halos, C _1-6 alkoxyls), or two R ^Q groups Form a 3- to 8-membered ring system containing 0 to 2 heteroatoms with the atoms to which they bond); R ^YL1 and R ^YL2 are independently H, OH, and C _1-6 alkyl. (Linear, branched, optionally substituted with one or more halos, C _1-6 alkoxyls), or R ¹ , R ² are 0 to 2 with the atom to which they are attached. Forming a 3- to 8-membered ring system containing heteroatoms of);
n is 0-10; and
The dashed line indicates the point of connection to the PTM or ULM moiety.

In any embodiment or embodiment described herein, L is a polyethyleneoxy group optionally substituted with aryl or phenyl, containing 1-10 ethylene glycol units.

In any embodiment or embodiment described herein, a compound comprises a plurality of ULMs, a plurality of PTMs, a plurality of linkers, or any combination thereof.

In any of the embodiments or embodiments described herein, the compound is selected from the group consisting of compounds 1-33 (Table 1 or Table 2).

In any of the embodiments or embodiments described herein, the compound is selected from Table 1 or Table 2 (ie, selected from Compounds 1-330).

In any of the embodiments or embodiments described herein, the compound has a chemical structure selected from the formulas CI-CV below:

During the ceremony:
R ¹⁰¹ is one or two substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;
R ¹⁰² is selected from H, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl;
R ¹⁰³ is one or two substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;
R ¹⁰⁴ is one or two substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;
R ¹⁰⁵ is one or two substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;
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 are independent of each other. And choose from H, alkyl, halogen or haloalkyl;
R ¹⁰⁸ is one or two 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 are together with the carbon atom to which they are attached, for example 3 to such as cyclopropane or oxetane. Represents a 6-membered cycloalkyl or heterocycloalkyl ring;
R ¹²⁴ and R ¹²⁵ are independently selected from H, alkyl, halogen or haloalkyl, or R ¹²⁴ and R ¹²⁵ , together with the carbon atom to which they are attached, such as cyclopropane or oxetane 3 ~ Represents a 6-membered cycloalkyl or heterocycloalkyl ring;
G is a phenyl, or 5- or 6-membered heteroaryl ring; and
Z is CH ₂ or C = O.

A further aspect of the present disclosure provides a composition comprising an effective amount of the bifunctional compound of the present disclosure and a pharmaceutically acceptable carrier.

In any aspect or embodiment described herein, the composition is at least one of the additional bioactive agents, another bifunctional compound of any one of claims 1-29. , Or combinations thereof.

In any embodiment or embodiment described herein, the additional bioactive agent is an anti-neurodegenerative agent.

In any embodiment or embodiment described herein, the additional bioactive agent is a P-gp inhibitor.

In any of the embodiments or embodiments described herein, the P-gp inhibitor is amiodarone, azithromycin, captopril, and the like.
Clarithromycin, Cyclosporine, Piperine, Quercetin, Quinidine, Quinine,
Reserpine, Ritonavir, Tariquidar, Elacridar or Verapamil.

Another aspect of the present disclosure is to provide a composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound of the present disclosure for treating a disease or disorder in a subject. The method comprises administering the composition to a subject in need thereof, wherein the compound is effective in treating or ameliorating at least one symptom of the disease or disorder.

In any aspect or embodiment described herein, the disease or disorder is associated with tau accumulation and aggregation.

In any aspect or embodiment described herein, the disease or disorder is a neurodegenerative disease associated with tau accumulation and aggregation.

