AAK1 degraders

Abstract

The present invention concerns relates to bifunctional compounds that target AP2 associated kinase 1 (AAK1) to E3 ubiquitin ligase for degradation. The disclosed degrader compounds can be useful in the treatment of a variety of diseases and disorders for which AAK1 dysfunction is implication including, but not limited to, cancer, pain, neurodegenerative diseases, and viral infections. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

AAK1 DEGRADERS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No.63 / 667,374, filed on July 3, 2024, the contents of which are incorporated herein by reference in their entirety. BACKGROUND

[0002] Ovarian cancer remains the most lethal gynecologic cancer. Treatment strategies developed over the past four decades, however, have only achieved limited success, evidenced by 5-year survival improving from 40% in 1985 to a still parlous 45% today (Matulonis et al. (2016) Nat. Rev. Dis. Primers 2: 16061). The lack of effective therapy for ovarian cancer stands in sharp contrast with the remarkable progress made in breast cancer, currently standing at 5- year survival rate of 90% mainly due to the availability of many targeted and precision medicine-based therapies (Ponde et al. (2019) Nat. Rev. Clin. Oncol.16: 27-44). In contrast, the results of many clinical trials for ovarian cancer have been disappointing. Other than PARP inhibitors approved for maintenance therapy, no approved first line targeted therapy is available for ovarian cancer, largely due to the lack of actionable oncogenic mutations. Immune checkpoint inhibitor (ICI) therapy such as anti-PD1 / PD-L1 antibodies have also shown limited efficacy for ovarian cancer (Barber et al. (2021) Lancet Oncol.22: 903-905; Chardin and Leary (2021) Front Oncol.11: 795547). The current standard of care is surgical debulking followed by paclitaxel / platinum-based chemotherapy (Seward and Winer (2015) Cancer Metastasis Reviews 34: 5-10). Although patients respond initially, almost all will relapse due to rapid development of chemotherapy resistance, the mechanism of which is still largely unknown. Therefore, there remains a need for the identification of critical pathways activated by paclitaxel / platinum treatment, which should improve understanding of drug resistance mechanisms and also lead to better patient stratification. SUMMARY

[0003] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to bifunctional compounds that targetAP2 associated kinase 1 (AAK1) to E3 ubiquitin ligase for degradation. The disclosed degrader compounds can be useful in the treatment of a variety of diseases and disorders for which AAK1 dysfunction is implication including, but not limited to, cancer (e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma)), pain (e.g., neuropathic pain, chronic pain), neurodegenerative diseases (e.g., Alzheimer’s disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, Lewy body disease), and viral infections (e.g., human immunodeficiency virus (HIV), human papillomavirus (HPV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), dengue (DENV), influenza, West Nile virus (WNV), zika (ZIKV)).

[0004] Thus, in one aspect, disclosed are compounds having a structure represented byformula:, wherein L is an E3 ligase binding ligand; wherein Q is selected from –N= and –; wherein Z is a bifunctional linker; wherein R1is a structure selected from:wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein R3is selected from – CHF2, –CF3, and –CN, or a pharmaceutically acceptable salt thereof.

[0005] Also disclosed are compounds selected from:,,,,,or a pharmaceutically acceptable salt thereof.

[0006] Also disclosed are pharmaceutical compositions comprising an effective amount adisclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0007] Also disclosed are methods of degrading a target protein in a cell, the methodcomprising contacting the cell with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0008] Also disclosed are methods of degrading a target protein in a subject in need thereof,the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0009] Also disclosed are methods of treating a disorder in a subject in need thereof, themethod comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof, wherein the disorder is cancer, pain, a neurodegenerative disease, or a viral infection.

[0010] Also disclosed are kits comprising a disclosed compound, or a pharmaceuticallyacceptable salt thereof, and one or more selected from: (a) an agent known to treat a disorder associated with activity of AP2 associated kinase 1 (AAK1); (b) instructions for administering the compound in connection with treating a disorder associated with activity of AP2 associatedkinase 1 (AAK1); and (c) instructions for treating a disorder associated with activity of AP2 associated kinase 1 (AAK1).

[0011] Additional advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. BRIEF DESCRIPTION OF THE FIGURES

[0012] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention.

[0013]

[0014] FIG.1 shows a representative cartoon illustrating the proposed mechanism of induced AAK1 degradation by PROTACs.

[0015] FIG.2A-E show representative data of a RNAi screening that identified AAK1 as a synthetic lethal target for taxane treatment in ovarian cancer.

[0016] FIG.3A-J show representative data indicating that targeting AAK1 sensitizes paclitaxel treatment in ovarian cancer.

[0017] FIG.4 shows representative data indicating that AAK1 inhibitor sensitizes ovarian cancer cells to paclitaxel.

[0018] FIG.5A-F show representative data illustrating that compound 14 is a potent AAK1 degrader.

[0019] FIG.6A-E show representative data indicating that compound 14 sensitizes ovarian cancer to taxane.

[0020] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.DETAILED DESCRIPTION

[0021] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0022] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0023] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0024] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.A. DEFINITIONS

[0025] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0026] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”

[0027] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0028] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0029] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article forwhich a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0030] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0031] As used herein, “EC50” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC50can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein.

[0032] As used herein, “EC90” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 90% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC90can refer to the concentration of a substance that is required for 90% agonism in vivo, as further defined elsewhere herein.

[0033] As used herein, “CC50” is intended to refer to the effective concentration of a cytotoxic compound, which produces 50% of the maximum possible cell death for that compound.

[0034] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0035] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0036] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causaltreatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).

[0037] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0038] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0039] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0040] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0041] As used herein, “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonyl phenol, sodium desoxycholate), solution and / or cryo / lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g.,polydimethylsilozone), preservatives (e.g., thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0042] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0043] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form, which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0044] As used herein, the terms “therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14thedition), the Physicians' Desk Reference (64thedition), and The Pharmacological Basis of Therapeutics (12thedition) , and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affectthe structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti- epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta- blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0045] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0046] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as theclaimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, and amides, salts of esters or amides, and N-oxides of a parent compound.

[0047] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0048] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same ordifferent for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0049] In defining various terms, “A1,” “A2,” “A3,” and “A4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0050] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0051] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s- butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0052] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0053] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0054] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a non-aromatic carbon-based ring type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0055] The term “polyalkylene group” as used herein is a group having two or more CH2groups linked to one another. The polyalkylene group can be represented by the formula — (CH2)a—, where “a” is an integer of from 2 to 500.

[0056] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA1—OA2or — OA1—(OA2)a—OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0057] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0058] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0059] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde,amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0060] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo- oxo, or thiol as described herein.

[0061] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0062] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ─NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon- carbon bond. For example, biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0063] The term “aldehyde” as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O.

[0064] The terms “amine” or “amino” as used herein are represented by the formula — NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ─NH2.

[0065] The term “alkylamino” as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.

[0066] The term “dialkylamino” as used herein is represented by the formula —N(-alkyl)2where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl- N-propylamino group and the like.

[0067] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

[0068] The term “ester” as used herein is represented by the formula —OC(O)A1or — C(O)OA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula —(A1O(O)C-A2-C(O)O)a— or —(A1O(O)C-A2-OC(O))a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0069] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula —(A1O-A2O)a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0070] The terms “halo,” “halogen,” or “halide” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0071] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0072] The term “heteroalkyl” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0073] The term “heteroaryl” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2- a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3- b]pyrazinyl.

[0074] The terms “heterocycle” or “heterocyclyl” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4- thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4- tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group that has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0075] The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6- membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2- b]pyridin-3-yl.

[0076] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0077] The term “hydroxyl” or “hydroxyl” as used herein is represented by the formula — OH.

[0078] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0079] The term “azide” or “azido” as used herein is represented by the formula —N3.

[0080] The term “nitro” as used herein is represented by the formula —NO2.

[0081] The term “nitrile” or “cyano” as used herein is represented by the formula —CN.

[0082] The term “silyl” as used herein is represented by the formula —SiA1A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0083] The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A1, — S(O)2A1, —OS(O)2A1, or —OS(O)2OA1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0084] The term “thiol” as used herein is represented by the formula —SH.

[0085] “R1,” “R2,” “R3,” “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0086] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not,means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0087] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0088] Suitable monovalent substituents on a substitutable carbon atom of an “optionallysubstituted” group are independently halogen; –(CH2)0–4R ; –(CH2)0–4OR ; -O(CH2)0-4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR )2; –(CH2)0–4SR ; –(CH2)0–4Ph, which may be substitutedwith R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –S(O)2NR 2; -(CH2)0–4S(O)R ; -N(R )S(O)2NR 2; –N(R )S(O)2R ; –N(OR )R ; –C(NH)NR 2;–P(O)2R ; -P(O)R 2; -OP(O)R 2; –OP(O)(OR )2; SiR 3; –(C1–4 straight or branchedalkylene)O–N(R )2; or –(C1–4 straight or branched alkylene)C(O)O–N(R )2, wherein each Rmay be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, – O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen,or sulfur, or, notwithstanding the definition above, two independent occurrences of R , takentogether with their intervening atom(s), form a 3–12–membered saturated, partiallyunsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0089] Suitable monovalent substituents on R (or the ring formed by taking two independentoccurrences of R together with their intervening atoms), are independently halogen, –(CH2)0–2R , –(haloR ), –(CH2)0–2OH, –(CH2)0–2OR , –(CH2)0–2CH(OR )2; -O(haloR ), –CN, –N3, –(CH2)0–2C(O)R , –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR , –(CH2)0–2SR , –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR , –(CH2)0–2NR 2, –NO2, –SiR 3, –OSiR 3, -C(O)SR , –(C1–4straight or branched alkylene)C(O)OR , or –SSR wherein each R is unsubstituted or wherepreceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen,or sulfur. Suitable divalent substituents on a saturated carbon atom of R include =O and =S.

[0090] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0091] Suitable substituents on the aliphatic group of R*include halogen, –R , -(haloR ), -OH, –OR , –O(haloR ), –CN, –C(O)OH, –C(O)OR , –NH2, –NHR , –NR 2,or –NO2, wherein each R is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0092] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, – S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below,unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0093] Suitable substituents on the aliphatic group of R†are independently halogen, –R , -(haloR ), –OH, –OR , –O(haloR ), –CN, –C(O)OH, –C(O)OR , –NH2, –NHR , –NR 2,or –NO2, wherein each R is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0094] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.

[0095] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

[0096] The term “organic residue” defines a carbon-containing residue, i., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0097] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a moleculedescribed herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure:, regardless of whether thiazolidinedione is used to prepare the compound. In various aspects the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0098] “Organic radicals,” as the term is defined and used herein, contain one or more carbonatoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In various aspects, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[0099] Compounds described herein can contain one or more double bonds and, thus,potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[0100] Unless stated to the contrary, a formula with chemical bonds shown only as solid linesand not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise todiastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0101] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0102] When the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0103] Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.). Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In one aspect, the designated enantiomer is substantially free from the other enantiomer. For example, the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.

[0104] When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S) / (R,R) and (R,S) / (S,R)). The pairs of enantiomers (e.g., (S,S) / (R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.

[0105] The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem.1988, 31, 318; Aligas-Martin et al., PCT WO 2000 / 041531, p.30). The nitrogen function converted inpreparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.

[0106] “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radioactively labeled forms, isomers, solvates and combinations thereof. The “combinations” mentioned in this context are refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radioactively labeled forms, isomers, and solvates. Examples of radioactively labeled forms include compounds labeled with tritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and the like.

[0107] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically labeled or isotopically substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F and36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0108] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with thecompounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0109] The term “co-crystal” means a physical association of two or more molecules that owetheir stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0110] It is also appreciated that certain compounds described herein can be present as anequilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form.

[0111] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide formand the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, N1-unsubstituted, 3-A3and N1-unsubstituted, 5-A3as shown below.Unless stated to the contrary, the invention includes all such possible tautomers.

[0112] It is known that chemical substances form solids that are present in different states oforder that are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0113] In some aspects, a structure of a compound can be represented by a formula:,

[0114] which is understood to be equivalent to a formula:, wherein n is typically an integer. That is, Rnis understood to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then Rn(b)is not necessarily halogen in that instance.

[0115] Certain materials, compounds, compositions, and components disclosed herein can beobtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0116] Unless otherwise expressly stated, it is in no way intended that any method set forthherein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0117] Disclosed are the components to be used to prepare the compositions of the inventionas well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0118] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result B. COMPOUNDS

[0119] In one aspect, the invention relates to relates to bifunctional compounds that target AP2 associated kinase 1 (AAK1) to E3 ubiquitin ligase for degradation. TThus, in one aspect, the compounds of the invention are useful in the treatment of a variety of diseases and disorders for which AAK1 dysfunction is implication including, but not limited to, cancer, pain, neurodegenerative diseases, and viral infections, as further detailed herein.

[0120] In particular, the present disclosure provides bifunctional compounds, which find utility as modulators of targeted ubiquitination of AAK1 kinases, which are then degraded and / or otherwise inhibited by the bifunctional compounds as described herein. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation / inhibition of AAK1 kinases. In addition, the descriptionprovides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as disorder is cancer, pain, a neurodegenerative disease, or a viral infections.

[0121] It is contemplated that each disclosed derivative can be optionally further substituted.It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using. 1. STRUCTURE

[0122] In one aspect, disclosed are compounds having a structure represented by formula:, wherein L is an E3 ligase binding ligand; wherein Q is selected from –N= and –CH=; wherein Z is a bifunctional linker; wherein R1is a structure selected from:wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein R3is selected from – CHF2, –CF3, and –CN, or a pharmaceutically acceptable salt thereof.

[0123] In one aspect, disclosed are compounds selected from:,,,, ,,,or a pharmaceutically acceptable salt thereof.

[0124] In various aspects, the compound has a structure represented by a formula:, wherein each of q, r, s, and t is independently selected from 0 and 1; wherein A1is selected from –O–, –NH–, –CF2–, –C≡C–, –CF2C≡C–, and –CF2C≡CCH2O–; wherein A2is a structure selected from:,wherein X and Y are independently selected from –N= and –CH= wherein A3is selected from –O–, –C(O)–, –C(O)(C1-C8 alkylene)–, –C(O)(CH2CH2O)n(C1-C4 alkylene)–, –(C1-C8 alkylene)–, –(C1-C8 alkylene)O–, and –CH2C≡C–; wherein n is selected from 1, 2, 3, and 4; wherein A4is a structure selected from: ,wherein A5is selected from –CH2– and –OCH2CH2– wherein L is an E3 ligase binding ligand; wherein Q is selected from –N= and –CH=; wherein R1is a structure selected from:wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein R3is selected from – CHF2, –CF3, and –CN, or a pharmaceutically acceptable salt thereof.

[0125] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0126] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0127] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0128] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0129] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0130] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0131] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0132] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0133] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0134] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0135] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0136] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0137] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0138] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0139] In various aspects, the compound is selected from:,,,,,,,or a pharmaceutically acceptable salt thereof.

[0140] In various aspects, the compound is selected from:,,,,,,,,,, ,,,,,,, or a pharmaceutically acceptable salt thereof.

[0141] In various aspects, the compound is selected from:, ,,,,or a pharmaceutically acceptable salt.

[0142] In various aspects, the compound is selected from:,,, ,,or a pharmaceutically acceptable salt thereof.

[0143] In one aspect, n is selected from 1, 2, 3, and 4. In a further aspect, n is selected from1, 2, and 3. In a still further aspect, n is selected from 2, 3, and 4. In yet a further aspect, n is selected from 1, 2, and 4. In an even further aspect, n is selected from 1, 3, and 4. In an even still further aspect, n is selected from 1 and 4. In yet an even further aspect, n is selected from 2 and 4. In a further aspect, n is selected from 3 and 4. In a still further aspect, n is selected from 1 and 3. In yet a further aspect, n is selected from 2 and 3. In an even further aspect, n is selected from 1 and 2. In an even still further aspect, n is 1. In yet an even further aspect, n is 2. In a futher aspect, n is 3. In a still further aspect, n is 4.

[0144] In one aspect, q, r, s, and t is independently selected from 0 and 1.

[0145] In various aspects, at least one of q, r, s, and t is 1.

[0146] In various aspects, each of q, r, and s is 1 and wherein t is 0.

[0147] In various aspects, q is selected from 0 and 1. In a further aspect, q is 0. In a still further aspect, q is 1.

[0148] In various aspects, r is selected from 0 and 1. In a further aspect, r is 0. In a still further aspect, r is 1..

[0149] In various aspects, s is selected from 0 and 1. In a further aspect, s is 0. In a still further aspect, s is 1.

[0150] In various aspects, t is selected from 0 and 1. In a further aspect, t is 0. In a still further aspect, t is 1. a. A1GROUPS

[0151] In one aspect, A1is selected from –O–, –NH–, –CF2–, –C≡C–, –CF2C≡C–, and – CF2C≡CCH2O–. In a further aspect, A1is selected from –O–, –NH–, –CF2–, –C≡C–, and – CF2C≡C–. In a still further aspect, A1is selected from –O–,–CF2–, –C≡C–, and – CF2C≡CCH2O–. In yet a further aspect, A1is selected from –O–, –NH–, –CF2–, –CF2C≡C–, and –CF2C≡CCH2O–. In an even further aspect, A1is selected from –O–, –NH–, –C≡C–, – CF2C≡C–, and –CF2C≡CCH2O–. In an even still further aspect, A1is selected from –O–, – CF2–, –C≡C–, –CF2C≡C–, and –CF2C≡CCH2O–. In yet an even further aspect, A1is selected from –NH–, –CF2–, and –C≡C–. In a further aspect, A1is selected from –O–, –NH–, –CF2–,and –CF2C≡CCH2O–. In a still further aspect, A1is selected from –O–, –NH–, –CF2C≡C–, and–CF2C≡CCH2O–. In yet a further aspect, A1is selected from –O–, –C≡C–, –CF2C≡C–, and – CF2C≡CCH2O–. In an even further aspect, A1is selected from –CF2–, –C≡C–, –CF2C≡C–, and –CF2C≡CCH2O–.

[0152] In various aspects, A1is selected from –O–, –NH–, and –CF2–. In a further aspect, A1is selected from –O– and –CF2–. In a still further aspect, A1is selected from –O– and –N–. In yet a further aspect, A1is selected from –N– and –CF2–. In an even further aspect, A1is selected from –O–. In an even still further aspect, A1is selected from –N–. In yet an even further aspect, A1is selected from –CF2–.

[0153] In various aspects, A1is selected from –C≡C–, –CF2C≡C–, and –CF2C≡CCH2O–. In a further aspect, A1is selected from –C≡C– and –CF2C≡CCH2O–. In a still further aspect, A1is selected from –C≡C– and –CF2C≡C–. In yet a further aspect, A1is selected from –CF2C≡C–and –CF2C≡CCH2O–. In an even further aspect, A1is selected from –C≡C–. In an even stillfurther aspect, A1is selected from –CF2C≡C–. In yet an even further aspect, A1is selected from –CF2C≡CCH2O–.

[0154] In various aspects, A1 is –NH–.

[0155] In various aspects, A1 is –C≡C–.b. A2 GROUPS

[0156] In one aspect, A2 is a structure selected from:,wherein X and Y are independently selected from –N= and –CH=.

[0157] In various aspects, A2 is a structure selected from:,

[0158] In various aspects, A2 is a structure selected from:,

[0159] In various aspects, A2 is a structure selected from:,

[0160] In various aspects, A2 is a structure:.

[0161] In a further aspect, A2 is a structure:.

[0162] In a further aspect, A2 is a structure:.

[0163] In various aspects, A2 is a structure:.

[0164] In various aspects, A2 is a structure:.

[0165] In various aspects, A2 is a structure:.

[0166] In a further aspect, A2 is a structure:.

[0167] In a further aspect, A2 is a structure:.

[0168] In various aspects, A2 is a structure:. c. A3 GROUPS

[0169] In one aspect, A3 is selected from –O–, –C(O)–, –C(O)(C1-C8 alkylene)–, –C(O)(CH2CH2O)n(C1-C4 alkylene)–, –(C1-C8 alkylene)–, –(C1-C8 alkylene)O–, and – CH2C≡C–, wherein n is selected from 1, 2, 3, and 4. In a further aspect, A3is selected from – O–, –C(O)–, –C(O)(C1-C4 alkylene)–, –C(O)(CH2CH2O)n(C1-C4 alkylene)–, –(C1-C4alkylene)–, –(C1-C4 alkylene)O–, and –CH2C≡C–. In a still further aspect, A3is selected from –O–, –C(O)–, –C(O)CH2–, –C(O)CH2CH2–, –C(O)CH2CH2CH2–, –C(O)CH(CH3)2–, – C(O)(CH2CH2O)nCH2–, –C(O)(CH2CH2O)nCH2CH2–, –C(O)(CH2CH2O)nCH2CH2CH2–, – C(O)(CH2CH2O)nCH(CH3)2–, –CH2–, –CH2CH2–, –CH2CH2CH2–, –CH(CH3)2–, –CH2O–, – CH2CH2O–, –CH2CH2CH2O–, –CH(CH3)CH2O–, and –CH2C≡C–. In yet a further aspect, A3is selected from –O–, –C(O)–, –C(O)CH2–, –C(O)CH2CH2–, –C(O)(CH2CH2O)nCH2–, –an even further aspect, A3is selected from –O–, –C(O)–, –C(O)CH2–, –C(O)(CH2CH2O)nCH2–, –CH2–, –CH2O–, and –CH2C≡C–.

[0170] In various aspects, A3is selected from –O– and –(C1-C8 alkylene)O–. In a further aspect, A3is selected from –O– and –(C1-C4 alkylene)O–. In a still further aspect, A3is selected from –O–, –CH2O–, –CH2CH2O–, –CH2CH2CH2O–, and –CH(CH3)CH2O– In yet a further aspect, A3is selected from –O–, –CH2O–, and –CH2CH2O–. In an even further aspect, A3is selected from –O– and –CH2O–.

[0171] In various aspects, A3is selected from –C(O)–, –C(O)(C1-C8 alkylene)–, and – C(O)(CH2CH2O)n(C1-C4 alkylene)–, wherein n is selected from 1, 2, 3, and 4. In a further aspect, A3is selected from –C(O)–, –C(O)(C1-C4 alkylene)–, and –C(O)(CH2CH2O)n(C1-C4 alkylene)–. In a still further aspect, A3is selected from –C(O)–, –C(O)CH2–, –C(O)CH2CH2–, –C(O)CH2CH2CH2–, –C(O)CH(CH3)2–, –C(O)(CH2CH2O)nCH2–, – C(O)(CH2CH2O)nCH2CH2–, –C(O)(CH2CH2O)nCH2CH2CH2–, and – C(O)(CH2CH2O)nCH(CH3)2–. In yet a further aspect, A3is selected from –C(O)–, –C(O)CH2–, –C(O)CH2CH2–, –C(O)(CH2CH2O)nCH2–, and –C(O)(CH2CH2O)nCH2CH2–. In an even further aspect, A3is selected from –C(O)–, –C(O)CH2–, and –C(O)(CH2CH2O)nCH2–.

[0172] In various aspects, A3is selected from –(C1-C8 alkylene)– and –CH2C≡C–, wherein n is selected from 1, 2, 3, and 4. In a further aspect, A3is selected from –(C1-C4 alkylene)– and –CH2C≡C–. In a still further aspect, A3is selected from –CH2–, –CH2CH2–, –CH2CH2CH2–, – CH(CH3)2–, and –CH2C≡C–. In yet a further aspect, A3is selected from –CH2–, –CH2CH2–, and –CH2C≡C–. In an even further aspect, A3is selected from –CH2– and –CH2C≡C–.

[0173] In various aspects, A3is selected from –O–, –C(O)–, –C(O)(C1-C8 alkylene)–, – C(O)(CH2CH2O)n(C1-C4 alkylene)–, and –(C1-C8 alkylene)–, wherein n is selected from 1, 2, 3, and 4. In a further aspect, A3is selected from –O–, –C(O)–, –C(O)(C1-C4 alkylene)–, – C(O)(CH2CH2O)n(C1-C4 alkylene)–, and –(C1-C4 alkylene)–. In a still further aspect, A3is selected from –O–, –C(O)–, –C(O)CH2–, –C(O)CH2CH2–, –C(O)CH2CH2CH2–, – C(O)CH(CH3)2–, –C(O)(CH2CH2O)nCH2–, –C(O)(CH2CH2O)nCH2CH2–, –C(O)(CH2CH2O)nCH2CH2CH2–, –C(O)(CH2CH2O)nCH(CH3)2–, –CH2–, –CH2CH2–, – CH2CH2CH2–, and –CH(CH3)2–. In yet a further aspect, A3is selected from –O–, –C(O)–, –

[0175] In various aspects, A4 is a structure selected from:.

[0176] In various aspects, A4 is a structure :.

[0177] In various aspects, A4 is a structure :.

[0178] In various aspects, A4 is a structure selected from:,

[0179] In various aspects, A4 is a structure selected from:.

[0180] In various aspects, A4 is a structure :.

[0181] In various aspects, A4 is a structure :. e. A5 GROUPS

[0182] In one aspect, A5 is selected from –CH2– and –OCH2CH2–.

[0183] In various aspects, A5 is –CH2–.

[0184] In various aspects,f. L GROUPS

[0185] In one aspect, L is an E3 ligase binding ligand. In various aspects, L is an E3 ligasebinding ligand is selected from:,,

[0186] In various aspects, L is a structure:.

[0187] In various aspects, L is a structure:.

[0188] In various aspects, L is a structure:.

[0189] In various aspects, L is a structure:.

[0190] In various aspects, L is a structure:. g. Q GROUPS

[0191] In one aspect, is selected from –N= and –CH=.

[0192] In various aspects, Q is –N=.