In any aspect or embodiment described herein, the disease or disorder is acquired epileptic aphagia, acute diffuse encephalomyelitis, ADHD, Addy pupil, Addy syndrome, adrenal leukodystrophy, cerebral bridge defect, Disapproval, Aicardi Syndrome, AIDS-Neurologic Complications, Alexander's Disease, Alpers Syndrome, Pediatric Alternate Hemiplegia, Alzheimer's Disease, Muscle Atrophic Lateral Sclerosis, Aencephalopathy, Aneurysm, Angelman Syndrome, Hemangiomas Symdrome, anoxia, aphrodisiac, asthma, spider cyst, spider inflammation, Arnoldchiari malformation, arteriovenous malformation, Asperger syndrome, ataxia, ataxia, capillary dilatation, ataxia and cerebral degeneration / spinal cord degeneration , Attention deficiency-hyperactivity disorder, autism, autonomic dysfunction, back pain, Bath syndrome, Batten's disease, Beckermyotny, Bechet's disease, bell paralysis, benign essential eyelid spasm, benign localized muscle atrophy , Benign intracranial hypertension, Bernhardt's syndrome, Binswanger's disease, eyelid spasm, Brochsartsburger's syndrome, arm plexus delivery trauma, traumatic arm neuropathy, pure autonomic imbalance, brain and spinal cord tumor, cerebral aneurysm, Brain trauma, Brown Sekar syndrome, bulbar spinal muscle atrophy, canavan disease, carpal canal syndrome, causalgia, cavernoma, spongy hemangiomas, spongy vascular malformations, central cervical spinal cord syndrome, central spinal cord syndrome, central Sexual pain syndrome, head disorder, cerebral degeneration, cerebral dysplasia, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral leg qi, cerebral giant disease, cerebral hypoxia, cerebral paralysis, brain-eye-face-skeletal Syndrome, Sharcomary Tooth disease, Chiari malformation, butoh disease, spinous erythrocyte butoh disease, chronic inflammatory demyelinating polyneuritis (CIDP), chronic orthostatic hypotension, chronic pain, cocaine syndrome type II, coffin lorry syndrome, COFS, cerebral beam defect, coma and persistent vegetative state, complex local pain syndrome, congenital bilateral facial nerve palsy, congenital myasthenia, congenital myopathy, congenital Vascular Cavernous, malformation, cerebral Cortical basal nucleus degeneration, head arteritis, skull fusion, Kreuzfeld-Jakob disease, cumulative trauma disease, Cushing syndrome, giant cell encapsulation, cytomegalovirus infection, Opsocronus myocronus syndrome, Dandy-Walker syndrome , Dawson's disease, Domorcia's syndrome, deep brain stimulation therapy for Parkinson's disease, arm plexus neuropathy, dementia, multiple infarct dementia, semantic dementia, subcortical dementia, Levi -Body dementia, myoclonic cerebral collaborative contractile dysfunction, dentate nucleus erythema atrophy, dermatitis, developmental Dyspraxia, Devic's disease, diabetic neuropathy, diffuse sclerosis, autonomic nerves Ataxia, writing disorders, reading disorders, swallowing disorders, integrated movement disorders, myoclonic joint movement disorders, progressive cerebral joint movement disorders, dystonia, early infantile epileptic encephalopathy, Turkish saddle cavity syndrome, drowsiness encephalitis, cerebral hernia , Encephalopathy, myoclonus hematoma, epilepsy, superior and inferior paralysis, elve paralysis,
Fabry's disease, Farr's disease, fainting, familial autonomic imbalance, familial hemangiomas, familial basal nucleus calcification, familial periodic paralysis, familial spastic paralysis, febrile spasm, Fisher syndrome, floppy infant syndrome, Friedrich's ataxia, frontotemporal dementia, Gaucher's disease, Gerstmann's syndrome, Gerstmann-Stroisler-Scheinker's disease, giant cell arteritis, giant cell inclusion body disease, globoid cell leukodystrophy, lingual neuropathy, Gillan Valley Syndrome, Hallerfolden-Spatz's disease, head injury, headache, persistent unilateral headache, unilateral facial spasm, alternate hemiplegia, hereditary neuropathy, hereditary spastic vs. paralysis, polyneuritis-type hereditary dysfunction, Herpes zoster, otral zoster, Hirayama syndrome, Holmes Addy syndrome, total anterior encephalopathy, HTLV-1-related myelopathy, Huntington's disease, hydrocephalus, hydrocephalus, normal pressure hydrocephalus, hydromyelopathy, hyperactivity, adrenal cortex Hyperactivity, hypersleep, hypertonia, hypotension-infant, hypoxia, immune-mediated encephalomyelitis, inclusion myositis, pigmentation, pediatric muscle tone hypotonia, pediatric neuroaxial dystrophy, pediatric phytan Acid storage, pediatric Leftham's disease, pediatric spasm, inflammatory myopathy, posterior foramen cerebral prolapse, enteric lipopostrophy, intracranial cyst, increased intracranial pressure, Isaac syndrome, Jubert syndrome, Keene's-Seyah syndrome, Kennedy's disease, Opso Kronus-Myokronus Syndrome (Kinsbourne syndrome), Kleine-Levin Syndrome, Klipel-File Syndrome, Klippel-Trenone-Weber Syndrome (KTS), Kluber-Beaucy Syndrome, Korsakov Oblivion Syndrome, Krabbe's Disease, Kugelberg-Wellander's Disease, Cool -, Lambert-Eaton Myasthenia Syndrome, Landow Clefner Syndrome, Lateral Femoral Skin Nervous Stranglement, Lateral Marrow Syndrome, Learning Disorders, Lee's Disease, Lennox-Gastow Syndrome, Resh-Naihan Syndrome, Cerebral White White Atrophy, Levine-Critchley Syndrome , Levy body dementia, lipid accumulation, cerebral circumflexion, confinement syndrome, Lou Gehrig's disease, erythema plaque-nervous type, sequelae, Lime's disease-nervous type, complications, Machad-Joseph's disease, encephalopathy, Manic disease, giant encephalomyelopathy, Mercerson-Rosenthal syndrome, meningitis, meningitis and encephalitis, Menquez's disease, dyssensitivity femoral nerve pain, atypical, cerebral white atrophy, small head disease, migraine, Millerfisher Syndrome, mild stroke, mitochondrial myopathy, Bius Syndrome, Hirayama Disease, Motor Neurological Disease, Moyamoya Disease, Mucolipidoses, Mucopolyglycosis, Multifocal Exercise Neuropathy, Multiple Infarct Dementia, Multiple Sclerosis, Multiline Atrophy, Orthostatic Hypotension Accompanied by polyline atrophy, muscular dystrophy, myasthenia-congenital, severe myasthenia, medullary shedding diffuse sclerosis, pediatric myochrony encephalopathy, myocronus, myopathy, myopathy-congenital, myopathy-thyroid addiction, myotney , Congenital myotney, Narcolepsy, Neurospinous erythema, Neurodegeneration with accumulation of iron in the brain, Neurofibromatosis, Nerve-relaxing drug-induced malignant syndrome, AIDS nervous system complications, Lime disease nervous system complications, Effects of cytomegalovirus infection on the nervous system, signs of the nervous system of Pompe's disease, sequelae of the nervous system of erythema plaque, optic neuromyelitis, neuromuscular tonicity, neuroceroid atrophy, nerve Cell migration disorders, neuropathy-hereditary, neurosarcoidosis, neurotoxicity, spongy vein homozygous plaque (Nevus Cavernosus), Niemannpic disease, normal pressure hydrocephalus, occipital neuropathy, obesity, split spinal cord, Otawara syndrome, Olive Bridge cerebral atrophy , Eyeball myoclonus, orthostatic hypotension, O'Sullivan-McLeod Syndrome, overuse syndrome, pain-chronic, pain, pantothenate kinase-related neurodegeneration, tumor-associated syndrome, sensory impairment, Parkinson's disease, Paroxysmal butoh atetose, paroxysmal migraine, hemi-facial atrophy, Peritzus-Merzbacher's disease, Penashocker syndrome type II, perineuronal cyst, periodic limb palsy, terminal neuropathy, periventricular leukomalacia, protracted Plant status, diffuse developmental disorders, phytanoic acid accumulation, Pick's disease, misplacement, pear muscle syndrome, pituitary tumor, polymyositis, Pompe's disease, encephalopathy, post-herpes neuropathy, post-infection encephalomyelitis, polio Post-syndrome, orthostatic hypotension, sothostatic tachycardia syndrome, orthostatic tachycardia syndrome, primary Dentatum Atrophy, primary lateral sclerosis, primary progressive aphrodisiac, prion disease , Progressive hemi-facial atrophy, Progressive gait dyskinesia, Progressive multifocal leukoencephalopathy, Progressive sclerosing polyojistrophy, Progressive nuclear paralysis, Facial disability, Pseudo-brain tumor, Ramsey Hunt syndrome I ( Past names), Ramsey Hunt Syndrome II
(Past names), Rasmussen's encephalitis, reflex sympathetic dystrophy syndrome, Leftham's disease, Leftham's disease-pediatric type, repetitive motility disorder, repetitive hypermotor injury, itchy leg syndrome, retrovirus-related myelopathy, Let's syndrome, Rye's syndrome , Relay-Day Syndrome, Sacral Nerve cyst, Butoh Disease, Salivary Gland Disease, Sandhoff's Disease, Sylder's Disease, Fissure Encephalopathy, Zeiterberger's Disease, Paroxysmal Disease, Semantic Dementia, Dichotomy, Swaying Syndrome, herpes zoster, Scheidlager syndrome, Schegren syndrome, sleep aspiration syndrome, African sleep disease, Sotos disease, spasm, dichotomy, spinal cord infarction, spinal cord injury, spinal cord tumor, spinal muscle atrophy, spinal cerebral atrophy, Spinal cerebral degeneration, Steel-Richardson-Orszevsky syndrome, Stiffperson syndrome, striatal melanosis, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, SUNCT headache SUNCT Headache Swallowing
Disorders), Sidenum butoh disease, fainting, plum toxic spinal sclerosis, spinal water cavities, spinal cavities, systemic erythema cyst, spinal cord epilepsy, late-onset dyskinesia, tarob cysts, Teisax disease, temporal arteritis, Tethered spinal cord syndrome, Thomsen's Myotonia, thoracic outlet syndrome, thyroid addictive myopathy, trigeminal nerve pain, Todd palsy, Turret syndrome, transient cerebral ischemic attack, transmissible spongy encephalopathy, transverse myelitis, trauma Sexual brain injury, tremors, trigeminal nerve pain, tropical spastic deficiency vs. paralysis, nodular sclerosis, vasculitis erectile Tumor, vasculitis-induced temporal arteritis (Vasculitis including Temporal Arteritis), von Hippel-Lonicitis Diseases, Von Hippel-Lindou's Disease (VHL), Von-Lecklinghausen's Disease, Wallenberg Syndrome, Weldnig-Hoffmann's Disease, Welnicke-Korsakov's Syndrome, West Syndrome, Whiplash, Whipple's Disease, William's Syndrome, Wilson's Disease, X-Chain Sphere Spinal muscle atrophy, or Zelberger syndrome.