[0193] In various aspects, Q is –CH=.h. X AND Y GROUPS

[0194] In various aspects, X and Y are independently selected from –N= and –CH=. In afurther aspect, X and Y are –N=. In a still further aspect, X and Y are –CH=. In yet a further aspect, X is –N= and Y is –CH=. In an even further aspect, X is –CH= and Y is –N=. i. Z GROUPS

[0195] In one aspect, Z is a bifunctional linker. In a further aspect, Z is a structurerepresented by a formula:, wherein each of q, r, s, and t is independently selected from 0 and 1; wherein A1is selected from –O–, –NH–, –CF2–, –C≡C–, –CF2C≡C–, and –CF2C≡CCH2O–; wherein A2is a structure selected from: ,wherein X and Y are independently selected from –N= and –CH=; wherein A3is selected from –O–, –C(O)–, –C(O)(C1-C8 alkylene)–, –C(O)(CH2CH2O)n(C1-C4 alkylene)–, –(C1-C8 alkylene)–, –(C1-C8 alkylene)O–, and –CH2C≡C–; wherein n is selected from 1, 2, 3, and 4; wherein A4is a structure selected from: ,wherein A5is selected from –CH2– and –OCH2CH2–.

[0196] In various aspects, Z has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0197] In various aspects, Z has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0198] In various aspects, Z has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0199] In various aspects, Z has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0200] In various aspects, Z has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0201] In various aspects, Z has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0202] In various aspects, Z has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0203] In various aspects, Z has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0204] In various aspects, Z has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof. j. R1 GROUPS

[0205] In one aspect, R1 is a structure selected from:.

[0206] In various aspects, R1 is a structure selected from:.

[0207] In one aspect, R1 is a structure selected from:.

[0208] In various aspects, R1 is a structure:.k. R2 GROUPS

[0209] In one aspect, R2 is selected from hydrogen and C1-C4 alkyl. In a further aspect, R2 isselected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a still further aspect, R2is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R2is selected from hydrogen and methyl.

[0210] In various aspects, R2 is C1-C4 alkyl. In a further aspect, R2 is selected from methyl,ethyl, propyl, and isopropyl. In a still further aspect, R2is selected from methyl and ethyl. In yet a further aspect, R2is methyl.

[0211] In various aspects, R2 is hydrogen.l. R3 GROUPS

[0212] In one aspect, R3 is selected from –CHF2, –CF3, and –CN. In a further aspect, R3 isselected from –CHF2and –CF3. In a further aspect, R3is selected from –CHF2and –CN. In a still further aspect, R3is selected from –CF3and –CN. In yet a further aspect, R3is –CHF2. In yet a further aspect, R3is –CF3. In yet a further aspect, R3is –CN. 2. EXAMPLE COMPOUNDS

[0213] In one aspect, a compound can be present as:,,,,,, ,,,,,,, ,,, ,,, or a pharmaceutically acceptable salt thereof.

[0214] In one aspect, a compound can be present as:,,,or a pharmaceutically acceptable salt thereof. 3. PROPHETIC COMPOUND EXAMPLES

[0215] The following compound examples are prophetic, and can be prepared using thesynthesis methods described herein above and other general methods as needed as would be known to one skilled in the art. It is anticipated that the prophetic compounds would be useful to target a protein to E3 ubiquitin ligase for degradation, and useful as AP2 associated kinase 1 (AAK1) degrader compounds and that such activity can be determined using the assay methods described herein below.

[0216] In one aspect, a compound can be present as:,,,,,,, or a pharmaceutically acceptable salt thereof.

[0217] In one aspect, a compound can be present as:,,,,,or a pharmaceutically acceptable salt thereof.

[0218] It is contemplated that one or more compounds can optionally be omitted from thedisclosed invention.

[0219] It is understood that the disclosed compounds can be used in connection with thedisclosed methods, compositions, kits, and uses. It is understood that pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses. The pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like.C. METHODS OF MAKING A COMPOUND

[0220] The compounds of this invention can be prepared by employing reactions as shown inthe following schemes, in addition to other standard manipulations that are known in theliterature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0221] Reactions used to generate the compounds of this invention are prepared byemploying reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Routes I-IX, as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting. 1. ROUTE I

[0222] In one aspect, the disclosed compounds can be prepared as shown below.SCHEME 1A.

[0223] Compounds are represented in generic form, wherein X1 is a halogen, A1 is –O– or –NH–, PG is an amino protecting group (e.g., e.g., carbobenzyloxy, p-methoxybenzyl carbonyl,t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p- methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, tosyl, 4-nitrobenzenesulfonyl) andwith other substituents as noted in compound descriptions elsewhere herein. A more specific non-limiting example of the synthesis shown in Scheme 1A is set forth below. SCHEME 1B.

[0224] In one aspect, compounds of type 1.12, and similar compounds, can be preparedaccording to reaction Scheme 1B above. Thus, compounds of type 1.9 can be prepared by a Mitsonobu reaction of an appropriate protected amino alcohol, e.g., 1.7 as shown above, and an appropriate aromatic alcohol, e.g., 1.8 as shown above. Appropriate protected amino alcohols and appropriate aromatic alcohols are commercially available or prepared by methods known to one skilled in the art. The Mitsonobu reaction can be carried out with an appropriate azo- reagent, e.g., diisopropyl azodicarboxylate (DIAD), and an appropriate phosphine reagent, e.g., triphenyl phosphine, in an appropriate solvent, e.g., tetrahydrofuran, at an appropriate temperature, e.g., room temperature, for an appropriate amount of time, e.g., 16 h. Compoundsof type 1.10 can be prepared by reaction of an appropriate aryl halide, e.g., 1.9 as shown above,and appropriate boronlyation reagent, e.g., bis(pinacolato)diboron. The reaction can be carried out in the presence of an appropriate catalyst, e.g., [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), and an appropriate base, e.g., potassium acetate, in an appropriate solvent, e.g., dioxane, at an appropriate temperature, e.g., 85 °C. Compounds of type 1.12 can be prepared by a Suzuki coupling of an appropriateboronate compound, e.g., 1.10 as shown above, and an appropriate ary halide, e.g., 1.11 as shown above. Appropirate aryl halides are commercially available or prepared by methods known to one skilled in the art. The Suzuki coupling can be carried out in the presence of an appropriate catalyst, e.g., tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and an appropriate ligand, e.g., 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos), with an appropriate base, e.g., potassium phosphonate, in an appropriate solvent, e.g., tetrahydrofuran, at an appropriate temperature, e.g., 70 °C, for an appropriate amount of time, e.g., 12 h. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compoundssimilar to 1.1, 1.2, 1.3, 1.4, and 1.5) can be substituted in the reaction to provide compoundssimilar to Formula 1.6. 2. ROUTE II

[0225] In one aspect, the disclosed compounds can be prepared as shown below.SCHEME 2A.

[0226] Compounds are represented in generic form, wherein each of X1 and X2 isindependently halogen, wherein PG is an amino protecting group (e.g., e.g., carbobenzyloxy, p-methoxybenzyl carbonyl, t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, tosyl, 4- nitrobenzenesulfonyl), and with other substituents as noted in compound descriptions elsewhere herein. A more specific non-limiting example of the synthesis shown in Scheme 2A is set forth below. SCHEME 2B.

[0227] In one aspect, compounds of type 2.6, and similar compounds, can be preparedaccording to reaction Scheme 2B above. Thus, compounds of type 2.6 can be prepared by protecting an appropriate amine, e.g., 2.4 as shown above, using an appropriate amine protecting group, e.g., 2.5 as shown above. Appropriate amines and appropriate amine protecting groups are commercially available or prepared by methods known to one skilled in the art. The reaction can be carried out with an appropriate base, e.g., potassium carbonate, in an appropriate solvent, e.g., tetrahydrofuran, at an appropriate temperature, e.g., 0 °C. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 2.1 and 2.2) can be substituted in the reaction to provide compounds similar to Formula 2.3. 3. ROUTE III

[0228] In one aspect, the disclosed compounds can be prepared as shown below.SCHEME 3A.

[0229] Compounds are represented in generic form, wherein X1 is halogen, wherein PG is anamino protecting group (e.g., e.g., carbobenzyloxy, p-methoxybenzyl carbonyl, t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p- methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, tosyl, 4-nitrobenzenesulfonyl), and with other substituents as noted in compound descriptions elsewhere herein. A more specific non-limiting example of the synthesis shown in Scheme 3A is set forth below.SCHEME 3B.

[0230] In one aspect, compounds of type 3.8, and similar compounds, can be preparedaccording to reaction Scheme 3B above. Thus, compounds of type 3.7 can be prepared by a coupling reaction between an appropriate amine, e.g., 3.5 as shown above, and an appropriate aryl halide, e.g., 3.6 as shown above. Appropriate amines and appropriate aryl halides are commercially available or prepared by methods known to one skilled in the art. The coupling reaction can be carried out in the presence of an appropriate catalyst, e.g., tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and an appropriate ligand, e.g., 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos), with an appropriate base, e.g., cesium carbonate, in an appropriate solvent, e.g., 1,4-dioxane, at an appropriate temperature, e.g., 100 °C. Compounds of type 3.8 can be prepared by deprotection of an appropriate protected amine, e.g., 3.7 as shown above. The deprotection reaction can be carried out in the presence of hydrogen gas and an appropriate catalyst, e.g., palladium on carbon, in an appropriate protic solvent, e.g., methanol. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar instructure to the specific reactions above (compounds similar to 3.1, 3.2, and 3.3) can be substituted in the reaction to provide compounds similar to Formula 3.4. 4. ROUTE IV

[0231] In one aspect, the disclosed compounds can be prepared as shown below.SCHEME 4A.

[0232] Compounds are represented in generic form, wherein each of X1 and X2 isindependently halogen, wherein PG is an amino protecting group (e.g., e.g., carbobenzyloxy, p-methoxybenzyl carbonyl, t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, tosyl, 4- nitrobenzenesulfonyl), and with other substituents as noted in compound descriptions elsewhere herein. A more specific non-limiting example of the synthesis shown in Scheme 4A is set forth below. SCHEME 4B.

[0233] In one aspect, compounds of type 4.10, and similar compounds, can be preparedaccording to reaction Scheme 4B above. Thus, compounds of type 4.8 can be prepared by a coupling reaction between an appropriate aryl halide, e.g., 4.6 as shown above, and an appropriate amine, e.g., 4.7 as shown above. Appropriate aryl halides and appropriate amines are commercially available or prepared by methods known to one skilled in the art. The coupling reaction can be carried out in the presence of an appropriate catalyst, e.g., tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and an appropriate ligand, e.g., 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos), with an appropriate base, e.g., cesium carbonate, in an appropriate solvent, e.g., 1,4-dioxane, at an appropriate temperature, e.g., 100 °C. Compounds of type 4.10 can be prepared by a coupling reaction between an appropriate aryl halide, e.g., 4.8 as shown above, and an appropriate boronate, e.g., 4.9 as shown above. Appropriate boronates are commercially available or prepared by methods known to one skilled in the art. The coupling reaction can be carried out in the presence of an appropriate catalyst, e.g., tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and an appropriate ligand, e.g., 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos), with an appropriate base, e.g., potassium phosphate, in an appropriate solvent, e.g., tetrahydrofuran, at an appropriate temperature, e.g., 70 °C. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 4.1, 4.2, 4.3, and 4.4) can be substituted in the reaction to provide compounds similar to Formula 4.5. 5. ROUTE V

[0234] In one aspect, the disclosed compounds can be prepared as shown below.SCHEME 5A.

[0235] Compounds are represented in generic form, wherein X1 is a halogen and with othersubstituents as noted in compound descriptions elsewhere herein. A more specific non-limiting example of the synthesis shown in Scheme 5A is set forth below. SCHEME 5B.

[0236] In one aspect, compounds of type 5.8, and similar compounds, can be preparedaccording to reaction Scheme 5B above. Thus, compounds of type 5.7 can be prepared by a coupling reaction between an appropriate aryl halide, e.g., 5.5 as shown above, and an appropriate amine, e.g., 5.6 as shown above. Appropriate aryl halides and appropriate amines are commercially available or prepared by methods known to one skilled in the art. The coupling reaction can be carried out in the presence of an appropriate catalyst system, e.g.,nickel (II) bromide ethylene glycol dimethyl ether complex and tris(2,2’-bipyridine)ruthenium (II) hexafluorophosphate, and an appropriate base, e.g., 1,4-diazabicyclo[2.2.2]octane (DABCO), in an appropriate solvent, e.g., dimethylsulfoxide (DMSO). Compounds of type 5.8 can be prepared by deprotection of an appropriate protected aldehyde, e.g., 5.7 as shown above. The deprotection can be carried out in the presence of an appropriate acid, e.g., 2M hydrochloric acid, in an appropriate solvent, e.g., tetrahydrofuran (THF), at an appropriate temperature, e.g., 50 °C, for an appropriate period of time, e.g., 2 hours. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 5.1, 5.2, and 5.3) can be substituted in the reaction to provide compounds similar to Formula 5.4. 6. ROUTE VI

[0237] In one aspect, the disclosed compounds can be prepared as shown below.SCHEME 6A.

[0238] Compounds are represented in generic form, wherein X1 is a halogen, wherein R is aC1-C4 alkyl, wherein A3contains a carboxyl terminus such that the terminus of 6.2 and 6.3 is CO2R and the terminus of 6.4 is CO2H, and with substituents as noted in compound descriptions elsewhere herein. A more specific non-limiting example of the synthesis shown in Scheme 6A is set forth below.SCHEME 6B.

[0239] In one aspect, compounds of type 6.8, and similar compounds, can be preparedaccording to reaction Scheme 6B above. Thus, compounds of type 6.7 can be prepared by a coupling reaction between an appropriate aryl halide, e.g., 6.5 as shown above, and an appropriate ester, e.g., 6.6 as shown above. Appropriate aryl halides and appropriate esters are commercially available or prepared by methods known to one skilled in the art. The coupling reaction can be carried out in the presence of an appropriate catalyst system, e.g., nickel (II) bromide ethylene glycol dimethyl ether complex and tris(2,2’-bipyridine)ruthenium (II) hexafluorophosphate, and an appropriate base, e.g., 1,4-diazabicyclo[2.2.2]octane (DABCO), in an appropriate solvent, e.g., dimethylsulfoxide (DMSO). Compounds of type 6.8 can be prepared by saponification of an appropriate ester, e.g., 6.7 as shown above. The deprotection can be carried out in the presence of an appropriate acid, e.g., 4M hydrochloric acid, in an appropriate solvent, e.g., 1,4-dioxane. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 6.1, 6.2, and 6.3) can be substituted in the reaction to provide compounds similar to Formula 6.4. 7. ROUTE VII

[0240] In one aspect, the disclosed compounds can be prepared as shown below.SCHEME 7A.

[0241] Compounds are represented in generic form, wherein A2 (or A1 when A2 is absent)contains an amine such that the terminus of 7.1 is NH, wherein A3contains a carboxyl terminus such that the terminus of 7.2 is CO2H, and with other substituents as noted in compound descriptions elsewhere herein. A more specific non-limiting example of the synthesis shown in Scheme 7A is set forth below. SCHEME 7B.

[0242] In one aspect, compounds of type 7.6, and similar compounds, can be preparedaccording to reaction Scheme 7B above. Thus, compounds of type 7.6 can be prepared by a coupling reaction between an appropriate amine, e.g., 7.4 as shown above, and an appropriate carboxylic acid, e.g., 7.5 as shown above. The coupling reaction can be carried out in the presence of an appropriate coupling agent, e.g., hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), and an appropriate base, e.g., N,N-diisopropylethylamine (DIEA), in an appropriate solvent, e.g., dimethylformamide (DMF). As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 7.1 and 7.2) can be substituted in the reaction to provide compounds similar to Formula 7.3. 8. ROUTE VIII

[0243] In one aspect, the disclosed compounds can be prepared as shown below.SCHEME 8A.

[0244] Compounds are represented in generic form, wherein A2 (or A1 when A2 is absent)contains an amine such that the terminus of 8.1 is NH, wherein A3is –(C2-C8 alkylene)–, – (C2-C8 alkylene)O–, or –C≡C–, and with other substituents as noted in compound descriptions elsewhere herein. A more specific non-limiting example of the synthesis shown in Scheme 8A is set forth below. SCHEME 8B.

[0245] In one aspect, compounds of type 8.6, and similar compounds, can be preparedaccording to reaction Scheme 8B above. Thus, compounds of type 8.6 can be prepared by a reductive amination between an appropriate amine, e.g., 8.4 as shown above, and an appropriate aldehyde, e.g., 8.5 as shown above. The reaction can be carried out in the presence of an appropriate reducing agent, e.g., sodium triacetoxyborohydride, in an appropriate solvent system, e.g., dichloromethane (DCM) and dimethylsulfoxide (DMSO). As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 8.1 and 8.2) can be substituted in the reaction to provide compounds similar to Formula 8.3.9. ROUTE IX

[0246] In one aspect, the disclosed compounds can be prepared as shown below.SCHEME 9A.

[0247] Compounds are represented in generic form, wherein X1 is a halogen, wherein A4 (orA2when A3and A4are absent or A1when A2, A3, and A4are absent) contains an amine such that the terminus of 9.1 is NH, and with other substituents as noted in compound descriptions elsewhere herein. A more specific non-limiting example of the synthesis shown in Scheme 9A is set forth below. SCHEME 9B.

[0248] In one aspect, compounds of type 9.6, and similar compounds, can be preparedaccording to reaction Scheme 9B above. Thus, compounds of type 9.6 can be prepared by a coupling reaction between an appropriate amine, e.g., 9.4 as shown above, and an appropriate aryl halide, e.g., 9.5 as shown above. The coupling reaction can be carried out in the presence of an appropriate catalyst system, e.g., nickel (II) bromide ethylene glycol dimethyl ether complex and tris(2,2’-bipyridine)ruthenium (II) hexafluorophosphate, and an appropriate base, e.g., 1,4-diazabicyclo[2.2.2]octane (DABCO), in an appropriate solvent, e.g., dimethylsulfoxide (DMSO). As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 9.1 and 9.2) can be substituted in the reaction to provide compounds similar to Formula 9.3.D. PHARMACEUTICAL COMPOSITIONS

[0249] In one aspect, disclosed are pharmaceutical compositions comprising a therapeuticallyeffective amount of a disclosed compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0250] Thus, in one aspect, disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a compounds having a structure represented by formula:, wherein L is an E3 ligase binding ligand; wherein Q is selected from –N= and –CH=; wherein Z is a bifunctional linker; wherein R1is a structure selected from:wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein R3is selected from – CHF2, –CF3, and –CN, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0251] In one aspect, disclosed are pharmaceutical compositions comprising a therapeuticallyeffective amount of a compound selected from: ,,,,,,or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0252] In various aspects, the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, e.g., administration by drops or injection, intravenous, topical, or oral administration.

[0253] The nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0254] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0255] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt ofthe compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0256] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0257] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques

[0258] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free- flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0259] The pharmaceutical compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0260] In a various aspects, the pharmaceutical composition is used to treat a disorder associated with activity of AP2 associated kinase 1 (AAK1). In a further aspect, the disorder is cancer, pain, a neurodegenerative disease, or a viral infection. In a still further aspect, thecancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). In yet a further aspect, the cancer is ovarian cancer. In a further aspect, the neurodegenerative disease is selected from Alzheimer’s disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, and Lewy body disease. In an even futher aspect, the viral infection is selected from human immunodeficiency virus (HIV), human papillomavirus (HPV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), dengue (DENV), influenza, West Nile virus (WNV), and zika (ZIKV).E. METHODS OF DEGRADING A TARGET PROTEIN IN A CELL

[0261] In one aspect, disclosed are methods of degrading a target protein in a cell, the methodcomprising contacting the cell with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0262] Thus, in one aspect, disclosed are methods of degrading a target protein in a cell, themethod comprising contacting the cell with an effective amount of a compound having a structure represented by formula:, wherein L is an E3 ligase binding ligand; wherein Q is selected from –N= and –CH=; wherein Z is a bifunctional linker; wherein R1is a structure selected from:wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein R3is selected from – CHF2, –CF3, and –CN, or a pharmaceutically acceptable salt thereof.

[0263] In one aspect, disclosed are methods of degrading a target protein in a cell, the methodcomprising contacting the cell with an effective amount of a compound selected from: ,,,,,,or a pharmaceutically acceptable salt thereof.

[0264] In various aspects, the target protein is AP2 associated kinase 1 (AAK1).

[0265] In various aspects, the cell in mammalian. In a further aspect, the cell is human. In astill further aspect, the cell has been isolated from a mammal prior to the contacting step.

[0266] In a further aspect, contacting is ex vivo. In a still further aspect, contacting is in vitro.

[0267] In various aspects, contacting is via administration to a mammal. In a further aspect,the mammal has been diagnosed with a need for degrading the target protein prior to the administering step. In a still further aspect, the mammal has been diagnosed with a need for degrading the target protein prior to the administering step. In yet a further aspect, the mammal has been diagnosed with a need for treatment of a cancer related to activity of the target protein prior to the administering step.F. METHODS OF DEGRADING A TARGET PROTEIN IN A SUBJECT

[0268] In one aspect, disclosed are methods of degrading a target protein in a subject in needthereof, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0269] Thus, in one aspect, disclosed are methods of degrading a target protein in a subject,the method comprising administering to the subject an effective amount of a compound having a structure represented by formula:, wherein L is an E3 ligase binding ligand; wherein Q is selected from= and –CH=; wherein Z is a bifunctional linker; wherein R1is a structure selected from:wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein R3is selected from – CHF2, –CF3, and –CN, or a pharmaceutically acceptable salt thereof.

[0270] In one aspect, disclosed are methods of degrading a target protein in a subject, themethod comprising administering to the subject an effective amount of a compound selected from: ,,,,,or a pharmaceutically acceptable salt thereof.

[0271] In various aspects, the subject is a mammal. In a further aspect, the mammal is ahuman.

[0272] In various aspects, administering is oral administration, intranasal administration,intramuscular administration, or intravenous administration. In a further aspect, administering is intravenous administration.

[0273] In various aspects, the subject has been diagnosed with a need for degrading the targetprotein prior to the administering step. In a further aspect, the method further comprises identifying a subject in need of degradation of the target protein.G. METHODS OF OF TREATING A DISORDER IN A SUBJECT

[0274] In one aspect, disclosed are methods of treating a disorder in a subject in need thereof,the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof, wherein the disorder is cancer, pain, a neurodegenerative disease, or a viral infection.

[0275] Thus, in one aspect, disclosed are methods of treating a disorder in a subject in needthereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by formula:, wherein L is an E3 ligase binding ligand; wherein Q is selected from= and –CH=; wherein Z is a bifunctional linker; wherein R1is a structure selected from:wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein R3is selected from – CHF2, –CF3, and –CN, or a pharmaceutically acceptable salt thereof, wherein the disorder is cancer, pain, a neurodegenerative disease, or a viral infection.

[0276] In one aspect, disclosed are methods of treating a disorder in a subject in need thereof,the method comprising administering to the subject an effective amount of a compound selected from:,,,, ,,,or a pharmaceutically acceptable salt thereof, wherein the disorder is cancer, pain, a neurodegenerative disease, or a viral infection.

[0277] In various aspects, the subject is a mammal. In a further aspect, the subject is human.

[0278] In various aspects, the subject has been diagnosed with a need for treatment of thedisorder prior to the administering step.

[0279] In various aspects, the method further comprises the step of identifying a subject inneed of treatment of the disorder.

[0280] In various aspects, the effective amount is a therapeutically effective amount. In afurther aspect, the effective amount is a prophylactically effective amount.

[0281] In various aspects, the disorder is associated with activity of AP2 associated kinase 1(AAK1).

[0282] In various aspects, the disorder is cancer. In a further aspect, the cancer is selectedfrom a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). In a still further aspect, the cancer is ovarian cancer.

[0283] In various aspects, the disorder is pain.

[0284] In various aspects, the disorder is a neurodegenerative disease. In a further aspect, the neurodegenerative disease is selected from Alzheimer’s disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, and Lewy body disease.

[0285] In various aspects, the disorder is a viral infection. In a further aspect, the viral infection is selected from human immunodeficiency virus (HIV), human papillomavirus (HPV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), dengue (DENV), influenza, West Nile virus (WNV), and zika (ZIKV). H. ADDITIONAL METHODS OF USING THE COMPOUNDS

[0286] The compounds and pharmaceutical compositions of the invention are useful in treating or controlling cancer (e.g., sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma)), pain (e.g., neuropathic pain, chronic pain), neurodegenerative diseases (e.g., Alzheimer’s disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, Lewy body disease), and viral infections (e.g., human immunodeficiency virus (HIV), human papillomavirus (HPV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), dengue (DENV), influenza, West Nile virus (WNV), zika (ZIKV)). To treat or control thecondition, the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian. The subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. The subject is preferably a mammal, such as a human. Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of cancer (e.g., sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma)), pain (e.g., neuropathic pain, chronic pain), neurodegenerative diseases (e.g., Alzheimer’s disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, Lewy body disease), and viral infections (e.g., human immunodeficiency virus (HIV), human papillomavirus (HPV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), dengue (DENV), influenza, West Nile virus (WNV), zika (ZIKV)).

[0287] The compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. A preparation can also be administered prophylactically; that is, administered forprevention of cancer (e.g., sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma)), pain (e.g., neuropathic pain, chronic pain), neurodegenerative diseases (e.g., Alzheimer’s disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, Lewy body disease), or viral infections (e.g., human immunodeficiency virus (HIV), human papillomavirus (HPV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), dengue (DENV), influenza, West Nile virus (WNV), zika (ZIKV)).

[0288] The therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. 1. USE OF COMPOUNDS

[0289] In one aspect, the invention relates to the use of a disclosed compound or a product of a disclosed method. In a further aspect, a use relates to the manufacture of a medicament for the treatment of cancer (e.g., sarcoma, a carcinoma, a hematological cancer, a solid tumor,breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma)), pain (e.g., neuropathic pain, chronic pain), neurodegenerative diseases (e.g., Alzheimer’s disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, Lewy body disease), or viral infections (e.g., human immunodeficiency virus (HIV), human papillomavirus (HPV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), dengue (DENV), influenza, West Nile virus (WNV), zika (ZIKV)).

[0290] Also provided are uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In a further aspect, the compound used is a product of a disclosed method of making.

[0291] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0292] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.