In any aspect or embodiment described herein, the disease or disorder is Huntington's disease, muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten's disease, spinal cord and brain injury, paroxysmal disorder, epilepsy, brain tumor, medullary membrane. Flames, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, muscular atrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulas, headaches, memory disorders, peripherals It is a neuropathy with at least one of neuropathy, post-herpes zoster neuropathy, spinal cord tumors, and stroke.

In any aspect or embodiment described herein, the disease or disorder is Alzheimer's disease.

Claims (33)

A bifunctional compound having the following chemical structure, or a pharmaceutically acceptable salt thereof :
ULM-L-PTM,
During the ceremony:
(A) The L is a binding or chemical linking moiety that connects ULM and PTM;
(B) The ULM is a cereblon E3 ubiquitin ligase binding moiety (CLM) represented by the following chemical structure ;

put it here,
W is CH ₂ , CHR, C = O, SO ₂ , NH, or N-alkyl;
Each X is selected independently of non-existence, O, and S;
Y is CH ₂ , -C = CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, or S;
Z is non-existent, O, or S;
G and G'independently substituted with H, R', linear or branched chain alkyl, OH, R'OCOOR, R'OCONRR ", optionally substituted with R'CH ₂ -heterocyclyl , And optionally a benzyl substituted with R';
Each of Q ₁ , Q ₂ , Q ₃ , and Q ₄ is independently N, CH, or CR;
A is H, alkyl, cycloalkyl, Cl or F;
n is 1, 2, 3, or 4,
R is -CONR'R ", -OR', -NR'R", -SR', -SO ₂ R', -SO ₂ NR'R ", -CR'R"-, -CR'NR'R "-, -Aryl, -Hetaryl, -Optionally substituted linear or branched alkyl, -Cycloalkyl, -Herocyclyl, -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 ; where 1 The two Rs are covalently attached to the chemical link that binds CLM to PTM;
R'and R'are independently bonded, H, NH, N-oxide, optionally substituted linear or branched chain alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally Selected from substituted heteroaryls and optionally substituted heterocyclyls;

Represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific; and
(C) The PTM is a tau protein target portion represented by the following formula (I).

During the ceremony:
Rings A, B, C, and D are independently selected from 5- or 6-membered aryls, 5- or 6-membered heteroaryls, and 4- to 7-membered cycloalkyls, where between the rings. The contact portion of the ring indicates ring fusion, where ring A, ring B, ring C, and ring D are each optionally substituted with 1-8 substituents, where each substituent is independently alkyl, alkoxy. , Haloalkyl, halogen, hydroxy, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, and cyano,;
L _PTMs are selected from bonds, alkyl, alkenyl, and alkynyl, respectively -O-, -S-, -NR ¹ _PTM- , -N = N-, -S (O)-, -SO ₂ -, -C (O)-, -NHC (O)-, -C (O) NH-, -NHSO _2- , -NHC (O) NH- , -NHC (O) O-, or -OC (O) ) Arbitrarily interrupted by one or more functional groups selected from NH-, where the functional group is optionally positioned at any end of the L _PTM in the formula;
R ¹ _PTM is a bifunctional compound or pharmaceutically acceptable salt thereof, selected from H or alkyl. One or more of rings A, B, and C are optionally substituted with 1-8 substituents 5- or 6-membered aryls or 1-8 substituents optionally substituted heteroaryl. Where each substituent is independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxy, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, and cyano. Item 1 The compound according to Item 1. Rings A, B, and C are independently 5- or 6-membered aryls or 5- or 6-membered heteroaryls;
L _PTM Is a bond or alkyl; and
Ring D is a 6-membered aryl, a 6-membered heteroaryl or a 6-membered heterocycloalkyl.
In the formula, each of ring A, ring B, ring C and ring D is arbitrarily substituted, where each substituent is independently alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, tri. The compound according to claim 1, which is fluoromethyl or cyano. Rings A and C are phenyl or 6-membered heteroaryl;
Ring B is a 5-membered heteroaryl;
L _PTM Is a bond; and
Ring D is a 6-membered heteroaryl or a 6-membered heterocycloalkyl,
In the formula, each of ring A, ring B, ring C and ring D is optionally substituted, where each substituent is independently alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, trifluoromethyl, Or cyano, where any nitrogen atom of ring A, ring B, ring C and ring D is not directly attached to a heteroatom or carbon atom, where another heteroatom is directly attached. The compound according to claim 1, which is added. The PTM is represented by a chemical structure selected from the group consisting of:

During the ceremony:
R ¹ Is 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 ^Ten Represents 1 to 8 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino, trifluoromethyl, or cyano, respectively. , The compound according to claim 1. The compound according to claim 1, wherein the PTM is represented by a chemical structure selected from the following:

The compound according to any one of claims 1 to 6, wherein the CLM has a chemical structure represented by the following.

The CLM has the chemical structure represented by:

During the ceremony:
W is CH ₂ , C = O, NH, or N-alkyl;
A is H, methyl, or alkyl;

Represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; the compound of any one of claims 1-6. The CLM has the chemical structure represented by:

put it here,

Is the compound according to any one of claims 1 to 6, indicating the bonding point of the chemical linking moiety that binds CLM to PTM. The chemically linked portion (L) contains a chemical structural unit represented by the following formula:
-(A ^L ) _{q q} -,
During the ceremony:
-(A ^L ) _{q q} -Is a group linked to ULM and PTM; and
q is an integer greater than or equal to 1
In the formula, each A ^L Is CR ^L1 R ^L2 , O, S, SO, SO ₂ , NR ^L3 , SO ₂ NR ^L3 , SONR ^L3 , CONR ^L3 , NR ^L3 CONR ^L4 , NR ^L3 SO ₂ NR ^L4 , CO, CR ^L1 = CR ^L2 , C≡C, SiR ^L1 R ^L2 , P (O) R ^L1 , P (O) OR ^L1 , NR ^L3 C (= NCN) NR ^L4 , NR ^L3 C (= NCN), NR ^L3 C (= CNO ₂ ) NR ^L4 , 1-6 R ^L1 And / or R ^L2 C that is optionally replaced by the group _3-11 Cycloalkyl, 1-6 R ^L1 And / or R ^L2 C that is optionally replaced by the group _3-11 Heterocyclyl, 1-6 R ^L1 And / or R ^L2 Aryl optionally substituted with a group, and 1-6 R ^L1 And / or R ^L2 Selected independently of the heteroaryl optionally substituted with the group, in the formula, R ^L1 Or R ^L2 Are independently and arbitrarily combined with each other, with 1 to 4 Rs ^L5 Forming cycloalkyl and / or heterocyclyl moieties that are optionally substituted with a group; and
R ^L1 , R ^L2 , R ^L3 , R ^L4 And R ^L5 Are 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 _3-8 Cycloalkyl, SC _3-8 Cycloalkyl, NHC _3-8 Cycloalkyl, N (C _3-8 Cycloalkyl) ₂ , N (C _3-8 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, CN, CF ₃ , CHF ₂ , CH ₂ F, NO ₂ ,SCIENCE FICTION _Five , 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 , Or NHSO ₂ NH ₂ The compound according to any one of claims 1 to 9. Each A ^L Is CR ^L1 R ^L2 , O, NR ^L3 , CONR ^L3 , CO, CR ^L1 = CR ^L2 , C≡C, 1-6 R ^L1 And / or R ^L2 C that is optionally replaced by the group _3-11 Cycloalkyl, 1-6 R ^L1 And / or R ^L2 C that is optionally replaced by the group _3-11 Heterocyclyl, 1-6 R ^L1 And / or R ^L2 Aryl optionally substituted with a group, and 1-6 R ^L1 And / or R ^L2 Selected independently of the heteroaryl optionally substituted with the group, in the formula, R ^L1 Or R ^L2 Are independently and arbitrarily combined with each other, with 1 to 4 Rs ^L5 Forming cycloalkyl and / or heterocyclyl moieties that are optionally substituted with a group;
R ^L1 , R ^L2 , R ^L3 , R ^L4 And R ^L5 Are independently H, Halogen, C _1-8 Alkyl, OC _1-8 Alkyl, NHC _1-8 Alkyl, N (C _1-8 Alkyl) ₂ , OH, NH ₂ , CCH, CO ₂ H, CN, CF ₃ , CHF ₂ , CH ₂ F, or NO ₂ The compound according to claim 10. The chemically connected portion is