[0293] In various aspects, the use relates to a treatment of a disorder is associated with activity of AP2 associated kinase 1 (AAK1). In one aspect, the use is characterized in that the subject is a human. In one aspect, the use is characterized in that the disorder is cancer, pain, a neurodegenerative disease, or a viral infection.

[0294] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of cancer in a mammal. In a further aspect, the cancer is synovial sarcoma or rhabdomyosarcoma. 2. MANUFACTURE OF A MEDICAMENT

[0295] In one aspect, the invention relates to a method for the manufacture of a medicament for treating a disorder in a subject in need thereof, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent, wherein the disorder is cancer, pain, a neurodegenerative disease, or a viral infection.

[0296] As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the treatment of cancer (e.g., sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma)), pain (e.g., neuropathic pain, chronic pain), neurodegenerative diseases (e.g., Alzheimer’s disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, Lewy body disease), or viral infections (e.g., human immunodeficiency virus (HIV), human papillomavirus (HPV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), dengue (DENV), influenza, West Nile virus (WNV), zika (ZIKV)). The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over areasonable timeframe. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal.

[0297] The total amount of the compound of the present disclosure administered in a typicaltreatment is preferably between about 0.05 mg / kg and about 100 mg / kg of body weight for mice, and more preferably between 0.05 mg / kg and about 50 mg / kg of body weight for mice, and between about 100 mg / kg and about 500 mg / kg of body weight for humans, and more preferably between 200 mg / kg and about 400 mg / kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.

[0298] The size of the dose also will be determined by the route, timing and frequency ofadministration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.

[0299] Thus, in one aspect, the invention relates to the manufacture of a medicamentcomprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or diluent. 3. KITS

[0300] In one aspect, disclosed are kits comprising a disclosed compound, and one or moreselected from: (a) an agent known to treat a disorder associated with activity of AP2 associated kinase 1 (AAK1); (b) instructions for administering the compound in connection with treating a a disorder associated with activity of AP2 associated kinase (AAK1); and (c) instructions for treating a disorder associated with activity of AP2 associated kinase 1 (AAK1).

[0301] Thus, in one aspect, disclosed are kits comprising a compound having a structurerepresented by formula:,wherein L is an E3 ligase binding ligand; wherein Q is selected from –N= and –CH=; wherein Z is a bifunctional linker; wherein R1is a structure selected from:wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein R3is selected from – CHF2, –CF3, and –CN, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent known to treat a disorder associated with activity of AP2 associated kinase 1 (AAK1); (b) instructions for administering the compound in connection with treating a disorder associated with activity of AP2 associated kinase 1 (AAK1); and (c) instructions for treating a disorder associated with activity of AP2 associated kinase 1 (AAK1).

[0302] In one aspect, disclosed are kits comprising a compound selected from:,,,,,,or a pharmaceutically acceptable salt thereof, (a) an agent known to treat a disorder associated with activity of AP2 associated kinase 1 (AAK1); (b) instructions for administering thecompound in connection with treating a disorder associated with activity of AP2 associated kinase 1 (AAK1); and (c) instructions for treating a disorder associated with activity of AP2 associated kinase 1 (AAK1).

[0303] In various aspects, the disorder is selected from cancer, pain, a neurodegenerative disease, and a viral infection.

[0304] In various aspects, the agent is a chemotherapeutic agent. In a further aspect, the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, and an mTor inhibitor agent.

[0305] In a further aspect, the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

[0306] In a further aspect, the antimetabolite agent is selected from gemcitabine, 5- fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

[0307] In a further aspect, the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

[0308] In a further aspect, the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

[0309] In a further aspect, the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0310] In various aspects, the agent in known to treat pain. In a further aspect, the agent is selected from a nonsteroidal anti-inflammatory drug (NSAID), an antimigraine agent, a COX-2 inhibitor, acetaminophen, ziconotide, a narcotic, and a salicylate.

[0311] In a further aspect, the NSAID is selected from flurbiprofen, ketorolac, ketoprofen, tolmetin, aspirin, ibuprofen, naproxen, indomethacin, sulindac, piroxicam, mefenamic acid, meloxicam, diclofenac, celecoxib, etodolac, etoricoxib, lumiracoxib, and rofecoxib.

[0312] In a further aspect, the COX-2 inhibitor is selected from celecoxib, rofecoxib, and valdecoxib.

[0313] In a further aspect, the narcotic is selected from alfentanil, buprenorphine, butorphano, codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, propoxyphene, tramadol, and tapentadol.

[0314] In a further aspect, the salicylate is selected form aspirin, diflunisal, magnesium salicylate, and salsalate.

[0315] In various aspects, the agent is known to treat a neurodegenerative disease. In a further aspect, the agent is selected from amantadine, apomorphine, baclofen, carbidopa, carbidopa / levodopa, dantrolene, donepiezil, entacapone, galantamine, levodopa, memantine, pramipexole, rasagiline, riluzole, rivastigmine, ropinirole, selegiline, tacrine, tetrabenazine, tizanidine, and tolcapone.

[0316] In various aspects, the agent is an antiviral agent. In a further aspect, the antiviral agent is selected from acemannan, acyclovir, acyclovir sodium, adamantanamine, adefovir, adenine arabinoside, alovudine, alvircept sudotox, amantadine hydrochloride, aranotin, arildone, atevirdine mesylate, avridine, cidofovir, cipamfylline, cytarabine hydrochloride, BMS 806, C31G, carrageenan, cellulose sulfate, cyclodextrins, dapivirine, delavirdine mesylate, desciclovir, dextrin 2-sulfate, didanosine, disoxaril, dolutegravir, edoxudine, enviradene, envirozime, etravirine, famciclovir, famotine hydrochloride, fiacitabine, fialuridine, fosarilate, foscarnet sodium, fosfonet sodium, FTC, ganciclovir, ganciclovir sodium, GSK 1265744, 9-2- hydroxy-ethoxy methylguanine, ibalizumab, idoxuridine, interferon, 5-iodo-2′-deoxyuridine, IQP-0528, kethoxal, lamivudine, lobucavir, maraviroc, memotine pirodavir, penciclovir, raltegravir, ribavirin, rimantadine hydrochloride, rilpivirine (TMC-278), saquinavir mesylate, SCH-C, SCH-D, somantadine hydrochloride, sorivudine, statolon, stavudine, T20, tilorone hydrochloride, TMC120, TMC125, trifluridine, trifluorothymidine, tenofovir, tenofovir alefenamide, tenofovir disoproxyl fumarate, prodrugs of tenofovir, UC-781, UK-427, UK-857, valacyclovir, valacyclovir hydrochloride, vidarabine, vidarabine phosphate, vidarabine sodium phosphate, viroxime, zalcitabene, zidovudine, and zinviroxime.

[0317] In various aspects, the compound and the agent are co-packaged.

[0318] The foregoing description illustrates and describes the disclosure. Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and / or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize thedisclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.

[0319] All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls. I. EXAMPLES

[0320] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0321] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way. 1. CHEMISTRY EXPERIMENTALS a. GENERAL CHEMISTRY ANALYSIS AND SYNTHESIS

[0322] The reagents (chemicals) were purchased from commercial sources and used without further purification unless otherwise specified. Thin layer chromatography (TLC) was performed on precoated plates and visualized by fluorescence quenching under UV light. Column chromatography was performed on silica gel. NMR spectra were recorded on a Bruker spectrometer at ambient temperature.1H NMR spectra are internally referenced to residual solvent signals (CDCl3, 7.26; DMSO-d6, 2.50). Data for1H NMR is reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz), integration. Mass spectra were acquired on LCMS systems using electrospray ionization methods.b. EXAMPLE 1: PREPARATION OF INTERMEDIATES

[0323] The intermediate compounds described herein are useful in the preparation ofconjugates of Formula (I). i. PREPARATION OF INTERMEDIATE TERT-BUTYL (S)-(4-METHYL-1-(4-(2-((4-(PIPERIDIN-4-YL)PHENYL)AMINO)PYRIDIN-4-YL)-2- (TRIFLUOROMETHYL)PHENOXY)PENTAN-2-YL)CARBAMATE (I-A)(a) STEP 1: SYNTHESIS OF BENZYL 4-(4-BROMOPHENYL)PIPERIDINE-1-CARBOXYLATE

[0324] To a solution of 4-(4-bromophenyl)piperidine (3.00 g, 12.49 mmol) and K2CO3 (5.18g, 37.48 mmol) in THF (30 mL) was added CbzCl (3.20 g, 18.74 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature overnight under an N2atmosphere. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 20% of EtOAc in hexanes) to afford benzyl 4-(4-bromophenyl)piperidine-1-carboxylate (4.00 g, 85% yield) as a yellow oil.1H NMR (600 MHz, CDCl3) δ 7.45 – 7.41 (m, 2H), 7.40 – 7.35 (m, 4H), 7.35 – 7.30 (m, 1H), 7.08 – 7.05 (m, 2H), 5.16 (s, 2H), 4.42 – 4.26 (m, 2H), 2.95 – 2.80 (m, 2H), 2.70 – 2.57 (m, 1H), 1.86 – 1.75 (m, 2H), 1.64 – 1.56 (m, 2H). LC / MS (ESI) m / z 374.1 [M+H]+.(b) STEP 2: SYNTHESIS OF TERT-BUTYL (S)-(1-(4-BROMO-2- (TRIFLUOROMETHYL)PHENOXY)-4-METHYLPENTAN-2- YL)CARBAMATE

[0325] To a solution of 4-bromo-2-(trifluoromethyl)phenol (6.00 g, 24.90 mmol), tert-butyl (S)-(1-hydroxy-4-methylpentan-2-yl)carbamate (6.49 g, 29.87 mmol), and PPh3(8.49 g, 32.36 mmol) in THF (60 mL) was added DIAD (7.55 g, 37.34 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 20% of EtOAc in hexanes) to afford tert-butyl (S)-(1-(4-bromo-2-(trifluoromethyl)phenoxy)-4-methylpentan-2-yl)carbamate (9.23 g, 84% yield) as a yellow solid.1HNMR (600 MHz, CDCl3) δ 7.67 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 8.8, 2.5 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.67 (d, J = 8.3 Hz, 1H), 4.09 – 3.87 (m, 3H), 1.70 – 1.61 (m, 1H), 1.54 – 1.47 (m, 2H), 1.44 – 1.40 (m, 9H), 0.96 – 0.91 (m, 6H). (c) STEP 3: SYNTHESIS OF TERT-BUTYL (S)-(4-METHYL-1- (4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)- 2-(TRIFLUOROMETHYL)PHENOXY)PENTAN-2- YL)CARBAMATE

[0326] To a solution of tert-butyl (S)-(1-(4-bromo-2-(trifluoromethyl)phenoxy)-4- methylpentan-2-yl)carbamate (5.00 g, 11.36 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (4.33 g, 17.03 mmol) in 1,4-dioxane (60 mL) was added Pd(dppf)Cl2(0.83 g, 1.14 mmol), and KOAc (2.23 g, 22.71 mmol). The resulting mixture was stirred at 85 °C overnight under N2atmosphere. After completion of the reaction, the mixture was filtered through a pad of Celite, and the filtrate was concentrated. The residue was purified by flash column chromatography (0% to 20% of EtOAc in hexanes) to afford tert-butyl (S)-(4- methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan- 2-yl)carbamate (5.51 g, 99% yield) as a yellow foam.1H NMR (600 MHz, CDCl3) δ 8.03 – 7.98 (m, 1H), 7.91 (dd, J = 8.3, 1.6 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 4.72 (d, J = 9.0 Hz, 1H), 4.13 – 3.96 (m, 3H), 1.73 – 1.62 (m, 1H), 1.55 – 1.50 (m, 2H), 1.43 (s, 9H), 1.34 (s, 12H), 0.95 – 0.92 (m, 6H). LC / MS (ESI) m / z 488.2 [M+H]+. (d) STEP 4: SYNTHESIS OF TERT-BUTYL (S)-(1-(4-(2- AMINOPYRIDIN-4-YL)-2-(TRIFLUOROMETHYL)PHENOXY)-4-METHYLPENTAN-2- YL)CARBAMATE

[0327] To a solution of tert-butyl (S)-(4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate (5.50 g, 11.29 mmol) and 4- chloropyridin-2-amine (1.74 g, 13.54 mmol) in THF (60 mL) was added Pd2(dba)3(1.03 g, 1.13 mmol), XPhos (1.08 g, 2.26 mmol), and K3PO4(7.19 g, 33.86 mmol). The resulting mixture was stirred at 70 °C overnight under N2atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, followed by dilution with water and extraction with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 90% of EtOAc in hexanes) to afford tert-butyl (S)-(1-(4-(2- aminopyridin-4-yl)-2-(trifluoromethyl)phenoxy)-4-methylpentan-2-yl)carbamate (3.06 g, 61% yield) as a yellow solid.1H NMR (600 MHz, CDCl3) δ 8.11 (dd, J = 5.4, 0.7 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.70 (dd, J = 8.6, 2.3 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.82 (dd, J = 5.4, 1.6 Hz, 1H), 6.64 (dd, J = 1.6, 0.8 Hz, 1H), 4.73 (d, J = 8.8 Hz, 1H), 4.53 (s, 2H), 4.16 – 4.00 (m, 3H), 1.71 – 1.63 (m, 1H), 1.58 – 1.50 (m, 2H), 1.44 (s, 9H), 0.98 – 0.93 (m, 6H). LC / MS (ESI) m / z 454.1 [M+H]+. (e) STEP 5: SYNTHESIS OF BENZYL (S)-4-(4-((4-(4-((2- ((TERT-BUTOXYCARBONYL)AMINO)-4- METHYLPENTYL)OXY)-3- (TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDINE-1-CARBOXYLATE

[0328] To a solution of tert-butyl (S)-(1-(4-(2-aminopyridin-4-yl)-2- (trifluoromethyl)phenoxy)-4-methylpentan-2-yl)carbamate (1.80 g, 3.97 mmol) and benzyl 4- (4-bromophenyl)piperidine-1-carboxylate (2.08 g, 5.56 mmol) in 1,4-dioxane (30 mL) was added Pd2(dba)3 (0.36 g, 0.40 mmol), XPhos (0.38 g, 0.79 mmol), and Cs2CO3 (2.59 g, 7.94 mmol). The resulting mixture was stirred at 100 °C overnight under N2 atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, followed by dilution with water and extraction with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 70% of EtOAc in hexanes) to afford benzyl (S)-4-(4-((4-(4-((2-((tert- butoxycarbonyl)amino)-4-methylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2- yl)amino)phenyl)piperidine-1-carboxylate (2.42 g, 82% yield) as a brown solid.1H NMR (600MHz, CDCl3) δ 8.26 – 8.21 (m, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.7, 2.3 Hz, 1H), 7.40 – 7.35 (m, 4H), 7.34 – 7.30 (m, 3H), 7.20 – 7.15 (m, 2H), 7.06 (d, J = 8.6 Hz, 1H), 6.97 – 6.94 (m, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.60 (s, 1H), 5.16 (s, 2H), 4.71 (d, J = 8.9 Hz, 1H), 4.47 – 4.22 (m, 2H), 4.15 – 3.99 (m, 3H), 3.02 – 2.79 (m, 2H), 2.70 – 2.59 (m, 1H), 1.92 – 1.79 (m, 2H), 1.74 – 1.62 (m, 3H), 1.56 – 1.52 (m, 2H), 1.44 (s, 9H), 0.98 – 0.93 (m, 6H). LC / MS (ESI) m / z 747.0 [M+H]+. (f) STEP 6: SYNTHESIS OF TERT-BUTYL (S)-(4-METHYL-1-(4-(2-((4-(PIPERIDIN-4-YL)PHENYL)AMINO)PYRIDIN-4- YL)-2-(TRIFLUOROMETHYL)PHENOXY)PENTAN-2- YL)CARBAMATE (I-A)

[0329] To a solution of benzyl (S)-4-(4-((4-(4-((2-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)amino)phenyl)piperidine-1- carboxylate (0.61 g, 0.81 mmol) in MeOH (20 mL) was added Pd / C (10 wt. % loading) (60.0 mg). The resulting mixture was stirred at room temperature overnight under H2atmosphere. After completion of the reaction, the mixture was filtered through a pad of Celite, and the filtrate was concentrated directly to afford tert-butyl (S)-(4-methyl-1-(4-(2-((4-(piperidin-4- yl)phenyl)amino)pyridin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate (I-A) (0.50 g, 99% yield) as a gray solid.1H NMR (600 MHz, CDCl3) δ 8.23 (dd, J = 5.3, 0.7 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.6, 2.3 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.24 – 7.17 (m, 2H), 7.05 (d, J = 8.6 Hz, 1H), 6.96 (dd, J = 1.5, 0.8 Hz, 1H), 6.89 (dd, J = 5.3, 1.6 Hz, 1H), 6.62 (s, 1H), 4.72 (d, J = 8.9 Hz, 1H), 4.16 – 4.01 (m, 3H), 3.24 – 3.13 (m, 2H), 2.81 – 2.71 (m, 2H), 2.65 – 2.57 (m, 1H), 2.07 – 1.87 (m, 2H), 1.87 – 1.81 (m, 2H), 1.69 – 1.62 (m, 2H), 1.57 – 1.51 (m, 2H), 1.44 (s, 9H), 0.99 – 0.91 (m, 6H). LC / MS (ESI) m / z 613.3 [M+H]+. ii. PREPARATION OF INTERMEDIATE TERT-BUTYL (S)-(1-(2-CYANO-4-(2-((4-(PIPERIDIN-4-YL)PHENYL)AMINO)PYRIDIN-4- YL)PHENOXY)-4-METHYLPENTAN-2-YL)CARBAMATE (I-B)

[0330] I-B was prepared by following the similar procedure for the preparation of I-A. 1HNMR (600 MHz, CDCl3) δ 8.23 (d, J = 5.3 Hz, 1H), 7.81 – 7.66 (m, 2H), 7.32 – 7.27 (m, 2H), 7.26 – 7.19 (m, 2H), 7.06 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 1.7 Hz, 1H), 6.84 (dd, J = 5.3, 1.5 Hz, 1H), 6.70 (s, 1H), 4.77 (d, J = 8.7 Hz, 1H), 4.22 – 3.97 (m, 3H), 3.31 – 3.11 (m, 2H), 2.84 – 2.70 (m, 2H), 2.68 – 2.57 (m, 1H), 2.08 – 1.95 (m, 2H), 1.90 – 1.81 (m, 2H), 1.71 – 1.55 (m, 4H), 1.44 (s, 9H), 1.04 – 0.86 (m, 6H). LC / MS (ESI) m / z 570.2 [M+H]+. iii. PREPARATION OF INTERMEDIATE TERT-BUTYL (S)-(4-METHYL-1-(4-(2-(PIPERIDIN-4-YLAMINO)PYRIDIN-4-YL)-2- (TRIFLUOROMETHYL)PHENOXY)PENTAN-2-YL)CARBAMATE (I-C)(a) STEP 1: SYNTHESIS OF BENZYL 4-((4-CHLOROPYRIDIN-2-YL)AMINO)PIPERIDINE-1-CARBOXYLATE

[0331] To a solution of 2-bromo-4-chloropyridine (1.50 g, 7.79 mmol) and benzyl 4-aminopiperidine-1-carboxylate (2.19 g, 9.35 mmol) in 1,4-dioxane (20 mL) was added Pd2(dba)3(0.71 g, 0.78 mmol), XPhos (0.74 g, 1.56 mmol), and Cs2CO3(5.08 g, 15.59 mmol). The resulting mixture was stirred at 100 °C overnight under N2atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, followed by dilution with water and extraction with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 40% of EtOAc in hexanes) to afford benzyl 4-((4-chloropyridin-2- yl)amino)piperidine-1-carboxylate (0.61 g, 22% yield) as an orange foam.1H NMR (600 MHz, CDCl3) δ 7.96 (d, J = 5.5 Hz, 1H), 7.37 – 7.30 (m, 5H), 6.57 (dd, J = 5.5, 1.7 Hz, 1H), 6.36 (d,J = 1.7 Hz, 1H), 5.14 (s, 2H), 4.44 (d, J = 7.9 Hz, 1H), 4.20 – 4.07 (m, 2H), 3.84 – 3.78 (m, 1H), 3.11 – 2.94 (m, 2H), 2.09 – 1.99 (m, 2H), 1.42 – 1.35 (m, 2H). (b) STEP 2: SYNTHESIS OF BENZYL (S)-4-((4-(4-((2-((TERT- BUTOXYCARBONYL)AMINO)-4-METHYLPENTYL)OXY)-3- (TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PIPERIDINE-1-CARBOXYLATE

[0332] To a solution of benzyl 4-((4-chloropyridin-2-yl)amino)piperidine-1-carboxylate (250.0 mg, 0.72 mmol) and tert-butyl (S)-(4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate (422.8 mg, 0.87 mmol) in THF (5 mL) and H2O (0.5 mL) was added Pd2(dba)3(66.1 mg, 0.07 mmol), XPhos (68.9 mg, 0.14 mmol), and K3PO4(383.6 mg, 1.81 mmol). The resulting mixture was stirred at 70 °C overnight under N2atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, followed by dilution with water and extraction with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 50% of EtOAc in hexanes) to afford benzyl (S)-4-((4-(4-((2-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)- 3-(trifluoromethyl)phenyl)pyridin-2-yl)amino)piperidine-1-carboxylate (303.0 mg, 62% yield) as an orange solid.(600 MHz, CDCl3) δ 8.12 (dd, J = 5.3, 0.7 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.6, 2.3 Hz, 1H), 7.40 – 7.30 (m, 5H), 7.06 (d, J = 8.7 Hz, 1H), 6.74 (dd, J = 5.4, 1.5 Hz, 1H), 6.48 (dd, J = 1.5, 0.7 Hz, 1H), 5.14 (s, 2H), 4.71 (d, J = 8.9 Hz, 1H), 4.41 (d, J = 8.0 Hz, 1H), 4.23 – 4.02 (m, 5H), 4.00 – 3.89 (m, 1H), 3.16 – 2.98 (m, 2H), 2.14 – 2.05 (m, 2H), 1.72 – 1.65 (m, 1H), 1.56 – 1.52 (m, 2H), 1.44 (s, 11H), 0.98 – 0.93 (m, 6H). LC / MS (ESI) m / z 671.4 [M+H]+. (c) STEP 3: SYNTHESIS OF TERT-BUTYL (S)-(4-METHYL-1- (4-(2-(PIPERIDIN-4-YLAMINO)PYRIDIN-4-YL)-2- (TRIFLUOROMETHYL)PHENOXY)PENTAN-2- YL)CARBAMATE (I-C)

[0333] To a solution of benzyl (S)-4-((4-(4-((2-((tert-butoxycarbonyl)amino)-4- methylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)amino)piperidine-1-carboxylate (270.0 mg, 0.40 mmol) in MeOH (5 mL) was added Pd / C (10 wt. % loading) (27.0 mg). The resulting mixture was stirred at room temperature for 2 hours under H2atmosphere. After completion of the reaction, the mixture was filtered through a pad of Celite, and the filtrate wasconcentrated directly to afford tert-butyl (S)-(4-methyl-1-(4-(2-(piperidin-4-ylamino)pyridin-4- yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate (I-C) (214.1 mg, 99% yield) as a gray solid.1H NMR (600 MHz, CDCl3) δ 8.12 (d, J = 5.3 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.70 (dd, J = 8.5, 2.3 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.72 (dd, J = 5.3, 1.6 Hz, 1H), 6.48 (t, J = 1.2 Hz, 1H), 4.72 (d, J = 8.9 Hz, 1H), 4.49 (d, J = 8.0 Hz, 1H), 4.19 – 3.99 (m, 3H), 3.86 – 3.76 (m, 1H), 3.18 – 3.05 (m, 2H), 2.82 – 2.73 (m, 2H), 2.13 – 2.05 (m, 2H), 1.70 – 1.67 (m, 1H), 1.56 – 1.51 (m, 2H), 1.51 – 1.30 (m, 11H), 1.00 – 0.90 (m, 6H). LC / MS (ESI) m / z 537.4 [M+H]+. iv. PREPARATION OF INTERMEDIATE TERT-BUTYL (S)-(1-(2-CYANO-4-(2-(PIPERIDIN-4-YLAMINO)PYRIDIN-4-YL)PHENOXY)-4- METHYLPENTAN-2-YL)CARBAMATE (I-D)

[0334] I-D was prepared by following the similar procedure for the preparation of I-C. 1HNMR (600 MHz, CDCl3) δ 8.12 (d, J = 5.1 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.73 (dd, J = 8.7, 2.4 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 6.68 (dd, J = 5.3, 1.6 Hz, 1H), 6.44 (t, J = 1.2 Hz, 1H), 4.77 (d, J = 8.7 Hz, 1H), 4.53 (d, J = 8.1 Hz, 1H), 4.22 – 3.96 (m, 3H), 3.82 – 3.74 (m, 1H), 3.17 – 3.08 (m, 2H), 2.83 – 2.74 (m, 2H), 2.13 – 2.06 (m, 2H), 1.73 – 1.68 (m, 1H), 1.65 – 1.52 (m, 2H), 1.47 – 1.37 (m, 11H), 0.98 – 0.95 (m, 6H). LC / MS (ESI) m / z 494.3 [M+H]+. v. PREPARATION OF (S)-5-((2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-N-(4-(PIPERIDIN-4-YL)PHENYL)-[2,4'- BIPYRIDIN]-2'-AMINE (I-E)(a) STEP 1: SYNTHESIS OF 6-BROMO-2-(DIFLUOROMETHYL)-3-FLUOROPYRIDINE

[0335] To a solution of 6-bromo-3-fluoropicolinaldehyde (2.70 g, 13.24 mmol) in DCM (50mL) was added DAST (4.69 g, 29.12 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was quenched with sat. NaHCO3 (aq.) and extracted with DCM. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified byflash column chromatography (0% to 24% of EtOAc in hexanes) to afford 6-bromo-2- (difluoromethyl)-3-fluoropyridine (2.87 g, 92% yield) as a light brown solid.1H NMR (600 MHz, CDCl3) δ 7.66 – 7.59 (m, 1H), 7.44 (t, J = 8.7 Hz, 1H), 6.70 (t, J = 53.4 Hz, 1H). (b) STEP 2: SYNTHESIS OF (9H-FLUOREN-9-YL)METHYL (S)- (1-HYDROXY-2,4-DIMETHYLPENTAN-2-YL)CARBAMATE