-N (R)-(CH ₂ ) _m -O (CH) ₂ ) _n -O (CH) ₂ ) _{o o} -O (CH) ₂ ) _p -O (CH) ₂ ) _{q q} -O (CH) ₂ ) _r -OCH ₂ -,
-O- (CH ₂ ) _m -O (CH) ₂ ) _n -O (CH) ₂ ) _{o o} -O (CH) ₂ ) _p -O (CH) ₂ ) _{q q} -O (CH) ₂ ) _r -OCH ₂ -,
-O- (CH ₂ ) _m -O (CH) ₂ ) _n -O (CH) ₂ ) _{o o} -O (CH) ₂ ) _p -O (CH) ₂ ) _{q q} -O (CH) ₂ ) _r -O-;
-N (R)-(CH ₂ ) _m -O (CH) ₂ ) _n -O (CH) ₂ ) _{o o} -O (CH) ₂ ) _p -O (CH) ₂ ) _{q q} -O (CH) ₂ ) _r -O-;
-(CH ₂ ) _m -O (CH) ₂ ) _n -O (CH) ₂ ) _{o o} -O (CH) ₂ ) _p -O (CH) ₂ ) _{q q} -O (CH) ₂ ) _r -O-;
-(CH ₂ ) _m -O (CH) ₂ ) _n -O (CH) ₂ ) _{o o} -O (CH) ₂ ) _p -O (CH) ₂ ) _{q q} -O (CH) ₂ ) _r -OCH ₂ -;

It is a group represented by the structure selected from
put it here,
The R of the chemically linked moiety is H, methyl or ethyl,
The X in the chemically linked moiety is an H or F group, and
Each m, n, o, p, q, and r of the chemical link is independently 0, 1, 2, 3, 4, 5, or 6, but if the number is zero. , No N-O bond or O-O bond,
The compound according to any one of claims 1 to 10. The chemical connection part is

The compound according to any one of claims 1 to 11, which is selected from the above. The chemical linking part is selected from:

The compound according to any one of claims 1 to 11, wherein each n and m of the chemically linked moiety is 0, 1, 2, 3, 4, 5, or 6 independently. The chemical connection part is

During the ceremony:
W ^L1 And W ^L2 Is a 4- to 8-membered ring with 0-4 heteroatoms, each independently and optionally substituted with RQ, and each RQ is independently H, halogen, OH, CN, CF. ₃ , Arbitrarily substituted straight chain or branched chain C1-C6 alkyl, optionally substituted linear or branched chain C1-C6 alkoxy, or two RQ groups with the atom to which they are attached. Together they form a 4- to 8-membered ring system containing 0-4 heteroatoms;
Each Y ^L1 Are independently bonded, optionally substituted linear or branched chain C1-C6 alkoxy, or optionally substituted linear or branched chain C1-C6 alkyl, and optionally one or more Cs. Atoms are replaced with O;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10,

Is the compound according to any one of claims 1 to 10, which indicates a binding point to PTM or ULM. The chemical connection part is

During the ceremony:
W ^L1 And W ^L2 Are independently aryl, heteroaryl, cyclic, heterocyclic, C _1-6 Alkyl, bicyclic, biaryl, biheteroaryl, or bicyclic, each optionally substituted with RQ, each RQ independently H, halogen, OH, NH ₂ , NR ^Y1 R ^Y2 , CN, CF ₃ , Hydroxy, Nitro, C≡CH, C _2-6 Alkenyl, C _2-6 Alkinyl, optionally substituted linear or branched chain C ₁ -C ₆ Alkyl, optionally substituted linear or branched chain C ₁ -C ₆ Alkoxy, OC optionally replaced by one or more -Fs _1-3 Alkyl or two RQ groups, together with the atom to which they are attached, form a 4- to 8-membered ring system containing 0-4 heteroatoms;
Each Y ^L1 Independently join, NRY ^L1 , O, S, NRY ^L2 , CRY ^L1 RY ^L2 , C = O, C = S, SO, SO ₂ , Arbitrarily substituted straight chain or branched chain C ₁ -C ₆ It is alkyl, and optionally one or more C atoms are substituted with O;
Q ^L Is a 3- to 6-membered alicyclic or aromatic ring with 0 to 4 heteroatoms, optionally crosslinked, and optionally 0 to 6 Rs. ^Q Replaced by each R ^Q Are independently H, optionally one or more halogens, or C _1-6 Linear or branched chain C substituted with alkoxyl _1-6 Alkyl or 2 R ^Q The groups form a 3- to 8-membered ring system containing 0 to 2 heteroatoms with the atoms to which they bond;
RY ^L1 And RY ^L2 Are independently H, OH, optionally one or more halogens or C _1-6 Linear or branched chain C substituted with alkoxyl _1-6 Alkyl or RY ^L1 , RY ^L2 Form a 3- to 8-membered ring system containing 0 to 2 heteroatoms with the atoms to which they bond;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

Is the compound according to any one of claims 1 to 10, which indicates a binding point to PTM or ULM. The compound according to any one of claims 1 to 10, wherein the chemically linked moiety is a polyethyleneoxy group optionally substituted with aryl or phenyl, which comprises 1 to 10 ethylene glycol units. The compound is

The bifunctional compound of claim 1, which is selected from, or is a pharmaceutically acceptable salt thereof. The compound is

The compound according to claim 1, which is selected from, or is a pharmaceutically acceptable salt thereof. The compound is

The compound according to claim 1, which is selected from, or is a pharmaceutically acceptable salt thereof. The compound is

The compound according to claim 1, which is selected from, or is a pharmaceutically acceptable salt thereof. The compound has a chemical structure selected from the following formulas CI-CV:

During the ceremony:
R ¹⁰¹ Is one or two substituents independently selected from H, alkyl, halogen, haloalkyl and cyano;
R ¹⁰² Is selected from H, alkyl, haloalkyl, cycloalkyl and heterocycloalkyl;
R ¹⁰³ Is one or two substituents independently selected from H, alkyl, halogen, haloalkyl and cyano;
R ¹⁰⁴ Is one or two substituents independently selected from H, alkyl, halogen, haloalkyl and cyano;
R ¹⁰⁵ Is one or two substituents independently selected from H, alkyl, halogen, haloalkyl and cyano;
R ¹⁰⁶ , R ^{107 107} , R ¹⁰⁹ , R ^{110 110} , R ¹¹¹ , R ^{112 112} , R ¹¹³ , R ^{114 114} , R ¹¹⁶ , R ^{117 117} , R ¹²⁰ , R ¹²¹ , R ¹²⁶ , R ^{127 127} , R ¹²² And R ^{one two three} Are independently selected from H, alkyl, halogen and haloalkyl;
R ¹⁰⁸ Is one or two substituents independently selected from H, alkyl, halogen, haloalkyl, cyano and methoxy;
R ^{115 115} Is selected from H, alkyl and haloalkyl;
R ¹¹⁸ And R ¹¹⁹ Are independently selected from H, alkyl, halogen and haloalkyl, or R ¹¹⁸ And R ¹¹⁹ Represents a 3- to 6-membered cycloalkyl or heterocycloalkyl ring, together with the carbon atom to which they bond;
R ¹²⁴ And R ¹²⁵ Are independently selected from H, alkyl, halogen and haloalkyl, or R ¹²⁴ And R ¹²⁵ Represents a 3- to 6-membered cycloalkyl or heterocycloalkyl ring, together with the carbon atom to which they bond;
G is a phenyl, or 5- or 6-membered heteroaryl ring; and
Z is CH ₂ Or the compound according to claim 1, wherein C = O. A composition comprising the bifunctional compound according to any one of claims 1 to 22 and a pharmaceutically acceptable carrier. 23. The composition of claim 23, further comprising at least one additional bioactive agent. 24. The composition of claim 24, wherein the additional bioactive agent is an anti-neurodegenerative agent. 25. The composition of claim 25, wherein the additional bioactive agent is a P-gp inhibitor. The P-gp inhibitors include Amiodarone, Azithromycin, Captopril, Clarithromycin, Cyclosporine, Piperine, Quercetin, and Quinidine. ), Quinine, Reserpine, Ritonavir, Tariquidar, Elacridar or Verapamil, according to claim 26. Includes a pharmaceutically acceptable carrier for use in a method of treating a disease or disorder associated with tau in a subject, and an effective amount of at least one compound according to any one of claims 1-22. A composition, wherein the method comprises administering the composition to a subject in need thereof, wherein the compound causes degradation of tau protein, thereby treating at least one symptom of the disease or disorder. Or a composition that improves. 28. The composition of claim 28, wherein the disease or disorder is associated with tau accumulation and aggregation. 28. The composition of claim 28 or 29, wherein the disease or disorder is a neurodegenerative disease associated with tau accumulation and aggregation. The disease or disorder is acquired epileptic aphagia, acute diffuse encephalomyelitis, ADHD, Adie's pupil, Adie's syndrome, adrenal leukodystrophy, cerebral canal defect, dementia, Icardi's syndrome, AIDS-neurological complications. , Alexander's disease, Alpers syndrome, pediatric alternating hemiplegia, Alzheimer's disease, muscular atrophic lateral sclerosis, encephalopathy, aneurysm, Angelman syndrome, hemangiomatosis, anoxia, aphrodisiac, asthma, spider membrane cyst , Spider membrane inflammation, Arnold Chiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, ataxia, capillary dilatation, ataxia and cerebral degeneration / spinal cerebral degeneration, attention deficit-hyperactivity disorder, autism, autonomy Neurological dysfunction, back pain, Bath syndrome, Batten's disease, Beckermiotony, Bechet's disease, Bell paralysis, benign essential eyelid spasm, benign localized muscle atrophy, benign intracranial hypertension, Bernhardt's syndrome, Binswanger's disease, Eyelid spasm, Blochsalzberger syndrome, arm plexus delivery trauma, traumatic arm plexus palsy, pure autonomic dysfunction, brain and spinal cord tumors, cerebral aneurysms, brain trauma, Brown Sekar syndrome, bulbar spinal muscle atrophy , Kanaban's disease, carpal canal syndrome, causalgia, spongy tumor, spongy hematoma, spongy vascular malformation, central cervical spinal cord syndrome, central spinal cord syndrome, central pain syndrome, head disorder, cerebral degeneration, cerebral formation Insufficiency, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral leg dysfunction, cerebral giant disease, cerebral hypoxia, cerebral paralysis, brain-eye-face-skeletal syndrome, Charcomary Tooth disease, Chiari malformation, butoh disease, yes Spinal erythroid butoh disease, chronic inflammatory demyelinating polyneuritis (CIDP), chronic orthostatic hypotension, chronic pain, cocaine syndrome type II, coffin lorry syndrome, COFS, ridge defect, coma and persistent phytostate, complex Sexual local pain syndrome, congenital bilateral facial nerve palsy, congenital myasthenia, congenital myopathy, congenital Vascular Cavernous, malformation, cerebral cortical basal nucleus degeneration, head arteritis, skull fusion , Kreuzfeld-Jakob disease, accumulated trauma disease, Cushing syndrome, giant cell inclusion body disease, cytomegalovirus infection, Opsocronus-myoclonus syndrome, Dandy-Walker syndrome, Dawson's disease, Domorcia syndrome, deep brain stimulation therapy for Parkinson's disease , Arm plexus neuropathy, dementia, multiple infarct dementia, semantic dementia, subcortical dementia, Levy body dementia, myochronous cerebral collaborative contractile abnormalities Syndrome, Dental Nucleus Red Nucleus Atrophy, Dermatitis, Developmental Dyspraxia, Devic Disease, Diabetic Neuropathy, Diffuse Sclerosis, Autonomic Ataxia, Writing Disorders, Reading Disorders, Swallowing Disorders, Integration Motor Disorders, Myocronus Co-motor Disorders, Progressive Cerebral Co-motor Disorders, Gistonia, Early Infant Epilepsy Encephalopathy, Turkish Saddle Cavity Syndrome, Drowsiness Encephalitis, Brain Hernia, Encephalopathy, Cerebral Trifurcation Neural Hemangiomatosis, Epilepsy, Top Type and subtype paralysis, Elb paralysis, Fabry's disease, Far's disease, fainting, familial autonomic imbalance, familial hemangiomas, familial basal nucleus calcification, familial periodic paralysis, familial spastic paralysis, febrile