[0336] To a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2,4- dimethylpentanoic acid (4.00 g, 10.89 mmol) and DIEA (1.69 g, 13.06 mmol) in THF (40 mL) was added isobutyl chloroformate (1.56 g, 11.43 mmol) dropwise at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 hour, then NaBH4 (1.24 g, 32.66 mmol) and H2O (4 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was quenched with 1 M HCl (aq.) and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 25% of EtOAc in hexanes) to afford (9H-fluoren-9-yl)methyl (S)-(1- hydroxy-2,4-dimethylpentan-2-yl)carbamate (3.82 g, 99% yield) as a colorless oil.1H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 7.5 Hz, 2H), 7.58 (dd, J = 7.8, 3.0 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.32 (td, J = 7.4, 1.1 Hz, 2H), 4.81 (s, 1H), 4.52 – 4.35 (m, 2H), 4.20 (t, J = 6.5 Hz, 1H), 3.80 – 3.64 (m, 1H), 3.61 – 3.47 (m, 1H), 1.85 – 1.66 (m, 2H), 1.47 – 1.37 (m, 1H), 1.22 (s, 3H), 1.04 – 0.83 (m, 6H). LC / MS (ESI) m / z 354.3 [M+H]+. (c) STEP 3: SYNTHESIS OF (S)-2-AMINO-2,4- DIMETHYLPENTAN-1-OL

[0337] To a solution of (9H-fluoren-9-yl)methyl (S)-(1-hydroxy-2,4-dimethylpentan-2- yl)carbamate (3.80 g, 10.75 mmol) in DCM (40 mL) was added diethylamine (2.36 g, 32.25 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated to afford (S)-2-amino-2,4-dimethylpentan- 1-ol (1.40 g, 99% yield) as a light yellow oil. The resulting residue was used directly without purification. LC / MS (ESI) m / z 132.2 [M+H]+. (d) STEP 4: SYNTHESIS OF (S)-1-((6-BROMO-2- (DIFLUOROMETHYL)PYRIDIN-3-YL)OXY)-2,4- DIMETHYLPENTAN-2-AMINE

[0338] A suspension of (S)-2-amino-2,4-dimethylpentan-1-ol (1.50 g, 11.43 mmol), 6-bromo- 2-(difluoromethyl)-3-fluoropyridine (2.58 g, 11.43 mmol), and tBuOK (1.54 g, 13.72 mmol) inTHF (30 mL) was stirred at 80 °C overnight under N2atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by flash column chromatography (0% to 12% of MeOH in DCM) to afford (S)-1- ((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine (2.49 g, 61% yield) as a brown oil.1H NMR (600 MHz, DMSO-d6) δ 7.78 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.22 (t, J = 53.4 Hz, 1H), 3.89 (s, 2H), 1.82 – 1.73 (m, 1H), 1.49 – 1.35 (m, 2H), 1.15 (s, 3H), 0.94 – 0.88 (m, 6H). LC / MS (ESI) m / z 337.0 [M+H]+. (e) STEP 5: SYNTHESIS OF TERT-BUTYL (S)-(1-((6-BROMO-2- (DIFLUOROMETHYL)PYRIDIN-3-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE

[0339] To a solution of (S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4- dimethylpentan-2-amine (2.10 g, 6.23 mmol) and DIEA (1.61 g, 12.46 mmol) in DCM (30 mL) was added Boc2O (1.63 g, 7.47 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated. The residue was purified by flash column chromatography (0% to 20% of EtOAc in hexanes) to afford tert- butyl (S)-(1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2- yl)carbamate (2.61 g, 96% yield) as a light brown oil.1H NMR (600 MHz, CDCl3) δ 7.49 (dd, J = 8.7, 1.1 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 6.72 (t, J = 53.9 Hz, 1H), 4.50 (s, 1H), 4.30 (d, J = 8.7 Hz, 1H), 4.06 (d, J = 8.8 Hz, 1H), 1.89 – 1.84 (m, 1H), 1.84 – 1.76 (m, 1H), 1.44 (dd, J = 14.1, 5.0 Hz, 1H), 1.37 – 1.34 (m, 12H), 1.00 – 0.95 (m, 6H). (f) STEP 6: SYNTHESIS OF BENZYL 4-(4- NITROPHENYL)PIPERIDINE-1-CARBOXYLATE

[0340] To a solution of 4-(4-nitrophenyl)piperidine (2.50 g, 12.12 mmol) and K2CO3(5.03 g, 36.36 mmol) in THF (30 mL) was added CbzCl (3.10 g, 18.18 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature overnight under an N2atmosphere. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 20% of EtOAc in hexanes) to afford benzyl 4-(4-nitrophenyl)piperidine-1-carboxylate (3.82 g, 92% yield) as a yellow solid.1H NMR (600 MHz, CDCl3) δ 8.20 – 8.14 (m, 2H), 7.41 – 7.31 (m, 7H), 5.16 (s, 2H), 4.52 – 4.21 (m, 2H), 3.00 – 2.84 (m, 2H), 2.84 – 2.75 (m, 1H), 1.94 – 1.80 (m, 2H), 1.73 – 1.61 (m, 2H).(g) STEP 7: SYNTHESIS OF BENZYL 4-(4- AMINOPHENYL)PIPERIDINE-1-CARBOXYLATE

[0341] To a solution of benzyl 4-(4-nitrophenyl)piperidine-1-carboxylate (3.30 g, 9.70 mmol) in ACN (60 mL) and sat. NH4Cl (aq.) (30 mL) was added Zn powder (3.80 g, 58.17 mmol). The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 80% of EtOAc in hexanes) to afford benzyl 4-(4-aminophenyl)piperidine-1-carboxylate (2.00 g, 66% yield) as a light yellow solid.NMR (600 MHz, CDCl3) δ 7.41 – 7.29 (m, 5H), 7.01 – 6.96 (m, 2H), 6.67 – 6.62 (m, 2H), 5.16 (s, 2H), 4.38 – 4.24 (m, 2H), 3.71 – 3.49 (m, 2H), 2.98 – 2.80 (m, 2H), 2.61 – 2.52 (m, 1H), 1.86 – 1.76 (m, 2H), 1.66 – 1.55 (m, 2H). LC / MS (ESI) m / z 311.1 [M+H]+. (h) STEP 8: SYNTHESIS OF BENZYL 4-(4-((4- CHLOROPYRIDIN-2-YL)AMINO)PHENYL)PIPERIDINE-1- CARBOXYLATE

[0342] To a solution of benzyl 4-(4-aminophenyl)piperidine-1-carboxylate (1.50 g, 4.83 mmol) and 2-bromo-4-chloropyridine (1.21 g, 6.28 mmol) in 1,4-dioxane (30 mL) was added RuPhos Pd G4 (0.40 g, 0.48 mmol), and Cs2CO3(3.15 g, 9.67 mmol). The resulting mixture was stirred at 100 °C overnight under N2atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, followed by dilution with water and extraction with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 80% of EtOAc in hexanes) to afford benzyl 4-(4-((4-chloropyridin-2- yl)amino)phenyl)piperidine-1-carboxylate (0.79 g, 39% yield) as a pink solid.1H NMR (600 MHz, CDCl3) δ 8.07 (d, J = 5.5 Hz, 1H), 7.41 – 7.35 (m, 4H), 7.34 – 7.30 (m, 1H), 7.25 (dd, J = 8.6, 2.5 Hz, 2H), 7.20 – 7.16 (m, 2H), 6.79 (d, J = 1.8 Hz, 1H), 6.71 (dd, J = 5.4, 1.7 Hz, 1H), 6.59 (s, 1H), 5.16 (s, 2H), 4.51 – 4.18 (m, 2H), 3.02 – 2.78 (m, 2H), 2.73 – 2.60 (m, 1H), 1.95 – 1.76 (m, 2H), 1.70 – 1.60 (m, 2H). LC / MS (ESI) m / z 422.4 [M+H]+.(i) STEP 9: SYNTHESIS OF BENZYL 4-(4-((4-(4,4,5,5- TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDINE-1-CARBOXYLATE

[0343] To a solution of benzyl 4-(4-((4-chloropyridin-2-yl)amino)phenyl)piperidine-1- carboxylate (0.50 g, 1.19 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.45 g, 1.78 mmol) in 1,4-dioxane (6 mL) was added Pd(dppf)Cl2(86.3 mg, 0.12 mmol), and KOAc (0.23 g, 2.37 mmol). The resulting mixture was stirred at 100 °C overnight under N2atmosphere. After completion of the reaction, the mixture was filtered through a pad of Celite, and the filtrate was concentrated to afford benzyl 4-(4-((4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2-yl)amino)phenyl)piperidine-1-carboxylate (602.0 mg, 99% yield) as an orange foam. The resulting residue was used directly without purification. LC / MS (ESI) m / z 513.9 [M+H]+. (j) STEP 10: SYNTHESIS OF BENZYL (S)-4-(4-((5-((2-((TERT- BUTOXYCARBONYL)AMINO)-2,4- DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'- BIPYRIDIN]-2'-YL)AMINO)PHENYL)PIPERIDINE-1- CARBOXYLATE

[0344] To a solution of tert-butyl (S)-(1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4- dimethylpentan-2-yl)carbamate (350.0 mg, 0.80 mmol) and benzyl 4-(4-((4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)amino)phenyl)piperidine-1-carboxylate (534.2 mg, 1.04 mmol) in THF (6 mL) was added Pd2(dba)3(73.2 mg, 0.08 mmol), XPhos (76.3 mg, 0.16 mmol), and K3PO4(509.6 mg, 2.40 mmol). The resulting mixture was stirred at 80 °C overnight under N2atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, followed by dilution with water and extraction with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 46% of EtOAc in hexanes) to afford benzyl (S)-4-(4-((5-((2-((tert-butoxycarbonyl)amino)-2,4- dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)amino)phenyl)piperidine-1- carboxylate (560.0 mg, 94% yield) as an orange foam.1H NMR (600 MHz, CDCl3) δ 8.27 (dd, J = 5.3, 0.7 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.45 – 7.30 (m, 9H), 7.25 – 7.23 (m, 1H), 7.20 – 7.15 (m, 2H), 6.84 (t, J = 54.2 Hz, 1H), 6.60 (s, 1H), 5.16 (s, 2H), 4.55 (s, 1H), 4.45 – 4.24 (m, 3H), 4.16 – 4.07 (m, 1H), 3.01 – 2.78 (m, 2H), 2.71 – 2.61 (m, 1H), 1.92 – 1.78 (m, 4H), 1.66 –1.60 (m, 2H), 1.49 (dd, J = 14.1, 5.1 Hz, 1H), 1.43 – 1.33 (m, 12H), 1.02 – 0.97 (m, 6H). LC / MS (ESI) m / z 744.1 [M+H]+. (k) STEP 11: SYNTHESIS OF TERT-BUTYL (S)-(1-((6-(DIFLUOROMETHYL)-2'-((4-(PIPERIDIN-4- YL)PHENYL)AMINO)-[2,4'-BIPYRIDIN]-5-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE (I-E)

[0345] To a solution of benzyl (S)-4-(4-((5-((2-((tert-butoxycarbonyl)amino)-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)amino)phenyl)piperidine-1- carboxylate (530.0 mg, 0.71 mmol) in MeOH (10 mL) was added Pd / C (10 wt. % loading) (50.0 mg). The resulting mixture was stirred at room temperature for 5 hours under H2atmosphere. After completion of the reaction, the mixture was filtered through a pad of Celite, and the filtrate was concentrated directly to afford tert-butyl (S)-(1-((6-(difluoromethyl)-2'-((4- (piperidin-4-yl)phenyl)amino)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (I-E) (433.1 mg, 99% yield) as a dark foam.1H NMR (600 MHz, CDCl3) δ 8.29 – 8.23 (m, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.45 – 7.39 (m, 2H), 7.37 – 7.32 (m, 2H), 7.25 – 7.18 (m, 3H), 6.83 (t, J = 54.2 Hz, 1H), 6.62 (s, 1H), 4.56 (s, 1H), 4.38 – 4.29 (m, 1H), 4.11 (d, J = 8.8 Hz, 1H), 3.26 – 3.12 (m, 2H), 2.83 – 2.71 (m, 2H), 2.67 – 2.58 (m, 1H), 1.90 – 1.79 (m, 4H), 1.70 – 1.61 (m, 2H), 1.49 (dd, J = 14.1, 5.1 Hz, 1H), 1.43 – 1.32 (m, 12H), 1.01 – 0.96 (m, 6H). LC / MS (ESI) m / z 609.9 [M+H]+. vi. PREPARATION OF INTERMEDIATE (S)-4-((5-((2-((TERT-BUTOXYCARBONYL)AMINO)-2,4-DIMETHYLPENTYL)OXY)-6- (DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'-YL)AMINO)BENZOIC ACID (I-F)(a) STEP 1: SYNTHESIS OF TERT-BUTYL 4-((4-CHLOROPYRIDIN-2-YL)AMINO)BENZOATE

[0346] To a solution of tert-butyl 4-aminobenzoate (2.00 g, 10.35 mmol) and 2-bromo-4-chloropyridine (2.59 g, 13.45 mmol) in 1,4-dioxane (30 mL) was added Pd2(dba)3(942.4 mg, 1.03 mmol), XPhos (986.8 mg, 2.07 mmol), and Cs2CO3(6.74 g, 20.70 mmol). The resultingmixture was stirred at 100 °C overnight under a N₂ atmosphere. After completion of thereaction by checking the thin layer chromatography, the reaction mixture was cooled to room temperature and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 35% of EtOAc in hexanes) to afford tert-butyl 4-((4-chloropyridin-2-yl)amino)benzoate (831.9 mg, 26% yield) as a yellow solid.1H NMR (600 MHz, Chloroform-d) δ 8.14 (d, J = 5.4 Hz, 1H), 8.00 – 7.93 (m, 2H), 7.42 – 7.35 (m, 2H), 7.04 (s, 1H), 6.93 (d, J = 1.7 Hz, 1H), 6.81 (dd, J = 5.4, 1.7 Hz, 1H), 1.59 (s, 9H). LC / MS (ESI) m / z 305.0 [M+H]+.(b) STEP 2: SYNTHESIS OF TERT-BUTYL 4-((4-(4,4,5,5- TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)PYRIDIN-2- YL)AMINO)BENZOATE

[0347] To a solution of tert-butyl 4-((4-chloropyridin-2-yl)amino)benzoate (0.40 g, 1.31 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.50 g, 1.97 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl2(95.7 mg, 0.13 mmol), and KOAc (0.25 g, 2.62 mmol). The resulting mixture was stirred at 100 °C overnight under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure to give the crude residue, which was used directly without purification. (c) STEP 3: SYNTHESIS OF TERT-BUTYL (S)-4-((5-((2-((TERT- BUTOXYCARBONYL)AMINO)-2,4- DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'- BIPYRIDIN]-2'-YL)AMINO)BENZOATE

[0348] To a solution of tert-butyl tert-butyl (S)-(1-((6-bromo-2-(difluoromethyl)pyridin-3- yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (200.0 mg, 0.46 mmol) and tert-butyl 4-((4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)amino)benzoate (271.8 mg, 0.68 mmol) in THF (3 mL) was added Pd2(dba)3(41.1 mg, 0.045 mmol), XPhos (43.6 mg, 0.091 mmol), and K3PO4(291.2 mg, 1.37 mmol). The resulting mixture was stirred at 80 °C overnight under a N₂ atmosphere. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was cooled to room temperature and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 35% of EtOAc in hexanes) to afford tert-butyl (S)-4-((5-((2-((tert- butoxycarbonyl)amino)-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'- yl)amino)benzoate (268.0 mg, 94% yield) as an orange solid.1H NMR (600 MHz, Chloroform- d) δ 8.34 (dd, J = 5.3, 0.7 Hz, 1H), 8.00 – 7.93 (m, 2H), 7.80 (d, J = 8.7 Hz, 1H), 7.57 – 7.54 (m, 1H), 7.53 – 7.47 (m, 2H), 7.43 (d, J = 8.7 Hz, 1H), 7.33 (dd, J = 5.3, 1.5 Hz, 1H), 6.96 – 6.73 (m, 2H), 4.56 (s, 1H), 4.36 (d, J = 8.8 Hz, 1H), 4.13 (d, J = 8.8 Hz, 1H), 1.95 – 1.87 (m, 1H), 1.86 – 1.77 (m, 1H), 1.60 (s, 9H), 1.52 – 1.46 (m, 1H), 1.45 – 1.32 (m, 12H), 1.04 – 0.96 (m, 6H). LC / MS (ESI) m / z 627.3 [M+H]+.(d) STEP 4: SYNTHESIS OF (S)-4-((5-((2-((TERT- BUTOXYCARBONYL)AMINO)-2,4- DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'- BIPYRIDIN]-2'-YL)AMINO)BENZOIC ACID (I-F)

[0349] To a solution of tert-butyl (S)-4-((5-((2-((tert-butoxycarbonyl)amino)-2,4- dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)amino)benzoate (220.0 mg, 0.35 mmol) in MeOH (10 mL) was added 4 M HCl in 1,4-dioxane (10 mL) at room temperature. After stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was used directly for the next step without purification. To a solution of the above residue in DCM (15 mL) and DIEA (2 mL) was added (Boc)2O (612.8 mg, 2.81 mmol) at room temperature. After the reaction mixture was stirred for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue was used directly for the next step without purification. To a solution of the above residue in THF (4 mL) and MeOH (4 mL) was added 2 M LiOH (aq.) (4 mL) at room temperature. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was adjusted to pH 2- 3 by the addition of 0.1 M aqueous citric acid, and then extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 11% of MeOH in DCM) to afford (S)-4-((5-((2-((tert-butoxycarbonyl)amino)-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)- [2,4'-bipyridin]-2'-yl)amino)benzoic acid (168.8 mg, 84% yield) as an orange solid.(600 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.72 (s, 1H), 8.33 (d, J = 5.4 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.88 – 7.83 (m, 4H), 7.77 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 5.5, 1.5 Hz, 1H), 7.18 (t, J = 53.9 Hz, 1H), 6.64 (s, 1H), 4.41 – 4.31 (m, 1H), 4.08 (d, J = 9.1 Hz, 1H), 1.87 – 1.80 (m, 1H), 1.80 – 1.73 (m, 1H), 1.47 – 1.42 (m, 1H), 1.31 (s, 9H), 1.29 (s, 3H), 0.93 – 0.90 (m, 6H). LC / MS (ESI) m / z 571.2 [M+H]+. vii. PREPARATION OF INTERMEDIATE TERT-BUTYL (S)-(1-((6- (DIFLUOROMETHYL)-2'-((4-(PIPERAZIN-1-YL)PHENYL)AMINO)-[2,4'-BIPYRIDIN]-5-YL)OXY)-2,4-DIMETHYLPENTAN-2- YL)CARBAMATE (I-G)(a) STEP 1: SYNTHESIS OF BENZYL 4-(4-NITROPHENYL)PIPERAZINE-1-CARBOXYLATE

[0350] To a solution of 1-fluoro-4-nitrobenzene (3.00 g, 21.26 mmol) and DIEA (8.24 g,63.78 mmol) in DMAc (30 mL) was added benzyl piperazine-1-carboxylate (4.92 g, 22.32mmol) at room temperature. The reaction mixture was stirred at 80 °C overnight. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was cooled to room temperature, and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 40% of EtOAc in DCM) to afford benzyl 4-(4-nitrophenyl)piperazine-1-carboxylate (5.50 g, 76% yield) as an orange solid.1H NMR (600 MHz, Chloroform-d) δ 8.17 – 8.09 (m, 2H), 7.42 – 7.29 (m, 5H), 6.86 – 6.78 (m, 2H), 5.17 (s, 2H), 3.75 – 3.63 (m, 4H), 3.49 – 3.36 (m, 4H). (b) STEP 2: SYNTHESIS OF BENZYL 4-(4- AMINOPHENYL)PIPERAZINE-1-CARBOXYLATE

[0351] To a solution of benzyl 4-(4-nitrophenyl)piperazine-1-carboxylate (3.00 g, 8.79 mmol) in ACN (30 mL) and saturated aqueous NH4Cl (10 mL) was added Zn (2.87 g, 43.94 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was filtered with Celite. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 75% of EtOAc in hexanes) to afford benzyl 4-(4- aminophenyl)piperazine-1-carboxylate (2.59 g, 95% yield) as a brown solid.1H NMR (600 MHz, Chloroform-d) δ 7.41 – 7.29 (m, 5H), 6.83 – 6.78 (m, 2H), 6.68 – 6.62 (m, 2H), 5.16 (s, 2H), 3.70 – 3.61 (m, 4H), 3.46 (s, 2H), 3.07 – 2.92 (m, 4H). LC / MS (ESI) m / z 312.1 [M+H]+. (c) STEP 3: SYNTHESIS OF BENZYL 4-(4-((4- CHLOROPYRIDIN-2-YL)AMINO)PHENYL)PIPERAZINE-1- CARBOXYLATE

[0352] To a solution of benzyl 4-(4-aminophenyl)piperazine-1-carboxylate (1.00 g, 3.21 mmol) and 2-bromo-4-chloropyridine (0.80 g, 4.17 mmol) in 1,4-dioxane (20 mL) was added RuPhos Pd G4 (0.27 g, 0.32 mmol), and Cs2CO3(2.09 g, 6.42 mmol). The resulting mixture was stirred at 100 °C overnight under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was cooled to room temperature and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 50% of EtOAc in hexanes) to afford benzyl 4-(4-((4- chloropyridin-2-yl)amino)phenyl)piperazine-1-carboxylate (510.0 mg, 38% yield) as a brownfoam.1H NMR (600 MHz, Chloroform-d) δ 8.03 (d, J = 5.3 Hz, 1H), 7.39 – 7.31 (m, 5H), 7.23 – 7.17 (m, 2H), 6.95 – 6.92 (m, 2H), 6.69 – 6.63 (m, 2H), 6.59 (s, 1H), 5.17 (s, 2H), 3.69 – 3.67 (m, 4H), 3.16 – 3.06 (m, 4H). LC / MS (ESI) m / z 423.0 [M+H]+. (d) STEP 4: SYNTHESIS OF BENZYL 4-(4-((4-(4,4,5,5- TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERAZINE-1-CARBOXYLATE

[0353] To a solution of benzyl 4-(4-((4-chloropyridin-2-yl)amino)phenyl)piperazine-1- carboxylate (200.0 mg, 0.47 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (180.1 mg, 0.71 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl2 (34.3 mg, 0.047 mmol), and KOAc (92.8 mg, 0.95 mmol). The resulting mixture was stirred at 100 °C overnight under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure to give the crude residue, which was used directly without purification. (e) STEP 5: SYNTHESIS OF BENZYL (S)-4-(4-((5-((2-((TERT- BUTOXYCARBONYL)AMINO)-2,4- DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'- BIPYRIDIN]-2'-YL)AMINO)PHENYL)PIPERAZINE-1- CARBOXYLATE

[0354] To a solution of tert-butyl (S)-(1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4- dimethylpentan-2-yl)carbamate (200.0 mg, 0.46 mmol) and benzyl 4-(4-((4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)amino)phenyl)piperazine-1-carboxylate (242.3 mg, 0.47 mmol) in THF (5 mL) was added Pd2(dba)3(41.1 mg, 0.045 mmol), XPhos (43.6 mg, 0.091 mmol), and K3PO4(291.2 mg, 1.37 mmol). The resulting mixture was stirred at 80 °C overnight under a N₂ atmosphere. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was cooled to room temperature and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 40% of EtOAc in hexanes) to afford benzyl (S)-4-(4-((5-((2-((tert- butoxycarbonyl)amino)-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'- yl)amino)phenyl)piperazine-1-carboxylate (193.7 mg, 57% yield) as a yellow solid.1H NMR(600 MHz, Chloroform-d) δ 8.23 (dd, J = 5.3, 0.8 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.44 – 7.28 (m, 9H), 7.23 – 7.20 (m, 1H), 6.99 – 6.92 (m, 2H), 6.82 (t, J = 54.2 Hz, 1H), 6.50 (s, 1H), 5.17 (s, 2H), 4.55 (s, 1H), 4.37 – 4.28 (m, 1H), 4.16 – 4.08 (m, 1H), 3.73 – 3.63 (m, 4H), 3.22 – 3.00 (m, 4H), 1.92 – 1.87 (m, 1H), 1.85 – 1.79 (m, 1H), 1.52 – 1.47 (m, 1H), 1.42 – 1.34 (m, 12H), 1.01 – 0.96 (m, 6H). LC / MS (ESI) m / z 745.4 [M+H]+. (f) STEP 6: SYNTHESIS OF TERT-BUTYL (S)-(1-((6-(DIFLUOROMETHYL)-2'-((4-(PIPERAZIN-1- YL)PHENYL)AMINO)-[2,4'-BIPYRIDIN]-5-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE (I-G)

[0355] To a solution of benzyl (S)-4-(4-((5-((2-((tert-butoxycarbonyl)amino)-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)amino)phenyl)piperazine-1- carboxylate (170.0 mg, 0.22 mmol) in MeOH (5 mL) was added Pd / C (10 wt.% loading) (30.0 mg). The resulting mixture was stirred at room temperature overnight under a H2atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was filtered with Celite, and the filtrate was concentrated directly to afford tert-butyl (S)-(1-((6- (difluoromethyl)-2'-((4-(piperazin-1-yl)phenyl)amino)-[2,4'-bipyridin]-5-yl)oxy)-2,4- dimethylpentan-2-yl)carbamate (119.5 mg, 86% yield) as a brown foam. LC / MS (ESI) m / z 611.3 [M+H]+. viii. PREPARATION OF INTERMEDIATE TERT-BUTYL (S)-(1-((6-(DIFLUOROMETHYL)-2'-((5-(PIPERIDIN-4-YL)PYRIDIN-2- YL)AMINO)-[2,4'-BIPYRIDIN]-5-YL)OXY)-2,4-DIMETHYLPENTAN-2- YL)CARBAMATE (I-H)(a) STEP 1: SYNTHESIS OF BENZYL 6-AMINO-3',6'-DIHYDRO-[3,4'-BIPYRIDINE]-1'(2'H)-CARBOXYLATE