spasm , Fisher Syndrome, Flop Infant Syndrome, Friedrich Ataxia, Frontotemporal Dementia, Gaucher's Disease, Gerstmann's Syndrome, Gerstmann-Stroisler-Scheinker's Disease, Giant Cell Artitis, Giant Encapsulation, Globoid cell leukodystrophy, lingual neuropathy, Gillan Valley syndrome, Hallerfolden-Spatz disease, head injury, headache, persistent unilateral headache, unilateral facial spasm, alternate hemiplegia, hereditary neuropathy, hereditary spastic vs. palsy, Polyneuritis hereditary dysfunction, herpes zoster, ear herpes zoster, Hirayama syndrome, Holmes Addy syndrome, total anterior encephalopathy, HTLV-1-related myelopathy, Huntington's disease, hydroencephalopathy, hydrocephalus, normal pressure hydrocephalus, Hydromyelopathy, hyperactivity, hyperadrenal cortex, hypersomnia, hypertonia, hypotension-infant, hypoxia, immune-mediated encephalomyelitis, encapsulation myitis, dyschromia, pediatric muscle tone hypotonia , Pediatric Neuroaxial Dystrophy, Pediatric Phytanic Acid Accumulation, Pediatric Leftam Disease, Pediatric Convulsions, Inflammatory Myopathy, Posterior Foramen Cerebral Prolapse, Enteric Lipipostrophy, Intracranial Fossil, Intracranial Pressure Increase, Isaac Syndrome, Jubert Syndrome, Keens -Sair-Syndrome, Kennedy's Disease, Opsocronus-Myocronus Syndrome (Kinsbourne syndrome), Kleine-Levin Syndrome, Klipel-File Syndrome, Klippel-Trenone-Weber Syndrome (KTS), Kluber-Beaucy Syndrome, Korsakov Oblivion Syndrome, Krabbe's Disease , Kugelberg-Welander's Disease, Cool-, Lambert-Eaton Muscle Incompetence Syndrome, Landow-Klefner Syndrome, Lateral Femoral Skin Nerve Stranglement, Lateral Marrow Syndrome, Learning Disorders, Lee's Disease, Lennox-Gastau Syndrome, Resh-Naihan Syndrome, Cerebral white atrophy, Levine-Critchley Syndrome, Levy Body Dementia, Lipid Accumulation, Brain Circular Deficiency, Confinement Syndrome, Lou Gehrig's Disease, Red spot wolf-nervous, sequelae, Lime's-nervous, complications, Machad-Joseph's disease , Cerebral encephalopathy, manic disease, giant encephalomyelopathy, Mercerson-Rosenthal syndrome, meningitis, meningitis and encephalitis, Menquez's disease, dysesthesia femoral nerve pain, metachromatic, cerebral white atrophy, small head disease, piece Headache, Millerfisher Syndrome, Mild Stroke, Mitochondrial Myopathy, Mobius Syndrome, Hirayama Disease, Motor Neurological Disorders, Moyamoya Disease, Mucolipidoses, Mucopolyglycosis, Multifocal Exercise Neuropathy, Multiple Infarct Dementia, Multiple Sclerosis, multisystem atrophy, multisystem atrophy with orthostatic hypotension, muscular dystrophy, myasthenia-congenital, severe myasthenia, medullary shedding diffuse sclerosis, myochrony encephalopathy in children, myocronus, myopathy Of Nervous system complications, Lime's disease nervous system complications, cytomegalovirus infections affecting the nervous system, signs of Pompe's nervous system, sequelae of erythema pyorrhea, optic neuromyelitis, neurogenic Muscle tonic, neuroseloid lipochlorination, nerve cell migration disorder, neuropathy-hereditary, neurosarcoidosis, neurotoxicity, spongy vein syndrome (Nevus Cavernosus), Niemannpick's disease, normal pressure hydrocephalus, occipital neuropathy, Obesity, split spinal cord, Otawara syndrome, Olive Bridge cerebral atrophy, eyeball myocronus, orthostatic hypotension, O'Sullivan-McLeod Syndrome, overuse syndrome, pain-chronic, pain, pantothenate kinase-related nerves Degeneration, tumor-associated syndrome, sensory impairment, Parkinson's disease, paroxysmal butoh atetose, paroxysmal migraine, hemi-facial atrophy, Periceus-Merzbacher's disease, Penashocker syndrome type II, perineuronal cyst, periodic limb palsy, Terminal neuropathy, periventricular leukomalacia, persistent vegetative state, diffuse developmental disorder, phytanoic acid accumulation, Pick's disease, misplacement, pear muscle syndrome, pituitary tumor, polymyositis, Pompe's disease, foramen Encephalopathy, post-herpes nerve pain, post-infection encephalomyelitis, post-polio syndrome, orthostatic hypotension, orthostatic tachycardia syndrome, orthostatic tachycardia syndrome, primary Primary Dentatum Atrophy, Primary lateral sclerosis, Primary progressive aphrodisiac, Prion's disease, Progressive hemilateral facial atrophy, Progressive gait ataxia, Progressive polyfocal leukoencephalopathy , Progressive sclerosing polyojistrophy, Progressive hepatic palsy, Facial disability, Pseudo-brain tumor, Ramsey Hunt syndrome I (past name), Ramsey Hunt syndrome II (past name), Rasmussen encephalitis, Reflex sympathetic dystrophy syndrome , Leftham's disease, Leftham's disease-pediatric, repetitive motility disorder, repetitive hyperinjury, itchy leg syndrome, retrovirus-related myelopathy, Let's syndrome, Rye's syndrome, Relay-Day syndrome, sacral nerve root cyst, butoh disease, Salivary gland disease, Sandhoff's disease, Sylder's disease, fissure encephalopathy, Seitelberger's disease, paroxysmal disease, semantic dementia, septal optic dysplasia, shaken skeleton syndrome, herpes zoster, Scheedlager's syndrome, Schegren's syndrome, during sleep Aspiration syndrome, African sleep disease, Sotos's disease, spasm, dichotomy, spinal cord infarction, spinal cord injury, spinal cord tumor, spinal muscle atrophy, spinal cerebral atrophy, spinal cerebral degeneration, Steel-Richardson-Orszevsky Syndrome, Stiffperson syndrome, striatal melanosis, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, SUNCT Headache Swallowing Disorders, Sidenum chorea, Fainting, pyogenic spinal sclerosis, spinal water cavities, spinal cavities, systemic erythema, spinal cord epilepsy, late-onset dyskinesia, turlob cysts, Teisax's disease, temporal arteritis, moored spinal cord syndrome, Tomsenmyotny (Thomsen's Myotonia), Thoracic exit syndrome, thyroid addictive myopathy, trigeminal nerve pain, Todd paralysis, Turret syndrome, transient cerebral ischemic attack, transmissible spongy encephalopathy, transverse myelitis, traumatic brain injury, tremors, trifurcation Nervous pain, tropical spastic deficiency vs. paralysis, nodular sclerosis, vascular Erectile Tumor, Vasculitis including Temporal Arteritis, von Echonomo disease, von Hippel-Lindau disease (VHL), von Recklinghausen's disease, Wallenberg's syndrome, Weldnig-Hoffmann's disease, Wernicke-Korsakov's syndrome, West's syndrome, whiplash, Whipple's disease, Willia The composition according to any one of claims 28 to 30, which is Mu syndrome, Wilson's disease, X-chain spinal and bulbar muscular atrophy, or Zellberger's syndrome. The disease or disorder is Huntington's disease, muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten's disease, spinal cord and brain injury, paroxysmal disorder, epilepsy, brain tumor, meningitis, autoimmune disease, multiple sclerosis, neurofibers. Of tumors, depression, muscular atrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulas, headaches, memory disorders, peripheral neuropathy, post-herpes zoster nerve pain, spinal cord tumors, and stroke The composition according to claim 28 or 29, which is a neurological disorder with at least one. The composition according to claim 28 or 29, wherein the disease or disorder is Alzheimer's disease.