[0356] To a solution of 5-bromopyridin-2-amine (1.95 g, 11.27 mmol) and benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.80 g, 16.91 mmol) in 1,4-dioxane (42 mL) and H2O (14 mL) was added Pd(dppf)Cl2(826.0 mg, 1.13 mmol), and K3PO4(7.18 g, 33.81 mmol). The resulting mixture was stirred at 100 °C overnight under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was filtered with Celite, and the filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 100% of EtOAc in hexanes) to afford benzyl 6-amino-3',6'-dihydro- [3,4'-bipyridine]-1'(2'H)-carboxylate (3.36 g, 96% yield) as a brown oil.1H NMR (600 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.45 (dd, J = 8.6, 2.5 Hz, 1H), 7.41 – 7.29 (m, 5H), 6.47 (dd, J = 8.6, 0.8 Hz, 1H), 6.01 – 5.80 (m, 1H), 5.17 (s, 2H), 4.45 (s, 2H), 4.17 – 4.11 (m, 2H), 3.78 – 3.67 (m, 2H), 2.56 – 2.41 (m, 2H). LC / MS (ESI) m / z 310.1 [M+H]+. (b) STEP 2: SYNTHESIS OF BENZYL 6-((4-CHLOROPYRIDIN-2-YL)AMINO)-3',6'-DIHYDRO-[3,4'-BIPYRIDINE]-1'(2'H)- CARBOXYLATE

[0357] To a solution of benzyl benzyl 6-amino-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (5.00 g, 16.16 mmol) and 2-bromo-4-chloropyridine (4.67 g, 24.24 mmol) in 1,4- dioxane (75 mL) was added Pd2(dba)3(1.48 g, 1.62 mmol), XPhos (1.54 g, 3.23 mmol), andCs2CO3(10.53 g, 32.32 mmol). The resulting mixture was stirred at 100 °C overnight under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was cooled to room temperature, and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 50% of EtOAc in hexanes) to afford benzyl 6-((4-chloropyridin-2-yl)amino)-3',6'-dihydro-[3,4'- bipyridine]-1'(2'H)-carboxylate (3.52 g, 52% yield) as a yellow solid.1H NMR (600 MHz, Chloroform-d) δ 8.31 (d, J = 2.6 Hz, 1H), 8.14 (d, J = 5.4 Hz, 1H), 7.89 (s, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.61 (dd, J = 8.7, 2.5 Hz, 1H), 7.43 – 7.29 (m, 6H), 6.86 (dd, J = 5.4, 1.8 Hz, 1H), 6.11 – 5.89 (m, 1H), 5.19 (s, 2H), 4.24 – 4.12 (m, 2H), 3.78 – 3.66 (m, 2H), 2.62 – 2.45 (m, 2H). LC / MS (ESI) m / z 421.0 [M+H]+. (c) STEP 3: SYNTHESIS OF BENZYL 6-((4-(4,4,5,5- TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)PYRIDIN-2- YL)AMINO)-3',6'-DIHYDRO-[3,4'-BIPYRIDINE]-1'(2'H)- CARBOXYLATE

[0358] To a solution of benzyl 6-((4-chloropyridin-2-yl)amino)-3',6'-dihydro-[3,4'- bipyridine]-1'(2'H)-carboxylate (2,00 g, 4.75 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (1.81 g, 7.13 mmol) in 1,4-dioxane (30 mL) was added Pd(dppf)Cl2(347.2 mg, 0.47 mmol), and KOAc (932.7 mg, 9.50 mmol). The resulting mixture was stirred at 100 °C overnight under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure to give the crude residue, which was used directly without purification. (d) STEP 4: SYNTHESIS OF BENZYL (S)-6-((5-((2-((TERT- BUTOXYCARBONYL)AMINO)-2,4- DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'- BIPYRIDIN]-2'-YL)AMINO)-3',6'-DIHYDRO-[3,4'- BIPYRIDINE]-1'(2'H)-CARBOXYLATE

[0359] To a solution of tert-butyl (S)-(1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4- dimethylpentan-2-yl)carbamate (1.60 g, 3.66 mmol) and benzyl 6-((4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-yl)amino)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate(2.25 g, 4.39 mmol) in 1,4-dioxane (24 mL) and H2O (6 mL) was added Pd(dppf)Cl2(266.8 mg, 0.36 mmol), and K3PO4(2.33 g, 10.98 mmol). The resulting mixture was stirred at 100 °C for 7 hours under a N₂ atmosphere. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was cooled to room temperature and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 70% of EtOAc in hexanes) to afford benzyl (S)-6-((5-((2-((tert- butoxycarbonyl)amino)-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'- yl)amino)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (1.03 g, 38% yield) as a brown oil.1H NMR (600 MHz, Chloroform-d) δ 8.36 – 8.29 (m, 2H), 8.04 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.69 – 7.62 (m, 2H), 7.51 (s, 1H), 7.47 – 7.42 (m, 2H), 7.41 – 7.35 (m, 4H), 7.35 – 7.28 (m, 1H), 6.86 (t, J = 54.2 Hz, 1H), 6.11 – 5.93 (m, 1H), 5.19 (s, 2H), 4.57 (s, 1H), 4.36 (d, J = 8.7 Hz, 1H), 4.22 – 4.07 (m, 3H), 3.77 – 3.67 (m, 2H), 2.63 – 2.45 (m, 2H), 1.94 – 1.87 (m, 1H), 1.87 – 1.78 (m, 1H), 1.53 – 1.47 (m, 1H), 1.44 – 1.35 (m, 12H), 1.03 – 0.95 (m, 6H). LC / MS (ESI) m / z 743.3 [M+H]+. (e) STEP 5: SYNTHESIS OF TERT-BUTYL (S)-(1-((6- (DIFLUOROMETHYL)-2'-((5-(PIPERIDIN-4-YL)PYRIDIN-2- YL)AMINO)-[2,4'-BIPYRIDIN]-5-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE (I-H)

[0360] To a solution of benzyl (S)-6-((5-((2-((tert-butoxycarbonyl)amino)-2,4- dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)amino)-3',6'-dihydro-[3,4'- bipyridine]-1'(2'H)-carboxylate (1.00 g, 1.35 mmol) in MeOH (20 mL) was added Pd / C (10 wt.% loading) (200.0 mg). The resulting mixture was stirred at room temperature overnight under a H₂ atmosphere and then stirred at 50 °C for 7 hours under a H₂ atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was filtered with Celite, and the filtrate was concentrated directly to afford tert-butyl (S)-(1-((6- (difluoromethyl)-2'-((5-(piperidin-4-yl)pyridin-2-yl)amino)-[2,4'-bipyridin]-5-yl)oxy)-2,4- dimethylpentan-2-yl)carbamate (770.0 mg, 94% yield) as a dark oil. LC / MS (ESI) m / z 611.2 [M+H]+. ix. PREPARATION OF INTERMEDIATE TERT-BUTYL (S)-(1-((6- (DIFLUOROMETHYL)-2'-((5-(PIPERAZIN-1-YL)PYRIDIN-2-YL)AMINO)-[2,4'-BIPYRIDIN]-5-YL)OXY)-2,4-DIMETHYLPENTAN-2- YL)CARBAMATE (I-I)(a) STEP 1: SYNTHESIS OF BENZYL 4-(6-NITROPYRIDIN-3-YL)PIPERAZINE-1-CARBOXYLATE

[0361] To a solution of 1-(6-nitropyridin-3-yl)piperazine (2.50 g, 12.01 mmol) and K2CO3(4.98 g, 36.02 mmol) in THF (30 mL) was added CbzCl (2.66 g, 15.61 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 5 hours under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the reactionmixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 30% of EtOAc in DCM) to afford benzyl 4- (6-nitropyridin-3-yl)piperazine-1-carboxylate (3.84 g, 93% yield) as a yellow solid.1H NMR (600 MHz, Chloroform-d) δ 7.77 (d, J = 2.9 Hz, 1H), 7.39 – 7.29 (m, 5H), 7.26 – 7.23 (m, 1H), 6.58 – 6.51 (m, 1H), 5.24 – 4.78 (m, 4H), 3.69 – 3.56 (m, 4H), 3.03 – 2.84 (m, 4H). LC / MS (ESI) m / z 313.1 [M+H]+. (b) STEP 2: SYNTHESIS OF BENZYL 4-(6-AMINOPYRIDIN-3- YL)PIPERAZINE-1-CARBOXYLATE

[0362] To a solution of benzyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (2.00 g, 5.84 mmol) in ACN (21 mL) and saturated aqueous NH4Cl (7 mL) was added Zn (1.91 g, 29.21 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was filtered with Celite. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 8% of MeOH in EtOAc) to afford benzyl 4- (6-aminopyridin-3-yl)piperazine-1-carboxylate (1.60 g, 88% yield) as a gray solid.1H NMR (600 MHz, Chloroform-d) δ 7.77 (d, J = 2.9 Hz, 1H), 7.39 – 7.29 (m, 5H), 7.26 – 7.23 (m, 1H), 6.58 – 6.51 (m, 1H), 5.24 – 4.78 (m, 4H), 3.69 – 3.56 (m, 4H), 3.03 – 2.84 (m, 4H). LC / MS (ESI) m / z 313.1 [M+H]+. (c) STEP 3: SYNTHESIS OF BENZYL 4-(6-((4- CHLOROPYRIDIN-2-YL)AMINO)PYRIDIN-3- YL)PIPERAZINE-1-CARBOXYLATE

[0363] To a solution of benzyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (0.80 g, 2.56 mmol) and 2-bromo-4-chloropyridine (0.64 g, 3.33 mmol) in 1,4-dioxane (15 mL) was added Pd2(dba)3(234.2 mg, 0.25 mmol), XPhos (244.2 mg, 0.51 mmol), and t-BuONa (492.2 mg, 5.12 mmol). The resulting mixture was stirred at 100 °C overnight under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was cooled to room temperature and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 60% of EtOAc in hexanes) to afford benzyl 4-(6-((4-chloropyridin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (320.0 mg, 29% yield) as an off-white solid. (600 MHz, Chloroform-d) δ 8.10 (d, J = 5.4 Hz, 1H), 8.00 – 7.96 (m, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.47 – 7.31 (m, 7H), 7.28 (dd, J = 9.0, 3.0 Hz, 1H), 6.80 (dd, J = 5.4, 1.8 Hz, 1H), 5.17 (s, 2H), 3.72 – 3.64 (m, 4H), 3.16 – 3.01 (m, 4H). LC / MS (ESI) m / z 424.1 [M+H]+. (d) STEP 4: SYNTHESIS OF BENZYL 4-(6-((4-(4,4,5,5- TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)PYRIDIN-2- YL)AMINO)PYRIDIN-3-YL)PIPERAZINE-1-CARBOXYLATE

[0364] To a solution of benzyl 4-(6-((4-chloropyridin-2-yl)amino)pyridin-3-yl)piperazine-1- carboxylate (200.0 mg, 0.47 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (179.7 mg, 0.71 mmol) in 1,4-dioxane (4 mL) was added Pd(dppf)Cl2(34.0 mg, 0.047 mmol), and KOAc (92.6 mg, 0.94 mmol). The resulting mixture was stirred at 100 °C overnight under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure to give the crude residue, which was used directly without purification. (e) STEP 5: SYNTHESIS OF BENZYL (S)-4-(6-((5-((2-((TERT- BUTOXYCARBONYL)AMINO)-2,4- DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'- BIPYRIDIN]-2'-YL)AMINO)PYRIDIN-3-YL)PIPERAZINE-1- CARBOXYLATE

[0365] To a solution of tert-butyl (S)-(1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4- dimethylpentan-2-yl)carbamate (200.0 mg, 0.46 mmol) and benzyl 4-(6-((4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (235.7 mg, 0.46 mmol) in THF (5 mL) was added Pd2(dba)3(41.1 mg, 0.045 mmol), XPhos (43.6 mg, 0.091 mmol), and K3PO4(291.2 mg, 1.37 mmol). The resulting mixture was stirred at 80 °C overnight under a N₂ atmosphere. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was cooled to room temperature and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 100% of EtOAc in hexanes) to afford benzyl (S)-4-(6-((5-((2-((tert- butoxycarbonyl)amino)-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (102.3 mg, 30% yield) as a yellow solid.1H NMR (600 MHz, Chloroform-d) δ 8.30 (d, J = 5.3 Hz, 1H), 7.98 (d, J = 2.9 Hz, 1H), 7.91 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.40 – 7.35 (m, 5H), 7.35 – 7.28 (m, 3H), 6.86 (t, J = 54.2 Hz, 1H), 5.17 (s, 2H), 4.56 (s, 1H), 4.35 (d, J = 8.9 Hz, 1H), 4.17 – 4.10 (m, 1H), 3.74 – 3.67 (m, 4H), 3.17 – 3.04 (m, 4H), 1.93 – 1.88 (m, 1H), 1.84 – 1.80 (m, 1H), 1.52 – 1.48 (m, 1H), 1.42 – 1.36 (m, 12H), 1.02 – 0.98 (m, 6H). LC / MS (ESI) m / z 746.3 [M+H]+. (f) STEP 6: SYNTHESIS OF TERT-BUTYL (S)-(1-((6-(DIFLUOROMETHYL)-2'-((5-(PIPERAZIN-1-YL)PYRIDIN-2- YL)AMINO)-[2,4'-BIPYRIDIN]-5-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE (I-I)

[0366] To a solution of benzyl (S)-4-(6-((5-((2-((tert-butoxycarbonyl)amino)-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)amino)pyridin-3-yl)piperazine-1- carboxylate (95.0 mg, 0.13 mmol) in MeOH (5 mL) was added Pd / C (10 wt.% loading) (20.0 mg). The resulting mixture was stirred at room temperature overnight under a H₂ atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was filtered with Celite, and the filtrate was concentrated directly to afford tert-butyl (S)-(1-((6- (difluoromethyl)-2'-((5-(piperazin-1-yl)pyridin-2-yl)amino)-[2,4'-bipyridin]-5-yl)oxy)-2,4- dimethylpentan-2-yl)carbamate (77.1 mg, 99% yield) as a brown solid. LC / MS (ESI) m / z 612.3 [M+H]+. x. PREPARATION OF INTERMEDIATE TERT-BUTYL (S)-(1-((2-(DIFLUOROMETHYL)-6-(6-(1,2,3,6-TETRAHYDROPYRIDIN-4-YL)- 9H-PYRIDO[2,3-B]INDOL-4-YL)PYRIDIN-3-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE (I-J)(a) STEP 1: SYNTHESIS OF 9H-PYRIDO[2,3-B]INDOLE 1-OXIDE

[0367] To a stirred solution of 9H-pyrido[2,3-b]indole (8.00 g, 47.56 mmol) in HOAc (80mL) was added H2O2 (30% aq., 10.8 mL, 95.13 mmol) dropwise. The mixture was heated to 110 °C. and refluxed for 4 h. The mixture was concentrated under reduced pressure to remove the solvent. The residue was adjusted to pH 8-9 with aq. K2CO3. The result solution was stirred overnight at room temperature. The mixture was filtered, and the solid was dried to give 9H- pyrido[2,3-b]indole 1-oxide (8.06 g, 92% yield) as a yellow solid. LC / MS (ESI) m / z 185.0 [M+H]+. (b) STEP 2: SYNTHESIS OF 4-CHLORO-9H-PYRIDO[2,3-B]INDOLE

[0368] To a stirred solution of 9H-pyrido[2,3-b]indole 1-oxide (4.00 g, 21.72 mmol) in DMF(20 mL) was added POCl3(5.04 mL, 54.29 mmol) dropwise. The mixture was stirred at room temperature overnight. After completion of the reaction by checking the thin layer chromatography, the mixture was quenched by the addition of water at 0 °C and then adjusted to pH 8-9 with 10% aq. KOH. The mixture was filtered, and the solid was dried to give 4- chloro-9H-pyrido[2,3-b]indole (4.35 g, 99% yield) as a gray solid.1H NMR (600 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.37 (d, J = 5.3 Hz, 1H), 8.35 – 8.32 (m, 1H), 7.58 – 7.51 (m, 2H), 7.34 – 7.28 (m, 2H). LC / MS (ESI) m / z 203.3 [M+H]+.(c) STEP 3: SYNTHESIS OF 4-(4,4,5,5-TETRAMETHYL-1,3,2- DIOXABOROLAN-2-YL)-9H-PYRIDO[2,3-B]INDOLE

[0369] To a solution of 4-chloro-9H-pyrido[2,3-b]indole (4.40 g, 21.71 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.17 g, 28.23 mmol) in 1,4-dioxane (60 mL) was added Pd(dppf)Cl2(793.1 mg, 1.08 mmol), and KOAc (4.26 g, 43.43 mmol). The resulting mixture was stirred at 100 °C overnight under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 40% of EtOAc in hexanes) to afford 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-9H-pyrido[2,3-b]indole (4.34 g, 68% yield) as an orange oil. (d) STEP 4: SYNTHESIS OF TERT-BUTYL (S)-(1-((2- (DIFLUOROMETHYL)-6-(9H-PYRIDO[2,3-B]INDOL-4- YL)PYRIDIN-3-YL)OXY)-2,4-DIMETHYLPENTAN-2- YL)CARBAMATE

[0370] To a solution of tert-butyl (S)-(1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4- dimethylpentan-2-yl)carbamate (700.0 mg, 1.60 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-9H-pyrido[2,3-b]indole (1.18 g, 4.00 mmol) in 1,4-dioxane (9 mL) and H2O (3 mL) was added Pd(dppf)Cl2(117.0 mg, 0.16 mmol) and K3PO4(1.02 g, 4.80 mmol). The resulting mixture was stirred at 100 °C overnight under a N2atmosphere. and K3PO4(291.2 mg, 1.37 mmol). The resulting mixture was stirred at 100 °C for 3 hours under a N₂ atmosphere. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was cooled to room temperature and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 50% of EtOAc in hexanes) to afford tert-butyl (S)-(1-((2-(difluoromethyl)-6-(9H-pyrido[2,3-b]indol-4- yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (738.0 mg, 88% yield) as a yellow solid.1H NMR (600 MHz, Chloroform-d) δ 10.41 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 7.91 (dd, J = 20.0, 8.2 Hz, 2H), 7.62 – 7.51 (m, 2H), 7.52 – 7.44 (m, 1H), 7.31 (d, J = 5.1 Hz, 1H), 7.18 – 7.09 (m, 1H), 6.96 (t, J = 54.1 Hz, 1H), 4.64 (s, 1H), 4.44 (d, J = 8.9 Hz, 1H), 4.22 (d, J = 8.8 Hz, 1H), 1.99 – 1.93 (m, 1H), 1.92 – 1.83 (m, 1H), 1.59 – 1.53 (m, 1H), 1.46 (s, 3H), 1.40 (s, 9H), 1.05 – 1.00 (m, 6H). LC / MS (ESI) m / z 525.1 [M+H]+.(e) STEP 5: SYNTHESIS OF TERT-BUTYL (S)-(1-((6-(6- BROMO-9H-PYRIDO[2,3-B]INDOL-4-YL)-2- (DIFLUOROMETHYL)PYRIDIN-3-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE

[0371] To a solution of tert-butyl (S)-(1-((2-(difluoromethyl)-6-(9H-pyrido[2,3-b]indol-4- yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (500.0 mg, 0.95 mmol) in THF (10 mL) was added NBS (186.6 mg, 1.05 mmol) partwise at room temperature under a N2atmosphere. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 60% of EtOAc in hexanes) to afford tert-butyl (S)-(1-((6-(6-bromo-9H- pyrido[2,3-b]indol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2- yl)carbamate (397.0 mg, 69% yield) as a brown solid.1H NMR (600 MHz, Chloroform-d) δ 10.36 (s, 1H), 8.56 (d, J = 5.0 Hz, 1H), 8.28 (d, J = 1.9 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.65 – 7.53 (m, 2H), 7.41 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 5.1 Hz, 1H), 7.01 (t, J = 54.1 Hz, 1H), 4.63 (s, 1H), 4.45 (d, J = 8.4 Hz, 1H), 4.22 (d, J = 8.8 Hz, 1H), 2.00 – 1.92 (m, 1H), 1.92 – 1.82 (m, 1H), 1.57 – 1.52 (m, 1H), 1.45 (s, 3H), 1.40 (s, 9H), 1.04 – 1.01 (m, 6H). LC / MS (ESI) m / z 603.0 [M+H]+. (f) STEP 6: SYNTHESIS OF TERT-BUTYL (S)-(1-((2- (DIFLUOROMETHYL)-6-(6-(1,2,3,6- TETRAHYDROPYRIDIN-4-YL)-9H-PYRIDO[2,3-B]INDOL-4- YL)PYRIDIN-3-YL)OXY)-2,4-DIMETHYLPENTAN-2- YL)CARBAMATE (I-J)

[0372] To a solution of tert-butyl (S)-(1-((6-(6-bromo-9H-pyrido[2,3-b]indol-4-yl)-2- (difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (260.0 mg, 0.43 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (180.1 mg, 0.86 mmol) in DMF (3.2 mL) and H2O (0.8 mL) was added Pd(PPh3)4(49.7 mg, 0.043 mmol) and K2CO3(119.1 mg, 0.86 mmol). The resulting mixture was stirred at 100 °C for 2 hours under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was cooled to room temperature and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 20% ofMeOH in DCM) to afford tert-butyl (S)-(1-((2-(difluoromethyl)-6-(6-(1,2,3,6- tetrahydropyridin-4-yl)-9H-pyrido[2,3-b]indol-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2- yl)carbamate (102 mg, 39% yield) as a yellow solid.1HNMR (600 MHz, Methanol-d4) δ 8.45 (d, J = 5.2 Hz, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.61 (dd, J = 8.5, 1.8 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 5.1 Hz, 1H), 7.11 (t, J = 54.0 Hz, 1H), 6.09 – 6.02 (m, 1H), 4.47 (d, J = 9.0 Hz, 1H), 4.22 (d, J = 9.0 Hz, 1H), 3.86 – 3.77 (m, 2H), 3.43 (t, J = 6.1 Hz, 2H), 2.83 – 2.72 (m, 2H), 2.03 – 1.95 (m, 1H), 1.93 – 1.82 (m, 1H), 1.60 – 1.53 (m, 1H), 1.43 (s, 3H), 1.39 (s, 9H), 1.04 – 0.98 (m, 6H). LC / MS (ESI) m / z 606.0 [M+H]+. xi. PREPARATION OF INTERMEDIATE TERT-BUTYL (S)-(1-((2-(DIFLUOROMETHYL)-6-(6-(PIPERIDIN-4-YL)-9H-PYRIDO[2,3- B]INDOL-4-YL)PYRIDIN-3-YL)OXY)-2,4-DIMETHYLPENTAN-2- YL)CARBAMATE (I-K)(a) STEP 1: SYNTHESIS OF TERT-BUTYL (S)-(1-((2-(DIFLUOROMETHYL)-6-(6-(PIPERIDIN-4-YL)-9H- PYRIDO[2,3-B]INDOL-4-YL)PYRIDIN-3-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE (I-K)

[0373] To a solution of tert-butyl (S)-(1-((2-(difluoromethyl)-6-(6-(1,2,3,6-tetrahydropyridin-4-yl)-9H-pyrido[2,3-b]indol-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (90.0 mg, 0.15 mmol) in AcOH (5 mL) was added Pd / C (10 wt.% loading) (90.0 mg). The resulting mixture was stirred at room temperature overnight under a H₂ atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was filtered with Celite, and the filtrate was concentrated under reduced pressure. The residue was quenched by the addition of saturated aqueous NaHCO3and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (S)-(1-((2-(difluoromethyl)-6-(6-(piperidin-4-yl)-9H-pyrido[2,3-b]indol-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2- yl)carbamate (80.3 mg, 89% yield) as a brown solid. LC / MS (ESI) m / z 608.1 [M+H]+. xii. PREPARATION OF INTERMEDIATE TERT-BUTYL (S)-(1-((2-(DIFLUOROMETHYL)-6-(2-(1,2,3,6-TETRAHYDROPYRIDIN-4- YL)PYRAZOLO[1,5-A]PYRIMIDIN-7-YL)PYRIDIN-3-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE (I-L)(a) STEP 1: SYNTHESIS OF TERT-BUTYL (S)-(1-((6-CYANO-2-(DIFLUOROMETHYL)PYRIDIN-3-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE

[0374] To a solution of tert-butyl (S)-(1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (2.00 g, 4.57 mmol) in DMF (20 mL) was added Zn(CN)2(805.46 mg, 6.86 mmol) and Pd(PPh3)4 (528.48 mg, 0.45 mmol). The reaction mixture was stirred at 100 °C overnight under a N₂ atmosphere. After completion of the reaction bychecking the thin layer chromatography, the reaction mixture was cooled to room temperature and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 20% of EtOAc in hexanes) to afford tert-butyl (S)-(1-((6- cyano-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (1.35 g, 77% yield) as a colorless oil.1H NMR (600 MHz, Chloroform-d) δ 7.74 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 6.73 (t, J = 53.7 Hz, 1H), 4.50 (s, 1H), 4.42 (d, J = 8.9 Hz, 1H), 4.16 (d, J = 8.9 Hz, 1H), 1.93 – 1.85 (m, 1H), 1.85 – 1.76 (m, 1H), 1.47 – 1.41 (m, 1H), 1.38 – 1.34 (m, 12H), 1.00 – 0.96 (m, 6H). LC / MS (ESI) m / z 384.1 [M+H]+. (b) STEP 2: SYNTHESIS OF TERT-BUTYL (S)-(1-((6-ACETYL- 2-(DIFLUOROMETHYL)PYRIDIN-3-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE

[0375] To a solution of tert-butyl (S)-(1-((6-cyano-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4- dimethylpentan-2-yl)carbamate (1.30 g, 3.39 mmol) in dry THF (25 mL) was added CH3MgBr (3.0 M, 3.39 mL, 10.17 mmol) drop wise at 0 °C and the reaction was stirred for 5 hours at the same temperature. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 29% of EtOAc in hexanes) to afford tert-butyl (S)-(1-((6-acetyl-2-(difluoromethyl)pyridin-3-yl)oxy)- 2,4-dimethylpentan-2-yl)carbamate (808.8 mg, 59% yield) as a yellow oil.1H NMR (600 MHz, Chloroform-d) δ 8.13 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 6.80 (t, J = 54.1 Hz, 1H), 4.53 (s, 1H), 4.37 (d, J = 8.9 Hz, 1H), 4.15 (d, J = 8.9 Hz, 1H), 2.68 (s, 3H), 1.93 – 1.86 (m, 1H), 1.86 – 1.74 (m, 1H), 1.52 – 1.44 (m, 1H), 1.40 – 1.33 (m, 12H), 1.03 – 0.93 (m, 6H). LC / MS (ESI) m / z 401.1 [M+H]+. (c) STEP 3: SYNTHESIS OF TERT-BUTYL (S,E)-(1-((2- (DIFLUOROMETHYL)-6-(3- (DIMETHYLAMINO)ACRYLOYL)PYRIDIN-3-YL)OXY)-2,4-

[0376] A solution of tert-butyl (S)-(1-((6-acetyl-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4- dimethylpentan-2-yl)carbamate (700.0 mg, 1.75 mmol) and DMF-DMA (11.61 mL, 87.40 mmol) was stirred at 110 °C overnight under a N2 atmosphere. After completion of the reactionby checking the thin layer chromatography, the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 100% of EtOAc in hexanes) to afford tert- butyl (S,E)-(1-((2-(difluoromethyl)-6-(3-(dimethylamino)acryloyl)pyridin-3-yl)oxy)-2,4- dimethylpentan-2-yl)carbamate (584.0 mg, 73% yield) as a yellow solid.1H NMR (600 MHz, Chloroform-d) δ 8.24 (d, J = 8.7 Hz, 1H), 7.88 (d, J = 12.7 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 6.83 (t, J = 54.2 Hz, 1H), 6.46 (d, J = 12.7 Hz, 1H), 4.55 (s, 1H), 4.31 (d, J = 8.9 Hz, 1H), 4.11 (d, J = 8.8 Hz, 1H), 3.16 (s, 3H), 2.99 (s, 3H), 1.92 – 1.85 (m, 1H), 1.85 – 1.77 (m, 1H), 1.54 – 1.48 (m, 1H), 1.41 – 1.35 (m, 12H), 1.02 – 0.95 (m, 6H). LC / MS (ESI) m / z 456.2 [M+H]+. (d) STEP 4: SYNTHESIS OF TERT-BUTYL (S)-(1-((6-(2- BROMOPYRAZOLO[1,5-A]PYRIMIDIN-7-YL)-2- (DIFLUOROMETHYL)PYRIDIN-3-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE

[0377] To a solution of tert-butyl (S,E)-(1-((2-(difluoromethyl)-6-(3- (dimethylamino)acryloyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (500.0 mg, 1.10 mmol) in AcOH (15 mL) was added 5-bromo-1H-pyrazol-3-amine (177.8 mg, 1.10 mmol). The reaction mixture was stirred at 80 °C for 2 hours under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 10% of EtOAc in hexanes) to afford tert-butyl (S)-(1-((6-(2- bromopyrazolo[1,5-a]pyrimidin-7-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan- 2-yl)carbamate (295.2 mg, 49% yield) as a yellow solid.1H NMR (600 MHz, Chloroform-d) δ 9.32 (d, J = 8.9 Hz, 1H), 8.59 (d, J = 4.5 Hz, 1H), 7.81 (d, J = 4.5 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.03 – 6.76 (m, 2H), 4.55 (s, 1H), 4.43 (d, J = 8.8 Hz, 1H), 4.19 (d, J = 8.8 Hz, 1H), 1.97 – 1.90 (m, 1H), 1.87 – 1.78 (m, 1H), 1.53 – 1.47 (m, 1H), 1.42 – 1.37 (m, 12H), 1.02 – 0.98 (m, 6H). LC / MS (ESI) m / z 554.4 [M+H]+. (e) STEP 5: SYNTHESIS OF TERT-BUTYL (S)-(1-((2- (DIFLUOROMETHYL)-6-(2-(1,2,3,6- TETRAHYDROPYRIDIN-4-YL)PYRAZOLO[1,5-A]PYRIMIDIN-7-YL)PYRIDIN-3-YL)OXY)-2,4- DIMETHYLPENTAN-2-YL)CARBAMATE (I-L)

[0378] To a solution of tert-butyl (S)-(1-((6-(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (60.0 mg, 0.11 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (45.3 mg, 0.22 mmol) in 1,4-dioxane (0.6 mL) and H2O (0.2 mL) was added Pd(dppf)Cl2(8.0 mg, 0.011 mmol) and K3PO4(68.9 mg, 0.32 mmol). The resulting mixture was stirred at 100 °C for 3 hours under a N2atmosphere. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 20% of MeOH in DCM) to afford tert-butyl (S)-(1-((2- (difluoromethyl)-6-(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-3- yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (59.6 mg, 99% yield) as a gray solid.1H NMR (600 MHz, Chloroform-d) δ 9.43 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 4.4 Hz, 1H), 7.78 (d, J = 4.5 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.00 – 6.78 (m, 2H), 6.66 – 6.58 (m, 1H), 4.57 (s, 1H), 4.43 (d, J = 8.9 Hz, 1H), 4.21 (d, J = 8.8 Hz, 1H), 3.85 – 3.74 (m, 2H), 3.34 (t, J = 5.9 Hz, 2H), 2.92 – 2.85 (m, 2H), 1.95 – 1.88 (m, 1H), 1.87 – 1.79 (m, 1H), 1.54 – 1.49 (m, 1H), 1.42 (s, 3H), 1.38 (s, 9H), 1.02 – 0.98 (m, 6H). LC / MS (ESI) m / z 557.3 [M+H]+. xiii. PREPARATION OF INTERMEDIATE 1-(2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)PIPERIDINE-4-CARBALDEHYDE (I-1)(a) STEP 1: SYNTHESIS OF 3-(5-(4- (DIMETHOXYMETHYL)PIPERIDIN-1-YL)-1- OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

[0379] To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.23 g, 10.00 mmol) and 4-(dimethoxymethyl)piperidine (3.18 g, 20.00 mmol) in DMSO (25 mL) was added NiBr2•glyme (308.5 mg, 1.00 mmol), DABCO (2.02 g, 18.00 mmol), and Ru(bpy)3(PF6)2(8.6 mg, 0.01 mmol). The reaction mixture was irradiated by two 40W blue lamps (456 nm) for 24 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with THF. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 100% of EtOAc in DCM) to afford 3-(5-(4- (dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2.28 g, 59% yield) as a white powder.1H NMR (600 MHz, CDCl3) δ 7.94 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 6.99 (dd, J = 8.6, 2.2 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.40 (d, J = 15.4 Hz, 1H), 4.24 (d, J = 15.4 Hz, 1H), 4.07 (d, J = 6.6 Hz, 1H), 3.90 – 3.82 (m, 2H), 3.38 (s, 6H), 2.95 – 2.87 (m, 1H), 2.87 – 2.77 (m, 3H), 2.38 – 2.27 (m, 1H), 2.24 – 2.14 (m, 1H), 1.91 – 1.79 (m, 3H), 1.49 – 1.38 (m, 2H). LC / MS (ESI) m / z 402.1 [M+H]+. (b) STEP 2: SYNTHESIS OF 1-(2-(2,6-DIOXOPIPERIDIN-3-YL)- 1-OXOISOINDOLIN-5-YL)PIPERIDINE-4-CARBALDEHYDE (I-1)

[0380] A suspension of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (1.00 g, 2.49 mmol) in THF (25 mL) and 2 M HCl (aq.) (25 mL) was stirred at 50 °C for 2 hours. After completion of the reaction, the reaction mixture was quenched with sat. NaHCO3(aq.) and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and then concentrated under reduced pressure to afford 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4- carbaldehyde (I-1) (731.0 mg, 83% yield) as a yellow solid. The resulting residue was used directly without purification. LC / MS (ESI) m / z 356.2 [M+H]+.xiv. PREPARATION OF INTERMEDIATE 1-(2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)PIPERIDINE-4-CARBOXYLIC ACID (I- 2)(a) STEP 1: SYNTHESIS OF TERT-BUTYL 1-(2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5- YL)PIPERIDINE-4-CARBOXYLATE

[0381] To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (387.8 mg,1.20 mmol) and tert-butyl piperidine-4-carboxylate (444.6 mg, 2.40 mmol) in DMSO (3 mL) was added NiBr2•glyme (37.0 mg, 0.12 mmol), DABCO (242.3 mg, 2.16 mmol), and Ru(bpy)3(PF6)2(1.0 mg, 0.001 mmol). The reaction mixture was irradiated by two 40W blue lamps (456 nm) for 24 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 75% of EtOAc in DCM) to afford tert-butyl 1-(2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carboxylate (242.0 mg, 47% yield) as a white solid.1H NMR (600 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.07 – 7.02 (m, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.32 (d, J = 16.7 Hz, 1H), 4.20 (d, J = 16.8 Hz, 1H), 3.84 – 3.76 (m, 2H), 2.98 – 2.85 (m, 3H), 2.61 – 2.55 (m, 1H), 2.49 – 2.43 (m, 1H), 2.41 – 2.30 (m, 1H), 1.98 – 1.92 (m, 1H), 1.89 – 1.82 (m, 2H), 1.64 – 1.54 (m, 2H), 1.40 (s, 9H). LC / MS (ESI) m / z 428.1 [M+H]+.(b) STEP 2: SYNTHESIS OF 1-(2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)PIPERIDINE-4-CARBOXYLIC ACID (I-2)

[0382] A suspension of tert-butyl 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carboxylate (100.0 mg, 0.23 mmol) in 4 M HCl in 1,4-dioxane (3 mL) was stirred at room temperature for 6 hours. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was concentrated under reduced pressure to afford 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carboxylic acid (I-2) (86.0 mg, 99% yield) as a white solid. The resulting residue was used directly without purification. xv. PREPARATION OF INTERMEDIATE 3-(1-OXO-5-(4-OXOPIPERIDIN-1-YL)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE (I-3)(a) STEP 1: SYNTHESIS OF 3-(5-(4-HYDROXYPIPERIDIN-1-YL)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

[0383] To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (387.8 mg,1.20 mmol) and piperidin-4-ol (242.8 mg, 2.40 mmol) in DMSO (3 mL) was added NiBr2•glyme (37.0 mg, 0.12 mmol), DABCO (242.3 mg, 2.16 mmol), and Ru(bpy)3(PF6)2(1.0 mg, 0.001 mmol). The reaction mixture was irradiated by two 40W blue lamps (456 nm) for 24 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 100% of EtOAc in DCM) to afford 3-(5-(4-hydroxypiperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (228.0 mg, 55% yield) as a white solid.1H NMR (600 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.07 – 7.02 (m, 2H), 5.04 (dd, J =13.3, 5.1 Hz, 1H), 4.31 (d, J = 16.7 Hz, 1H), 4.19 (d, J = 16.7 Hz, 1H), 3.75 – 3.63 (m, 3H), 3.06 – 2.97 (m, 2H), 2.94 – 2.84 (m, 1H), 2.61 – 2.56 (m, 1H), 2.40 – 2.29 (m, 1H), 2.00 – 1.93 (m, 1H), 1.85 – 1.76 (m, 2H), 1.49 – 1.37 (m, 2H). LC / MS (ESI) m / z 344.1 [M+H]+. (b) STEP 2: SYNTHESIS OF 3-(1-OXO-5-(4-OXOPIPERIDIN-1-YL)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE (I-3)

[0384] To a solution of 3-(5-(4-hydroxypiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100.0 mg, 0.29 mmol) in DMSO (1 mL) was added IBX (244.6 mg, 0.87 mmol). The reaction mixture was stirred at room temperature for 7 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with THF. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 15% of MeOH in EtOAc) to afford 3-(1-oxo- 5-(4-oxopiperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (I-3) (48.9 mg, 49% yield) as a white solid.1H NMR (600 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.17 – 7.09 (m, 2H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.34 (d, J = 16.7 Hz, 1H), 4.22 (d, J = 16.7 Hz, 1H), 3.75 (t, J6.1 Hz, 4H), 2.95 – 2.86 (m, 1H), 2.62 – 2.55 (m, 1H), 2.44 (t, J = 6.1 Hz, 4H), 2.42 – 2.32 (m, 1H), 2.01 – 1.93 (m, 1H). LC / MS (ESI) m / z 342.1 [M+H]+. xvi. PREPARATION OF INTERMEDIATE 1-(4-((2,6-DIOXOPIPERIDIN-3-YL)AMINO)-2-FLUOROPHENYL)PIPERIDINE-4-CARBALDEHYDE (I- 4)(a) STEP 1: SYNTHESIS OF 4-(DIMETHOXYMETHYL)-1-(2-FLUORO-4-NITROPHENYL)PIPERIDINE

[0385] A solution of 1,2-difluoro-4-nitrobenzene (2.50 g, 15.71 mmol), 4-(dimethoxymethyl)piperidine (3.00 g, 18.86 mmol), and DIEA (4.06 g, 31.43 mmol) in DMSO (25 mL) was stirred at 90 °C overnight. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 20% of EtOAc in hexanes) to afford 4-(dimethoxymethyl)-1- (2-fluoro-4-nitrophenyl)piperidine (4.49 g, 96% yield) as a yellow solid.1H NMR (600 MHz, CDCl3) δ 7.99 – 7.94 (m, 1H), 7.88 (dd, J = 13.2, 2.6 Hz, 1H), 6.90 (t, J = 8.8 Hz, 1H), 4.09 (d, J = 6.9 Hz, 1H), 3.76 – 3.70 (m, 2H), 3.38 (s, 6H), 2.84 (td, J = 12.5, 2.4 Hz, 2H), 1.91 – 1.79 (m, 3H), 1.54 – 1.46 (m, 2H). (b) STEP 2: SYNTHESIS OF 4-(4-(DIMETHOXYMETHYL)PIPERIDIN-1-YL)-3- FLUOROANILINE

[0386] To a solution of 4-(dimethoxymethyl)-1-(2-fluoro-4-nitrophenyl)piperidine (4.40 g,14.75 mmol) in THF (50 mL) was added Pd / C (10 wt. % loading) (440.0 mg). The resulting mixture was stirred at room temperature overnight under H2atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was filtered through a pad of Celite, and the filtrate was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 50% of EtOAc in hexanes) to afford 4-(4- (dimethoxymethyl)piperidin-1-yl)-3-fluoroaniline (3.75 g, 95% yield) as a light yellow solid.1H NMR (600 MHz, CDCl3) δ 6.80 (dd, J = 9.5, 8.4 Hz, 1H), 6.45 – 6.36 (m, 2H), 4.09 (d, J = 7.4 Hz, 1H), 3.51 (s, 2H), 3.40 – 3.33 (m, 6H), 3.32 – 3.26 (m, 2H), 2.56 (td, J = 11.9, 2.4 Hz, 2H), 1.86 – 1.78 (m, 2H), 1.74 – 1.67 (m, 1H), 1.57 – 1.47 (m, 2H).(c) STEP 3: SYNTHESIS OF 3-((4-(4- (DIMETHOXYMETHYL)PIPERIDIN-1-YL)-3- FLUOROPHENYL)AMINO)PIPERIDINE-2,6-DIONE

[0387] A solution of 4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluoroaniline (300.0 mg, 1.12 mmol), 3-bromopiperidine-2,6-dione (322.0 mg, 1.68 mmol), and DIEA (578.0 mg, 4.47 mmol) in DMSO (5 mL) was stirred at 70 °C overnight. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 55% of EtOAc in hexanes) to afford 3-((4-(4- (dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (225.0 mg, 53% yield) as a green solid.1H NMR (600 MHz, CDCl3) δ 8.04 (s, 1H), 6.87 (t, J = 9.0 Hz, 1H), 6.46 – 6.36 (m, 2H), 4.59 (d, J = 3.7 Hz, 1H), 4.10 (d, J = 7.4 Hz, 1H), 4.03 – 3.94 (m, 1H), 3.41 – 3.34 (m, 6H), 3.34 – 3.26 (m, 2H), 2.90 – 2.82 (m, 1H), 2.78 – 2.70 (m, 1H), 2.63 – 2.47 (m, 3H), 1.94 – 1.78 (m, 3H), 1.75 – 1.67 (m, 1H), 1.57 – 1.47 (m, 2H). (d) STEP 4: SYNTHESIS OF 1-(4-((2,6-DIOXOPIPERIDIN-3- YL)AMINO)-2-FLUOROPHENYL)PIPERIDINE-4- CARBALDEHYDE (I-4)

[0388] A solution of 3-((4-(4-(dimethoxymethyl)piperidin-1-yl)-3- fluorophenyl)amino)piperidine-2,6-dione (200.0 mg, 0.53 mmol) in THF (3 mL) and 2 M HCl (aq.) (3 mL) was stirred at 50 °C for 1 hour. After completion of the reaction, the reaction mixture was quenched with sat. NaHCO3(aq.) and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 60% of EtOAc in hexanes) to afford 1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (I-4) (34 mg, 19% yield) as a light green solid.1H NMR (600 MHz, CDCl3) δ 9.69 (d, J = 1.2 Hz, 1H), 8.47 (s, 1H), 6.85 (t, J = 9.0 Hz, 1H), 6.44 – 6.35 (m, 2H), 4.62 (d, J = 4.0 Hz, 1H), 4.05 – 3.94 (m, 1H), 3.30 – 3.19 (m, 2H), 2.89 – 2.80 (m, 1H), 2.78 – 2.67 (m, 3H), 2.53 – 2.45 (m, 1H), 2.40 – 2.30 (m, 1H), 2.03 – 1.97 (m, 2H), 1.92 – 1.81 (m, 3H). LC / MS (ESI) m / z 334.0 [M+H]+.xvii. PREPARATION OF INTERMEDIATE (S)-N-(2,6-DIOXOPIPERIDIN-3-YL)-5-(4-FORMYLPIPERIDIN-1-YL)PICOLINAMIDE (I-5)(a) STEP 1: SYNTHESIS OF METHYL 5-(4-(1,3-DIOXOLAN-2-YL)PIPERIDIN-1-YL)PICOLINATE

[0389] A solution of methyl 5-fluoropicolinate (750.0 mg, 4.83 mmol), 4-(1,3-dioxolan-2-yl)piperidine (836.1 mg, 5.32 mmol), and DIEA (1.25 g, 9.67 mmol) in DMSO (8 mL) was stirred at 90 °C overnight. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 60% of EtOAc in DCM) to afford methyl 5-(4-(1,3-dioxolan-2- yl)piperidin-1-yl)picolinate (1.40 g, 79% yield) as a white solid.1H NMR (600 MHz, CDCl3) δ 8.33 (d, J = 3.0 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.13 (dd, J = 8.9, 3.0 Hz, 1H), 4.68 (d, J = 4.9 Hz, 1H), 4.00 – 3.84 (m, 9H), 2.89 (td, J = 12.7, 2.8 Hz, 2H), 1.92 – 1.85 (m, 2H), 1.85 – 1.77 (m, 1H), 1.57 – 1.47 (m, 2H). LC / MS (ESI) m / z 293.0 [M+H]+. (b) STEP 2: SYNTHESIS OF 5-(4-(1,3-DIOXOLAN-2-YL)PIPERIDIN-1-YL)PICOLINIC ACID

[0390] To a solution of methyl 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)picolinate (1.00 g, 3.42mmol) in THF (10 mL) and H2O (5 mL) was added LiOH•H2O (0.72 g, 17.10 mmol). The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was adjusted pH to 4-5 with 0.5 M HCl (aq.), followed by extraction with DCM. The combined organic layers were washed with brine and then concentrated underreduced pressure to afford 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)picolinic acid (0.94 g, 99% yield) as a white solid. The resulting residue was used directly without purification. LC / MS (ESI) m / z 279.2 [M+H]+. (c) STEP 3: SYNTHESIS OF (S)-5-(4-(1,3-DIOXOLAN-2- YL)PIPERIDIN-1-YL)-N-(2,6-DIOXOPIPERIDIN-3- YL)PICOLINAMIDE

[0391] To a solution of 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)picolinic acid (100.0 mg, 0.36 mmol) in DMF (3 mL) was added DIEA (232.2 mg, 1.80 mmol), HATU (204.9 mg, 0.54 mmol), and (S)-3-aminopiperidine-2,6-dione hydrochloride (76.9 mg, 0.47 mmol), successively. The resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 100% of EtOAc in hexanes) to afford (S)-5-(4-(1,3-dioxolan-2- yl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (116.0 mg, 83% yield) as a white solid.1H NMR (600 MHz, CDCl3) δ 8.43 (d, J = 6.8 Hz, 1H), 8.20 (d, J = 2.9 Hz, 1H), 8.07 – 7.98 (m, 2H), 7.20 (dd, J = 8.8, 2.9 Hz, 1H), 4.83 – 4.75 (m, 1H), 4.69 (d, J = 4.9 Hz, 1H), 3.97 – 3.85 (m, 6H), 2.91 – 2.75 (m, 4H), 2.66 – 2.57 (m, 1H), 2.07 – 1.95 (m, 1H), 1.92 – 1.85 (m, 2H), 1.84 – 1.76 (m, 1H), 1.58 – 1.48 (m, 2H). LC / MS (ESI) m / z 389.0 [M+H]+. (d) STEP 4: SYNTHESIS OF (S)-N-(2,6-DIOXOPIPERIDIN-3- YL)-5-(4-FORMYLPIPERIDIN-1-YL)PICOLINAMIDE (I-5)

[0392] A suspension of (S)-5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3- yl)picolinamide (80.0 mg, 0.21 mmol) in THF (1.5 mL) and 2 M HCl (aq.) (1.5 mL) was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was quenched with sat. NaHCO3(aq.) and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and then concentrated under reduced pressure to afford (S)-N-(2,6-dioxopiperidin-3-yl)-5-(4-formylpiperidin-1-yl)picolinamide (I-5) (70.2 mg, 99% yield) as a colorless oil. The resulting residue was used directly without purification. xviii. PREPARATION OF INTERMEDIATE 2-(1-(2-(((S)-1-((2S,4R)-4- HYDROXY-2-(((S)-1-(4-(4-METHYLTHIAZOL-5- YL)PHENYL)ETHYL)CARBAMOYL)PYRROLIDIN-1-YL)-3,3-DIMETHYL-1-OXOBUTAN-2-YL)AMINO)-2-OXOETHYL)PIPERIDIN- 4-YL)ACETIC ACID (I-6)(a) STEP 1: SYNTHESIS OF TERT-BUTYL 2-(1-(2-ETHOXY-2-OXOETHYL)PIPERIDIN-4-YL)ACETATE

[0393] A solution of tert-butyl 2-(piperidin-4-yl)acetate (300.0 mg, 1.51 mmol), ethyl 2-bromoacetate (276.5 mg, 1.66 mmol), and DIEA (228.5 mg, 2.26 mmol) in THF (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 60% of EtOAc in hexanes) to afford tert-butyl 2-(1-(2-ethoxy-2- oxoethyl)piperidin-4-yl)acetate (258.0 mg, 66% yield) as a colorless oil.1H NMR (600 MHz, CDCl3) δ 4.17 (q, J = 7.1 Hz, 2H), 3.18 (s, 2H), 2.95 – 2.85 (m, 2H), 2.20 – 2.14 (m, 2H), 2.13 (d, J = 7.0 Hz, 2H), 1.77 – 1.67 (m, 3H), 1.43 (s, 9H), 1.41 – 1.33 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H).(b) STEP 2: SYNTHESIS OF 2-(4-(2-(TERT-BUTOXY)-2- OXOETHYL)PIPERIDIN-1-YL)ACETIC ACID

[0394] To a solution of tert-butyl 2-(1-(2-ethoxy-2-oxoethyl)piperidin-4-yl)acetate (200.0 mg, 0.70 mmol) in MeOH (6 mL) and H2O (3 mL) was added LiOH•H2O (58.8 mg, 1.40 mmol). The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was adjusted pH to 4-5 with 4 M HCl (aq.), followed by concentration directly under reduced pressure to afford 2-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-1-yl)acetic acid (178.5 mg, 99% yield) as a colorless oil. The resulting residue was used directly without purification. (c) STEP 3: SYNTHESIS OF TERT-BUTYL 2-(1-(2-(((S)-1- ((2S,4R)-4-HYDROXY-2-(((S)-1-(4-(4-METHYLTHIAZOL- 5-YL)PHENYL)ETHYL)CARBAMOYL)PYRROLIDIN-1-YL)- 3,3-DIMETHYL-1-OXOBUTAN-2-YL)AMINO)-2- OXOETHYL)PIPERIDIN-4-YL)ACETATE

[0395] To a solution of 2-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-1-yl)acetic acid (80.0 mg, 0.31 mmol) in DMF (5 mL) was added DIEA (160.7 mg, 1.24 mmol), HATU (153.7 mg, 0.40 mmol), and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (164.5 mg, 0.34 mmol), successively. The resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 12% of MeOH in DCM) to afford tert-butyl 2-(1-(2-(((S)-1-((2S,4R)- 4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperidin-4-yl)acetate (184.1 mg, 86% yield) as a white foam.1H NMR (600 MHz, CDCl3) δ 8.67 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 5.07 (p, J = 7.1 Hz, 1H), 4.76 (t, J = 7.9 Hz, 1H), 4.52 – 4.47 (m, 1H), 4.41 (d, J = 8.2 Hz, 1H), 4.20 (dt, J = 11.6, 2.0 Hz, 1H), 3.57 (dd, J = 11.4, 3.6 Hz, 1H), 3.01 (d, J = 16.7 Hz, 1H), 2.94 (d, J = 16.6 Hz, 1H), 2.86 – 2.79 (m, 2H), 2.60 – 2.55 (m, 1H), 2.53 (s, 3H), 2.26 – 2.20 (m, 1H), 2.20 – 2.13 (m, 3H), 2.10 – 2.01 (m, 1H), 1.78 – 1.71 (m, 4H), 1.47 (d, J = 7.0 Hz, 3H), 1.44 (s, 9H), 1.35 – 1.25 (m, 2H), 1.06 (s, 9H). LC / MS (ESI) m / z 684.4 [M+H]+.(d) STEP 4: SYNTHESIS OF 2-(1-(2-(((S)-1-((2S,4R)-4-HYDROXY-2-(((S)-1-(4-(4-METHYLTHIAZOL-5- YL)PHENYL)ETHYL)CARBAMOYL)PYRROLIDIN-1-YL)- 3,3-DIMETHYL-1-OXOBUTAN-2-YL)AMINO)-2- OXOETHYL)PIPERIDIN-4-YL)ACETIC ACID (I-6)

[0396] A suspension of tert-butyl 2-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoethyl)piperidin-4-yl)acetate (150.0 mg, 0.22 mmol) in DCM (2 mL) and 4 M HCl in 1,4-dioxane (4 mL) was stirred at room temperature overnight. After completion of the reaction by checking the thin layer chromatography, the reaction mixture was concentrated under reduced pressure to afford 2-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoethyl)piperidin-4-yl)acetic acid (I-6) (143.5 mg, 99% yield) as a colorless oil. The resulting residue was used directly without purification. LC / MS (ESI) m / z 628.4 [M+H]+. xix. PREPARATION OF INTERMEDIATE 2-(4-(2-(((S)-1-((2S,4R)-4-HYDROXY-2-(((S)-1-(4-(4-METHYLTHIAZOL-5- YL)PHENYL)ETHYL)CARBAMOYL)PYRROLIDIN-1-YL)-3,3- DIMETHYL-1-OXOBUTAN-2-YL)AMINO)-2-OXOETHYL)PIPERAZIN- 1-YL)ACETIC ACID (I-7)

[0397] I-7 was prepared by following the similar procedure for the preparation of I-6. Theresulting residue was used directly without purification. LC / MS (ESI) m / z 629.3 [M+H]+.xx. PREPARATION OF 1-(2-(1-METHYL-2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)PIPERIDINE-4-CARBALDEHYDE (I-8)(a) STEP 1: SYNTHESIS OF 3-(5-(4-(DIMETHOXYMETHYL)PIPERIDIN-1-YL)-1- OXOISOINDOLIN-2-YL)-1-METHYLPIPERIDINE-2,6-DIONE

[0398] To a solution of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100.0 mg, 0.25 mmol) in DMF (1 mL) was added K2CO3(68.8 mg, 0.50 mmol), and iodomethane (42.2 mg, 0.30 mmol). The resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction by checking the thin layer chromatography, the mixture was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 95% of EtOAc in hexanes) to afford 3-(5-(4- (dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-1-methylpiperidine-2,6-dione (82.8 mg, 80% yield) as a white solid.1H NMR (600 MHz, Chloroform-d) δ 7.71 (d, J = 8.6 Hz, 1H), 6.99 (dd, J = 8.6, 2.2 Hz, 1H), 6.87 (d, J = 2.1 Hz, 1H), 5.15 (dd, J = 13.5, 5.0 Hz, 1H), 4.36 (d, J = 15.5 Hz, 1H), 4.24 (d, J = 15.6 Hz, 1H), 4.07 (d, J = 6.7 Hz, 1H), 3.90 – 3.81 (m, 2H), 3.38 (s, 6H), 3.18 (s, 3H), 3.01 – 2.94 (m, 1H), 2.89 – 2.77 (m, 3H), 2.34 – 2.22 (m, 1H), 2.19 – 2.12 (m, 1H), 1.91 – 1.78 (m, 3H), 1.49 – 1.37 (m, 2H). LC / MS (ESI) m / z 416.2 [M+H]+.(b) STEP 2: SYNTHESIS OF 1-(2-(1-METHYL-2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5- YL)PIPERIDINE-4-CARBALDEHYDE (I-8)

[0399] A solution of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-1-methylpiperidine-2,6-dione (70.0 mg, 0.17 mmol) in THF (2 mL) and 2 M aqueous HCl (2 mL) was stirred at 50 °C for 2 hours. After completion of the reaction by checking the thin layer chromatography, the mixture was quenched with saturated aqueous NaHCO3and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and then concentrated to afford the crude residue, which was used directly without purification.(a) STEP 1: SYNTHESIS OF 3-(4-(4-(DIMETHOXYMETHYL)PIPERIDIN-1- YL)PHENYL)PIPERIDINE-2,6-DIONE

[0400] To a solution of 3-(4-bromophenyl)piperidine-2,6-dione (643.5 mg, 2.40 mmol) and4-(dimethoxymethyl)piperidine (764.3 mg, 4.80 mmol) in DMSO (6 mL) was added NiBr2.glyme (74.0 mg, 0.24 mmol), DABCO (484.6 mg, 4.32 mmol), and Ru(bpy)3(PF6)2(2.1 mg, 0.002 mmol) The reaction mixture was irradiated by two 40W blue lamps (456 nm) for 24 hours. After completion of the reaction by checking the thin layer chromatography, the reactionmixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 70% of EtOAc in DCM) to afford 3-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione (93.0 mg, 11% yield) as a white solid.1H NMR (600 MHz, Chloroform-d) δ 7.91 (s, 1H), 7.09 – 7.05 (m, 2H), 6.94 – 6.89 (m, 2H), 4.08 (d, J = 7.3 Hz, 1H), 3.76 – 3.66 (m, 3H), 3.37 (s, 6H), 2.75 – 2.58 (m, 4H), 2.30 – 2.16 (m, 2H), 1.88 – 1.81 (m, 2H), 1.80 – 1.70 (m, 1H), 1.49 – 1.39 (m, 2H). LC / MS (ESI) m / z 347.1 [M+H]+. (b) STEP 2: SYNTHESIS OF 1-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDINE-4-CARBALDEHYDE (I-9)

[0401] A solution of 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione(14.4 mg, 0.041 mmol) in HCOOH (1 mL) was stirred at room temperature for 1 hour. After completion of the reaction by checking the thin layer chromatography, the mixture was concentrated, quenched with saturated aqueous NaHCO3,and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and then concentrated to afford the crude residue, which was used directly without purification. xxii. PREPARATION OF INTERMEDIATE 1-(3-(2,4-DIOXOTETRAHYDROPYRIMIDIN-1(2H)-YL)-4- METHOXYBENZOYL)PIPERIDINE-4-CARBALDEHYDE (I-10)(a) STEP 1: SYNTHESIS OF 1-(5-(4-(DIMETHOXYMETHYL)PIPERIDINE-1-CARBONYL)-2-METHOXYPHENYL)DIHYDROPYRIMIDINE-2,4(1H,3H)- DIONE

[0402] To a solution of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (300.0 mg, 1.14 mmol) in DMF (5 mL) was added DIEA (440.2 mg, 3.41 mmol), HATU (561.2 mg, 1.48 mmol), and 4-(dimethoxymethyl)piperidine (216.9 mg, 1.36 mmol), successively. The resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction by checking the thin layer chromatography, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 10% of EtOAc in hexanes) to afford 1-(5-(4-(dimethoxymethyl)piperidine-1-carbonyl)-2- methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (283.0 mg, 61% yield) as a white foam.1H NMR (600 MHz, Chloroform-d) δ 7.63 (s, 1H), 7.41 (dd, J = 8.5, 2.2 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 4.89 – 4.45 (m, 1H), 4.05 (d, J = 6.8 Hz, 1H), 3.89 (s, 3H), 3.70 (s, 2H), 3.36 (s, 6H), 3.03 – 2.58 (m, 5H), 1.90 – 1.73 (m, 3H), 1.38 – 1.18 (m, 2H). LC / MS (ESI) m / z 406.1 [M+H]+. (b) 1-(3-(2,4-DIOXOTETRAHYDROPYRIMIDIN-1(2H)-YL)-4- METHOXYBENZOYL)PIPERIDINE-4-CARBALDEHYDE (I-10 )

[0403] A solution of 1-(5-(4-(dimethoxymethyl)piperidine-1-carbonyl)-2- methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (150.0 mg, 0.37 mmol) in THF (3 mL) and 2 M aqueous HCl (3 mL) was stirred at 50 °C for 2 hours. After completion of the reaction by checking the thin layer chromatography, the mixture was quenched with saturated aqueous NaHCO3and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and then concentrated to afford the crude residue, which was used directly without purification. c. EXAMPLE 2: PREPARATION OF COMPOUNDS OF FORMULA (I) xxiii. PREPARATION OF 4-((2-(4-(4-((4-(4-(((S)-2-AMINO-4- METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-2-OXOETHYL)AMINO)-2-(2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE (COMPOUND 1)(a) STEP 1: SYNTHESIS OF TERT-BUTYL ((2S)-1-(4-(2-((4-(1-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1,3-DIOXOISOINDOLIN- 4-YL)GLYCYL)PIPERIDIN-4-YL)PHENYL)AMINO)PYRIDIN-4-YL)-2-(TRIFLUOROMETHYL)PHENOXY)-4- METHYLPENTAN-2-YL)CARBAMATE

[0404] To a solution of (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (21.6 mg, 0.065 mmol) in DMF (1 mL) was added DIEA (21.1 mg, 0.163 mmol), HATU (24.8 mg, 0.065 mmol), and tert-butyl (S)-(4-methyl-1-(4-(2-((4-(piperidin-4-yl)phenyl)amino)pyridin-4- yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate (I-A) (20.0 mg, 0.033 mmol), successively. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 80% of EtOAc in hexanes) to afford 4-((2-(4-(4-((4-(4-(((S)-2-amino-4- methylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)amino)phenyl)piperidin-1-yl)-2- oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (22.8 mg, 75% yield) as a yellow solid.1H NMR (600 MHz, CDCl3) δ 9.80 – 9.45 (m, 1H), 8.25 (dd, J = 5.1, 2.0 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.6, 2.3 Hz, 1H), 7.50 – 7.42 (m, 1H), 7.33 – 7.28 (m, 2H), 7.23 (dd, J = 13.7, 9.2 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 7.1 Hz, 1H), 7.04 (d, 8.6 Hz, 1H), 6.98 (s, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.78 (dd, J = 8.5, 1.8 Hz, 1H), 4.98 – 4.89 (m, 1H), 4.84 – 4.65 (m, 2H), 4.14 – 3.95 (m, 5H), 3.85 (d, J = 13.1 Hz, 1H), 3.25 – 3.12 (m, 1H), 2.93 – 2.67 (m, 5H), 2.15 – 2.06 (m, 1H), 1.99 – 1.86 (m, 2H), 1.72 – 1.58 (m, 3H), 1.56 – 1.37 (m, 11H), 0.98 – 0.90 (m, 6H). LC / MS (ESI) m / z 926.1 [M+H]+. (b) STEP 2: SYNTHESIS OF 4-((2-(4-(4-((4-(4-(((S)-2-AMINO- 4-METHYLPENTYL)OXY)-3- (TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDIN-1-YL)-2- OXOETHYL)AMINO)-2-(2,6-DIOXOPIPERIDIN-3- YL)ISOINDOLINE-1,3-DIONE (COMPOUND 1)

[0405] A solution of tert-butyl ((2S)-1-(4-(2-((4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)phenyl)amino)pyridin-4-yl)-2- (trifluoromethyl)phenoxy)-4-methylpentan-2-yl)carbamate (22.0 mg, 0.024 mmol) in DCM (1.5 mL) and TFA (0.5 mL) was stirred at room temperature for 1 hour. The mixture was quenched with sat. NaHCO3(aq.) and extracted with DCM. The combined organic layers were concentrated. The residue was purified by Pre-TLC (DCM : 0.5 M NH3in MeOH = 10 / 1) to afford 4-((2-(4-(4-((4-(4-(((S)-2-amino-4-methylpentyl)oxy)-3- (trifluoromethyl)phenyl)pyridin-2-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 1) (15.8 mg, 80% yield) as a yellow solid.1H NMR (600 MHz, CDCl3) δ 8.24 (dd, J = 5.2, 1.6 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.7, 2.3 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.21 (q, J = 4.8 Hz, 1H), 7.19 – 7.12 (m, 3H), 7.09 (d, J = 7.1 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 6.98 (s, 1H), 6.88 (dd, J = 5.4, 1.5 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.98 – 4.87 (m, 1H), 4.78 (d, J = 13.1 Hz, 1H), 4.10 – 3.98 (m, 3H), 3.91 – 3.77 (m, 2H), 3.35 – 3.26 (m, 1H), 3.19 (t, J = 12.9 Hz, 1H), 2.92 – 2.66 (m, 5H), 2.14 – 2.07 (m, 1H), 1.97 – 1.88 (m, 2H), 1.79 – 1.73 (m, 1H), 1.68 – 1.60 (m, 2H), 1.36 (t, J = 7.0 Hz, 2H), 0.99 – 0.91 (m, 6H). LC / MS (ESI) m / z 826.4 [M+H]+.

[0406] The following compounds were prepared by following the similar proceduredescribed above for the synthesis of compound 1: xxiv. 4-((4-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDIN-1-YL)-4-OXOBUTYL)AMINO)-2- (2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE (COMPOUND 2)

[0407] Compound 2 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.23 (d, J =5.3 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.6, 2.4 Hz, 1H), 7.50 (dd, J = 8.6, 7.1 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 7.1 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.89-6.87 (m, 1H), 6.34 (t, J = 5.9 Hz, 1H), 4.90-4.88 (m, 1H), 4.84-4.78 (m, 1H), 4.07-4.05 (m, 1H), 3.96-3.93 (m, 1H), 3.87-3.83 (m, 1H), 3.44-3.36 (m, 2H), 3.35-3.31 (m, 1H), 3.13-3.11 (m, 1H), 2.86-2.84 (m, 1H), 2.80-2.78 (m, 1H), 2.76 – 2.69 (m, 2H), 2.64-2.62 (m, 1H), 2.49-2.46 (m, 2H), 2.12-2.08 (m, 1H), 2.06- 2.01 (m, 2H), 1.90-1.87 (m, 2H), 1.77-1.74 (m, 1H), 1.63-1.55 (m, 2H), 1.38 (t, J = 7.0 Hz, 2H), 0.95 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). LC / MS (ESI) m / z 854.4 [M+H]+.xxv. 4-((6-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDIN-1-YL)-6-OXOHEXYL)AMINO)-2- (2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE (COMPOUND 3)

[0408] Compound 3 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.23 (d, J =5.3 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.68 (dd, J = 8.6, 2.3 Hz, 1H), 7.48 (dd, J = 8.5, 7.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 7.1 Hz, 1H), 7.03 (t, J = 9.5 Hz, 2H), 6.98 (s, 1H), 6.91 – 6.86 (m, 2H), 6.24 (t, J = 5.6 Hz, 1H), 4.90-4.88 (m, 1H), 4.81- 4.78 (m, 1H), 4.07-4.05 (m, 1H), 3.97-3.94 (m, 1H), 3.84 (t, J = 7.8 Hz, 1H), 3.29 (p, J = 7.1 Hz, 3H), 3.12-3.10 (m, 1H), 2.88-2.84 (m, 1H), 2.79-2.76 (m, 1H), 2.72-2.70 (m, 2H), 2.65- 2.60 (m, 1H), 2.40-2.38 (m, 2H), 2.12-2.09 (m, 1H), 1.90-1.87 (m, 3H), 1.79-1.75 (m, 1H), 1.72-1.66 (m, 3H), 1.63-1.58 (m, 2H), 1.52-1.48 (m, 2H), 1.37 (t, J = 7.0 Hz, 2H), 0.95 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). LC / MS (ESI) m / z 882.4 [M+H]+. xxvi. 4-((8-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDIN-1-YL)-8-OXOOCTYL)AMINO)-2-(2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE (COMPOUND 4)

[0409] Compound 4 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.23 (d, J =5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.6, 2.3 Hz, 1H), 7.48 (dd, J = 8.5, 7.1 Hz, 1H), 7.32 – 7.29 (m, 2H), 7.18-7.15 (m, 2H), 7.08 (d, J = 7.1 Hz, 2H), 7.05 (d, J = 8.7 Hz, 1H), 6.99 (s, 1H), 6.90-6.88 (m, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.23 (t, J = 5.6 Hz, 1H), 4.90-4.87 (m, 1H), 4.81-4.78 (m, 1H), 4.07-4.05 (m, 1H), 3.98-3.96 (m, 1H), 3.85 (t, J = 7.8 Hz, 1H), 3.33 (m, 1H), 3.26 (q, J = 6.6 Hz, 2H), 3.13-3.10 (m, 1H), 2.90-2.85 (m, 1H), 2.84-2.76 (m, 1H), 2.75-2.70 (m, 2H), 2.65-2.59 (m, 1H), 2.38-2.35 (m, 2H), 2.15-2.10 (m, 1H), 1.90-1.87 (m, 3H), 1.78-1.75 (m, 1H), 1.67 (t, J = 7.3 Hz, 3H), 1.60-1.57 (m, 2H), 1.43 (t, J = 4.7 Hz, 2H), 1.39 (dd, J = 7.6, 4.2 Hz, 6H), 0.95 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). LC / MS (ESI) m / z 910.5 [M+H]+. xxvii. 4-((2-(3-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDIN-1-YL)-3-OXOPROPOXY)ETHYL)AMINO)-2-(2,6-DIOXOPIPERIDIN-3- YL)ISOINDOLINE-1,3-DIONE (COMPOUND 5)

[0410] Compound 5 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.22 (d, J =5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.6, 2.4 Hz, 1H), 7.48 (dd, J = 8.5, 7.1 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.16-7.13 (m, 2H), 7.09 (d, J = 7.1 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 6.98-6.97 (m, 1H), 6.9-6.88 (m, 2H), 6.49 (t, J = 5.6 Hz, 1H), 4.88-4.86 (m, 1H), 4.82- 4.77 (m, 1H), 4.08-4.05 (m, 1H), 4.03-4.00 (m, 1H), 3.88-3.81 (m, 3H), 3.72 (t, J = 5.3 Hz, 2H), 3.47-3.44 (m, 2H), 3.33-3.30 (m, 1H), 3.13-3.09 (m, 1H), 2.85-2.81 (m, 1H), 2.78-2.75 (m, 1H), 2.73-2.66 (m, 3H), 2.66-2.61 (m, 2H), 2.09-2.05 (m, 1H), 1.90-1.86 (m, 2H), 1.77- 1.74 (m, 1H), 1.64-1.60 (m, 2H), 1.37 (t, J = 7.0 Hz, 2H), 0.95 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). LC / MS (ESI) m / z 884.5 [M+H]+. xxviii. 4-((2-(2-(3-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDIN-1-YL)-3- OXOPROPOXY)ETHOXY)ETHYL)AMINO)-2-(2,6-DIOXOPIPERIDIN- 3-YL)ISOINDOLINE-1,3-DIONE (COMPOUND 6)

[0411] Compound 6 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.22 (d, J =5.4 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.6, 2.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.30-7.27 (m, 2H), 7.16-7.12 (m, 3H), 7.08 (d, J = 7.1 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.99 (t, J = 2.1 Hz, 1H), 6.91-6.88 (m, 2H), 6.47 (t, J = 5.7 Hz, 1H), 4.90-4.88 (m, 1H), 4.79 (d, J = 13.1 Hz, 1H), 4.08-4.04 (m, 1H), 4.00-3.98 (m, 1H), 3.85-3.78 (m, 3H), 3.69 (t, J = 5.6 Hz, 2H), 3.66 (s, 3H), 3.67-3.64 (m, 1H), 3.45 (q, J = 5.6 Hz, 2H), 3.33-3.30 (m, 1H), 3.12-3.10 (m, 1H), 2.88 – 2.84 (m, 1H), 2.80-2.76 (m, 1H), 2.75-2.69 (m, 3H), 2.65-2.59 (m, 2H), 2.13-2.08 (m, 1H), 1.89-1.86 (m, 2H), 1.79-1.74 (m, 1H), 1.64-1.58 (m, 2H), 1.37 (t, J = 7.0 Hz, 2H), 0.95 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). LC / MS (ESI) m / z 928.4 [M+H]+. xxix. 4-((2-(2-(2-(3-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-3- OXOPROPOXY)ETHOXY)ETHOXY)ETHYL)AMINO)-2-(2,6- DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE (COMPOUND 7)

[0412] Compound 7 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.19 (d, J =5.5 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.6, 2.3 Hz, 1H), 7.49-7.46 (m, 1H), 7.29 (dd, J = 8.1, 4.2 Hz, 2H), 7.18-7.15 (m, 3H), 7.10-7.04 (m, 2H), 7.00 (s, 1H), 6.92-6.88 (m, 2H), 6.48 (t, J = 5.6 Hz, 1H), 4.93-4.89 (m, 1H), 4.79 (d, J = 13.2 Hz, 1H), 4.13-4.10 (m, 1H), 4.02-4.00 (m, 1H), 3.90 (t, J = 7.8 Hz, 1H), 3.84-3.78 (m, 2H), 3.70 (t, J = 5.3 Hz, 2H), 3.67- 3.64 (m, 8H), 3.46-3.44 (m, 2H), 3.14-3.09 (m, 2H), 2.88-2.84 (m, 1H), 2.80-2.76 (m, 1H), 2.75-2.71 (m, 3H), 2.67-2.60 (m, 2H), 2.13-2.09 (m, 1H), 1.88-1.85 (m, 2H), 1.75-1.65 (m, 1H), 1.61-1.55 (m, 1H), 1.43 (t, J = 7.0 Hz, 2H), 1.33 (t, J = 7.3 Hz, 1H), 0.95 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). LC / MS (ESI) m / z 972.5 [M+H]+.xxx. (2S,4R)-1-((S)-2-(4-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-4-OXOBUTANAMIDO)-3,3- DIMETHYLBUTANOYL)-4-HYDROXY-N-((S)-1-(4-(4- METHYLTHIAZOL-5-YL)PHENYL)ETHYL)PYRROLIDINE-2- CARBOXAMIDE (COMPOUND 8)

[0413] Compound 8 was synthesized from I-A.(600 MHz, CDCl3) δ 8.67 (d, J =5.2 Hz, 1H), 8.19 (t, J = 4.3 Hz, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.54-7.50 (m, 1H), 7.41-7.35 (m, 5H), 7.33-7.27 (m, 2H), 7.17 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.96 (s, 1H), 6.90 (d, J = 5.2 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 5.09-5.06 (m, 1H), 4.78 (q, J = 7.7 Hz, 1H), 4.72-4.70 (m, 1H), 4.49 (dd, J = 8.5, 3.1 Hz, 1H), 4.46 (s, 1H), 4.08 (t, J = 13.5 Hz, 2H), 3.99-3.96 (m, 1H), 3.86 (d, J = 7.8 Hz, 1H), 3.54-3.52 (m, 1H), 3.34 (d, J = 7.3 Hz, 1H), 3.16-3.11 (m, 1H), 2.80-2.75 (m, 1H), 2.76-2.69 (m, 1H), 2.67-2.60 (m, 2H), 2.58- 2.55 (m, 2H), 2.52 (d, J = 9.6 Hz, 3H), 2.34 (t, J = 7.6 Hz, 2H), 1.93-1.90 (m, 1H), 1.81-1.75 (m, 4H), 1.66-1.61 (m, 3H), 1.47 (t, J = 7.4 Hz, 2H), 1.06 (s, 9H), 0.95 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). LC / MS (ESI) m / z 1039.7 [M+H]+. xxxi. (2S,4R)-1-((S)-2-(6-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-6-OXOHEXANAMIDO)-3,3- DIMETHYLBUTANOYL)-4-HYDROXY-N-((S)-1-(4-(4-METHYLTHIAZOL-5-YL)PHENYL)ETHYL)PYRROLIDINE-2- CARBOXAMIDE (COMPOUND 9)

[0414] Compound 9 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.66 (s, 1H),8.19 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.7, 2.4 Hz, 1H), 7.49 (dd, J = 7.9, 3.3 Hz, 1H), 7.41-7.34 (m, 4H), 7.31 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.97 (s, 1H), 6.90 (d, J = 5.4 Hz, 1H), 6.52 (t, J = 7.7 Hz, 1H), 5.09-5.07 (m, 1H), 4.76 (q, J = 8.3 Hz, 2H), 4.58 (dd, J = 8.6, 5.4 Hz, 1H), 4.49 (s, 1H), 4.13-4.05 (m, 2H), 3.96-3.93 (m, 1H), 3.85 (t, J = 7.8 Hz, 1H), 3.60-3.55 (m, 1H), 3.33 (dd, J = 7.0, 3.6 Hz, 1H), 3.13-3.08 (m, 1H), 2.72-2.68 (m, 1H), 2.63-2.58 (m, 2H), 2.56-2.53 (m, 2H), 2.52 (s, 3H), 2.37- 2.35 (m, 1H), 2.34-2.30 (m, 1H), 2.29 -2.26 (m, 1H), 2.25-2.23 (m, 1H), 2.11-2.06 (m, 1H), 1.90-1.88 (m, 2H), 1.79-1.75 (m, 1H), 1.69-1.63 (m, 3H), 1.60-1.57 (m, 1H), 1.47 (d, J = 6.9 Hz, 3H), 1.38 (t, J = 7.0 Hz, 2H), 1.05 (s, 9H), 0.95 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H). LC / MS (ESI) m / z 1067.6 [M+H]+. xxxii. (2S,4R)-1-((S)-2-(8-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-8-OXOOCTANAMIDO)-3,3- DIMETHYLBUTANOYL)-4-HYDROXY-N-((S)-1-(4-(4-METHYLTHIAZOL-5-YL)PHENYL)ETHYL)PYRROLIDINE-2- CARBOXAMIDE (COMPOUND 10)

[0415] Compound 10 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.67 (s, 1H),8.20 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.6, 2.3 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.42-7.34 (m, 5H), 7.33-7.29 (m, 2H), 7.20-7.15 (m, 2H), 7.05 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.92-6.88 (m, 1H), 6.22 (d, J = 8.7 Hz, 1H), 5.09-5.07 (m, 1H), 4.76 (q, J = 9.8 Hz, 2H), 4.58 (dd, J = 8.8, 2.6 Hz, 1H), 4.51 (d, J = 4.5 Hz, 1H), 4.12 (d, J = 11.3 Hz, 1H), 4.07 (dd, J = 8.6, 3.6 Hz, 1H), 3.98-3.94 (m, 1H), 3.84-3.82 (m, 1H), 3.57 (dd, J = 11.3, 3.6 Hz, 1H), 3.32 (dd, J = 7.0, 3.5 Hz, 1H), 3.14-3.11 (m, 1H), 2.74-2.69 (m, 1H), 2.65-2.58 (m, 1H), 2.53- 2.51 (m, 2H), 2.52 (s, 3H), 2.38-2.31 (m, 2H), 2.24-2.21 (m, 2H), 2.12-2.06 (m, 1H), 1.95-1.87 (m, 4H), 1.80-1.74 (m, 1H), 1.67-1.59 (m, 6H), 1.47 (d, J = 6.9 Hz, 3H), 1.37 (t, J = 7.0 Hz, 2H), 1.35-1.33 (m, 1H), 1.04 (s, 9H), 0.95 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). LC / MS (ESI) m / z 1095.7 [M+H]+. xxxiii. (2S,4R)-1-((S)-2-(2-(3-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-3- OXOPROPOXY)ACETAMIDO)-3,3-DIMETHYLBUTANOYL)-4- HYDROXY-N-((S)-1-(4-(4-METHYLTHIAZOL-5-YL)PHENYL)ETHYL)PYRROLIDINE-2-CARBOXAMIDE (COMPOUND 11)

[0416] Compound 11 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.66 (d, J =3.4 Hz, 1H), 8.18 (d, J = 5.4 Hz, 1H), 8.01 (t, J = 8.5 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.55 (t, J = 9.2 Hz, 1H), 7.40-7.33 (m, 5H), 7.31 (t, J = 7.8 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.06 (dd, J = 8.7, 4.1 Hz, 1H), 6.97 (s, 1H), 6.90 (d, J = 5.4 Hz, 1H), 5.08-5.06 (m, 1H), 4.80-4.71 (m, 2H), 4.53-4.47 (m, 2H), 4.37-4.34 (m, 1H), 4.29-4.26 (m, 1H), 4.20- 4.18 (m, 1H), 4.13-4.12 (m, 1H), 4.09-4.07 (m, 1H), 4.04-4.02 (m, 1H), 3.86 (t, J = 7.8 Hz, 1H), 3.75 (s, 1H), 3.59-3.56 (m, 1H), 3.35 (d, J = 6.6 Hz, 1H), 3.14-3.11 (m, 1H), 2.73-2.70 (m, 3H), 2.57-2.54 (m, 1H), 2.52 (s, 3H), 2.33 (t, J = 7.6 Hz, 1H), 2.08-2.02 (m, 1H), 1.94-1.89 (m, 2H), 1.80-1.76 (m, 1H), 1.67-1.61 (m, 2H), 1.46 (t, J = 6.7 Hz, 2H), 1.39 (t, J = 7.0 Hz, 1H), 1.09 (d, J = 9.2 Hz, 9H), 0.96 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H). LC / MS (ESI) m / z 1055.6 [M+H]+. xxxiv. (2S,4R)-1-((S)-2-(2-(2-(3-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-3- OXOPROPOXY)ETHOXY)ACETAMIDO)-3,3-DIMETHYLBUTANOYL)- 4-HYDROXY-N-((S)-1-(4-(4-METHYLTHIAZOL-5-YL)PHENYL)ETHYL)PYRROLIDINE-2-CARBOXAMIDE (COMPOUND 12)

[0417] Compound 12 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.66 (s, 1H),8.17 (d, J = 5.4 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.6, 2.3 Hz, 1H), 7.45-7.40 (m, 2H), 7.38 (dd, J = 8.3, 2.0 Hz, 3H), 7.34 (d, J = 8.0 Hz, 2H), 7.29 (dd, J = 7.9, 4.8 Hz, 2H), 7.16 (dd, J = 8.5, 4.3 Hz, 2H), 7.07 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 4.9 Hz, 1H), 6.89 (d, J = 5.4 Hz, 1H), 5.08-5.06 (m, 1H), 4.72-4.70 (m, 2H), 4.57-4.54 (m, 1H), 4.49 (s, 1H), 4.31-4.27 (m, 1H), 4.23-4.20 (m, 1H), 4.10-4.07 (m, 3H), 4.03-3.99 (m, 2H), 3.91-3.87 (m, 1H), 3.75 (t, J = 4.9 Hz, 4H), 3.58-3.55 (m, 1H), 3.37-3.34 (m, 1H), 3.14-3.09 (m, 1H), 2.72-2.68 (m, 3H), 2.51 (s, 3H), 2.33 (t, J = 7.6 Hz, 2H), 2.08-2.04 (m, 1H), 1.92-1.87 (m, 2H), 1.80-1.78 (m, 1H), 1.65-1.62 (m, 2H), 1.46 (d, J = 6.9 Hz, 2H), 1.42 (t, J = 6.7 Hz, 1H), 1.05 (s, 9H), 0.95 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H). LC / MS (ESI) m / z 1099.5 [M+H]+. xxxv. (2S,4R)-1-((S)-15-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-2-(TERT-BUTYL)-4,15- DIOXO-6,9,12-TRIOXA-3-AZAPENTADECANOYL)-4-HYDROXY-N- ((S)-1-(4-(4-METHYLTHIAZOL-5- YL)PHENYL)ETHYL)PYRROLIDINE-2-CARBOXAMIDE (COMPOUND 13)

[0418] Compound 13 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.67 (s, 1H),8.15 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.6, 2.4 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.38 (q, J = 8.3 Hz, 5H), 7.32-7.30 (m, 3H), 7.17 (d, J = 7.9 Hz, 2H), 7.06 (s, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H), 5.09-5.06 (m, 1H), 4.76 (q, J = 4.7 Hz, 1H), 4.71-4.69 (m, 1H), 4.56 (d, J = 8.5 Hz, 1H), 4.52 (s, 1H), 4.34-4.27 (m, 1H), 4.21-4.15 (m, 1H), 4.08-4.05 (m, 2H), 4.03-3.97 (m, 1H), 3.96-3.90 (m, 1H), 3.84 (t, J = 7.9 Hz, 1H), 3.72-3.66 (m, 8H), 3.63-3.60 (m, 1H), 3.32 (s, 1H), 3.12-3.09 (m, 1H), 2.77-2.63 (m, 2H), 2.52 (s, 3H), 2.50 (m, 1H), 2.34 (t, J = 7.5 Hz, 1H), 2.12-2.07 (m, 2H), 1.92-1.90 (m, 2H), 1.75-1.69 (m, 1H), 1.65-1.62 (m, 2H), 1.48 (d, J = 6.9 Hz, 3H), 1.05 (s, 9H), 0.95 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). LC / MS (ESI) m / z 1143.5 [M+H]+. xxxvi. 3-(5-(4-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDINE-1-CARBONYL)PIPERIDIN-1-YL)-1- OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE (COMPOUND 16)

[0419] Compound 16 was synthesized from I-A and I-2. 1H NMR (600 MHz, CDCl3) δ 8.24(d, J = 5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.4 Hz, 1H), 7.37 – 7.30 (m, 2H), 7.22 – 7.15 (m, 2H), 7.05 (d, J = 8.6 Hz, 2H), 7.01 – 6.96 (m, 2H), 6.93 – 6.86 (m, 2H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.82 (d, J = 13.1 Hz, 1H), 4.40 (d, J = 15.6 Hz, 1H), 4.25 (d, J = 15.6 Hz, 1H), 4.11 – 4.01 (m, 2H), 3.92 – 3.80 (m, 3H), 3.32 (s, 1H), 3.24 – 3.14 (m, 1H), 2.97 – 2.86 (m, 3H), 2.85 – 2.72 (m, 3H), 2.65 (t, J = 12.8 Hz, 1H), 2.36 – 2.27 (m, 1H), 2.22 – 2.17 (m, 1H), 2.05 – 1.89 (m, 6H), 1.79 – 1.73 (m, 1H), 1.66 – 1.58 (m, 2H), 1.37 (t, J = 7.0 Hz, 2H), 1.03 – 0.92 (m, 6H). LC / MS (ESI) m / z 866.4 [M+H]+. xxxvii. (2S,4R)-1-((S)-2-(2-(4-(2-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-2-OXOETHYL)PIPERIDIN- 1-YL)ACETAMIDO)-3,3-DIMETHYLBUTANOYL)-4-HYDROXY-N- ((S)-1-(4-(4-METHYLTHIAZOL-5- YL)PHENYL)ETHYL)PYRROLIDINE-2-CARBOXAMIDE (COMPOUND 20)

[0420] Compound 20 was synthesized from I-A and I-6. 1H NMR (600 MHz, CDCl3) δ 8.66(d, J = 1.9 Hz, 1H), 8.21 (d, J = 5.3 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.7, 2.3 Hz, 1H), 7.46 (dd, J = 15.9, 7.8 Hz, 1H), 7.42 – 7.38 (m, 2H), 7.38 – 7.34 (m, 2H), 7.34 – 7.30 (m, 2H), 7.21 – 7.13 (m, 2H), 7.06 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 1.6 Hz, 1H), 6.92 – 6.87 (m, 1H), 6.84 (d, J = 10.8 Hz, 1H), 5.07 (p, J = 7.1 Hz, 1H), 4.84 – 4.72 (m,2H), 4.50 (s, 1H), 4.44 (t, J = 7.8 Hz, 1H), 4.23 – 4.15 (m, 1H), 4.10 – 4.05 (m, 1H), 3.99 (d, J = 13.3 Hz, 1H), 3.85 (t, J = 7.8 Hz, 1H), 3.60 – 3.53 (m, 1H), 3.34 (d, J = 10.9 Hz, 1H), 3.14 (t, J = 12.9 Hz, 1H), 3.03 (dd, J = 16.6, 3.3 Hz, 1H), 2.96 (dd, J = 16.6, 3.3 Hz, 1H), 2.89 – 2.81 (m, 2H), 2.74 (td, J = 9.9, 8.6, 5.8 Hz, 1H), 2.63 (t, J = 12.7 Hz, 1H), 2.59 – 2.51 (m, 4H), 2.36 – 2.20 (m, 5H), 2.09 – 2.05 (m, 2H), 1.93 – 1.81 (m, 5H), 1.63 – 1.57 (m, 2H), 1.49 – 1.45 (m, 3H), 1.41 – 1.35 (m, 3H), 1.06 (s, 9H), 0.98 – 0.93 (m, 6H). LC / MS (ESI) m / z 1122.6 [M+H]+. xxxviii. (2S,4R)-1-((S)-2-(2-(4-(2-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-2-OXOETHYL)PIPERAZIN- 1-YL)ACETAMIDO)-3,3-DIMETHYLBUTANOYL)-4-HYDROXY-N- ((S)-1-(4-(4-METHYLTHIAZOL-5- YL)PHENYL)ETHYL)PYRROLIDINE-2-CARBOXAMIDE (COMPOUND 21)

[0421] Compound 21 was synthesized from I-A and I-7. 1H NMR (600 MHz, CDCl3) δ 8.67(s, 1H), 8.20 (d, J = 5.3 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 3.7 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.1 Hz, 3H), 7.31 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.06 (t, J = 7.7 Hz, 1H), 7.00 (d, J = 4.6 Hz, 1H), 6.90 (dd, J = 5.4, 1.5 Hz, 1H), 5.09-5.07 (m, 1H), 4.77-4.73 (m, 2H), 4.50 (s, 1H), 4.41 (dd, J = 8.4, 5.0 Hz, 1H), 4.23-4.16 (m, 2H), 4.08 (dd, J = 8.9, 3.6 Hz, 1H), 3.90-3.86 (m, 1H), 3.58- 3.55 (m, 1H), 3.39-3.32 (m, 2H), 3.18-3.11 (m, 1H), 3.10-3.06 (m, 1H), 3.04-2.95 (m, 2H), 2.76-2.73 (m, 1H), 2.66- 2.60 (m, 8H), 2.53 (s, 3H), 2.34 (t, J = 7.5 Hz, 2H), 2.08-2.04 (m, 2H),1.93-1.90 (m, 3H), 1.79-1.76 (m, 1H), 1.64 (m, 2H), 1.48 (d, J = 6.9 Hz, 3H), 1.07 (s, 9H), 0.95 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). LC / MS (ESI) m / z 1123.7 [M+H]+. xxxix. (S)-1-(5-(4-(4-((5-((2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'- YL)AMINO)PHENYL)PIPERIDINE-1-CARBONYL)-2- METHOXYPHENYL)DIHYDROPYRIMIDINE-2,4(1H,3H)-DIONE (COMPOUND 28)

[0422] Compound 28 was synthesized from I-E. 1H NMR (600 MHz, CDCl3) δ 9.04 (s, 1H),8.34 – 8.27 (m, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.50 – 7.44 (m, 2H), 7.41 (d, J = 2.1 Hz, 1H), 7.38 – 7.28 (m, 4H), 7.24 (dd, J = 5.4, 1.5 Hz, 1H), 7.19 – 7.10 (m, 2H), 7.01 (d, J = 8.6 Hz, 1H), 6.82 (t, J = 54.1 Hz, 1H), 4.96 – 4.65 (m, 1H), 4.13 – 3.97 (m, 1H), 3.89 (s, 3H), 3.86 – 3.79 (m, 2H), 3.80 – 3.62 (m, 2H), 3.25 – 2.68 (m, 5H), 1.98 – 1.65 (m, 7H), 1.55 – 1.46 (m, 2H), 1.25 (s, 3H), 1.01 – 0.95 (m, 6H). LC / MS (ESI) m / z 756.3 [M+H]+. xl. (2S,4R)-1-((R)-3-((4-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-4-OXOBUTYL)THIO)-2-(1- FLUOROCYCLOPROPANE-1-CARBOXAMIDO)-3- METHYLBUTANOYL)-4-HYDROXY-N-((S)-1-(4-(4-METHYLTHIAZOL-5-YL)PHENYL)ETHYL)PYRROLIDINE-2- CARBOXAMIDE (COMPOUND 30)

[0423] Compound 30 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.66 (s, 1H),8.21 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.6, 2.4 Hz, 1H), 7.41-7.36 (m, 6H), 7.32 (d, J = 8.2 Hz, 2H), 7.18 (t, J = 9.1 Hz, 2H), 7.05 (d, J = 8.6 Hz, 1H), 6.97 (s, 1H), 6.90 (dd, J = 5.4, 1.5 Hz, 1H), 6.82 (s, 1H), 5.12 (p, J = 7.2 Hz, 1H), 4.88 (t, J = 7.7 Hz, 1H), 4.77-4.73 (m, 2H), 4.555-4.51 (m, 1H), 4.07-4.04 (m, 1H), 3.98-3.94 (m, 2H), 3.88-3.81 (m, 2H), 3.67-3.63 (m, 1H), 3.35-3.29 (m, 1H), 3.14-3.10 (m, 1H), 2.76-2.70 (m, 2H), 2.67-2.63 (m, 2H), 2.52 (s, 3H), 2.50-2.44 (m, 2H), 2.18-2.13 (m, 1H), 1.98-1.94 (m, 1H), 1.92-1.88 (m, 2H), 1.79-1.75 (m, 2H), 1.63-1.59 (m, 2H), 1.50 (d, J = 7.0 Hz, 3H), 1.43 (s, 3H), 1.37 (s, 3H), 1.35-1.32 (m, 3H), 1.30-1.28 (m, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H) ppm. LC / MS (ESI) m / z 1129.4 [M+H]+. xli. (2S,4R)-1-((R)-3-((6-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-6-OXOHEXYL)THIO)-2-(1- FLUOROCYCLOPROPANE-1-CARBOXAMIDO)-3- METHYLBUTANOYL)-4-HYDROXY-N-((S)-1-(4-(4-METHYLTHIAZOL-5-YL)PHENYL)ETHYL)PYRROLIDINE-2- CARBOXAMIDE (COMPOUND 31)

[0424] Compound 31 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.66 (s, 1H),8.20 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.6, 2.4 Hz, 1H), 7.41-7.36 (m, 6H), 7.32 (d, J = 8.1 Hz, 2H), 7.19-7.16 (m, 2H), 7.05 (d, J = 8.6 Hz, 1H), 7.00-6.97 (m, 2H), 6.90 (dd, J = 5.3, 1.6 Hz, 1H), 5.13-5.10 (m, 1H), 4.90-4.86 (m, 1H), 4.78-4.74 (m, 2H), 4.55- 4.53 (m, 1H), 4.06-4.00 (m, 1H), 3.99-3.91 (m, 2H), 3.85-3.78 (m, 2H), 3.66-3.63 (m, 2H), 3.33-3.30 (m, 1H), 3.14-3.10 (m, 1H), 2.76-2.71 (m, 1H), 2.63-2.60 (m, 2H), 2.52 (s, 3H), 2.50- 2.47 (m, 1H), 2.42-2.37 (m, 2H), 2.36-2.31 (m, 1H), 2.18-2.12 (m, 1H), 1.83-1.79 (m, 1H), 1.70-1.66 (m, 2H), 1.64-1.58 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H), 1.42 (s, 3H), 1.37 (s, 3H), 1.36- 1.33 (m, 6H), 1.32-1.29 (m, 4H), 0.97 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H) ppm. LC / MS (ESI) m / z 1157.5 [M+H]+. xlii. (2S,4R)-1-((R)-3-((8-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-8-OXOOCTYL)THIO)-2-(1- FLUOROCYCLOPROPANE-1-CARBOXAMIDO)-3- METHYLBUTANOYL)-4-HYDROXY-N-((S)-1-(4-(4-METHYLTHIAZOL-5-YL)PHENYL)ETHYL)PYRROLIDINE-2- CARBOXAMIDE (COMPOUND 32)

[0425] Compound 32 was synthesized from I-A. 1H NMR (600 MHz, CDCl3) δ 8.67 (s, 1H),8.20 (d, J = 5.4 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.6, 2.3 Hz, 1H), 7.41-7.36 (m, 6H), 7.33-7.31 (m, 2H), 7.24-7.20 (m, 1H),7.18 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.90 (dd, J = 5.4, 1.5 Hz, 1H), 5.14-5.08 (m, 1H), 4.85-4.83 (m, 1H), 4.80-4.75 (m, 2H), 4.55-4.51 (m, 1H), 4.06-4.03 (m, 1H), 3.97-3.94 (m, 2H), 3.85-3.78 (m, 2H), 3.65- 3.62 (m, 3H), 3.31-3.28 (m, 1H), 3.14-3.11 (m, 1H), 3.04-3.00 (m, 1H), 2.74-2.72 (m, 1H), 2.63-2.60 (m, 1H), 2.60-2.56 (m, 1H), 2.52 (s, 3H), 2.51-2.47 (m, 1H), 2.39-2.35 (m, 1H), 2.34- 2.30 (m, 2H), 2.16-2.12 (m, 1H), 2.01-1.97 (m, 1H), 1.92-1.86 (m, 2H), 1.72-1.68 (m, 2H), 1.57-1.54 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H), 1.42 (s, 3H), 1.38 (s, 3H), 1.37-1.29 (m, 10H), 0.97 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H) ppm. LC / MS (ESI) m / z 1185.5 [M+H]+. xliii. (2S,4R)-N-(2-(4-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-4-OXOBUTOXY)-4-(4- METHYLTHIAZOL-5-YL)BENZYL)-1-((S)-2-(1- FLUOROCYCLOPROPANE-1-CARBOXAMIDO)-3,3-DIMETHYLBUTANOYL)-4-HYDROXYPYRROLIDINE-2- CARBOXAMIDE (COMPOUND 33)

[0426] Compound 33 was synthesized from I-A. 1H NMR (600 MHz, Chloroform-d) δ 8.67(s, 1H), 8.21 (d, J = 5.4 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.6, 2.3 Hz, 1H), 7.36- 7.28 (m, 5H), 7.16 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.6 Hz, 1H), 7.01 (t, J = 9.9 Hz, 1H), 6.97- 6.94 (m, 1H), 6.90-6.88 (m, 2H), 6.79-6.76 (m, 1H), 4.81 (d, J = 13.3 Hz, 1H), 4.72 (q, J = 7.2 Hz, 1H), 4.55-4.48 (m, 4H), 4.42-4.38 (m, 1H), 4.11 (t, J = 5.9 Hz, 2H), 4.08-4.05 (m, 1H), 3.96 (t, J = 10.6 Hz, 1H), 3.83 (t, J = 7.9 Hz, 1H), 3.67-3.57 (m, 2H), 3.33-3.29 (m, 1H), 3.17- 3.10 (m, 1H), 2.74-2.69 (m, 1H), 2.67-2.61 (m, 2H), 2.52 (s, 3H), 2.25-2.22 (m, 1H), 2.08-2.02 (m, 1H), 1.89-1.75 (m, 6H), 1.64-1.57 (m, 2H), 1.37-1.35 (m, 2H), 0.97 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 8.8 Hz, 9H), 0.88-0.86 (m, 2H), 0.86-0.81 (m, 2H) ppm. LC / MS (ESI) m / z 1113.6 [M+H]+. xliv. (2S,4R)-N-(2-((6-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-6-OXOHEXYL)OXY)-4-(4- METHYLTHIAZOL-5-YL)BENZYL)-1-((S)-2-(1- FLUOROCYCLOPROPANE-1-CARBOXAMIDO)-3,3-DIMETHYLBUTANOYL)-4-HYDROXYPYRROLIDINE-2- CARBOXAMIDE (COMPOUND 34)

[0427] Compound 34 was synthesized from I-A.1H NMR (600 MHz, Chloroform-d) δ 8.67 (s, 1H), 8.21 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.6, 2.3 Hz, 1H), 7.34- 7.29 (m, 3H), 7.20 (t, J = 5.9 Hz, 1H), 7.17 (d, J = 8.1 Hz, 2H), 7.06-7.03 (m, 2H), 6.96 (d, J1.5 Hz, 1H), 6.94 (dd, J = 7.7, 1.6 Hz, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.86 (d, J = 1.6 Hz, 1H), 6.80-6.78 (m, 1H), 4.78 (d, J = 13.2 Hz, 1H), 4.72 (t, J = 7.7 Hz, 1H), 4.55-4.49 (dt, J = 15.0, 7.8 Hz, 4H), 4.45-4.40 (m, 1H), 4.09-3.95 (m, 4H), 3.84 (t, J = 7.8 Hz, 1H), 3.65-3.61 (m, 2H), 3.35-3.29 (m, 1H), 3.14 (t, J = 12.9 Hz, 1H), 2.76-2.70 (m, 1H), 2.65-2.60 (m, 1H), 2.52 (s, 3H), 2.50-2.47 (m, 1H), 2.43 (t, J = 7.7 Hz, 2H), 2.12-2.07 (m, 1H), 1.92-1.87 (m, 3H), 1.80-1.74 (m, 6H), 1.62-1.58 (m, 2H), 1.38 (t, J = 7.0 Hz, 2H), 0.97 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 0.94 (s, 9H), 0.89-0.82 (m, 4H) ppm. LC / MS (ESI) m / z 1141.7 [M+H]+. xlv. (2S,4R)-N-(2-((8-(4-(4-((4-(4-(((S)-2-AMINO-4- METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)-8-OXOOCTYL)OXY)-4-(4- METHYLTHIAZOL-5-YL)BENZYL)-1-((S)-2-(1- FLUOROCYCLOPROPANE-1-CARBOXAMIDO)-3,3-DIMETHYLBUTANOYL)-4-HYDROXYPYRROLIDINE-2- CARBOXAMIDE (COMPOUND 35)

[0428] Compound 35 was synthesized from I-A. 1H NMR (600 MHz, Chloroform-d) δ 8.67(s, 1H), 8.19 (d, J = 5.4 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.6, 2.3 Hz, 1H), 7.33- 7.29 (m, 3H), 7.18 (d, J = 8.1 Hz, 2H), 7.14 (t, J = 6.0 Hz, 1H), 7.09-7.03 (m, 3H), 6.99 (s, 1H), 6.94 (dd, J = 7.6, 1.6 Hz, 1H), 6.90 (dd, J = 5.4, 1.6 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 4.77 (d, J = 13.1 Hz, 1H), 4.71 (t, J = 7.7 Hz, 1H), 4.56-4.49 (m, 3H), 4.42 (dd, J = 14.5, 5.3 Hz, 1H), 4.07-3.95 (m, 4H), 3.84 (t, J = 7.9 Hz, 1H), 3.67-3.61 (m, 3H), 3.33-3.29 (m, 1H), 3.13 (t, J = 12.9 Hz, 1H), 2.76-2.70 (m, 1H), 2.62 (t, J = 12.8 Hz, 1H), 2.53 (s, 3H), 2.38-2.32 (m, 3H), 2.11-2.07 (m, 1H), 2.02-1.83 (m, 9H), 1.80-1.74 (m, 1H), 1.67-1.58 (m, 4H), 1.54-1.50 (m, 2H), 1.44-1.40 (m, 2H), 0.97 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 0.93 (s, 9H), 0.86- 0.80 (m, 4H) ppm. LC / MS (ESI) m / z 1169.7 [M+H]+. xlvi. 3-(5-(4-(4-((5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'- YL)AMINO)BENZOYL)PIPERAZIN-1-YL)-1-OXOISOINDOLIN-2- YL)PIPERIDINE-2,6-DIONE (COMPOUND 38)

[0429] Compound 38 was synthesized from I-F and I-2. 1H NMR (600 MHz, Chloroform-d)δ 8.32 (d, J = 5.4 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.73 – 7.64 (m, 2H), 7.55 (s, 1H), 7.52 – 7.44 (m, 2H), 7.44 – 7.38 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 5.6 Hz, 1H), 6.96 – 6.72 (m, 3H), 5.21 – 5.07 (m, 1H), 4.32 (d, J = 15.8 Hz, 1H), 4.20 (d, J = 15.8 Hz, 1H), 3.98 – 3.63 (m, 6H), 3.39 – 3.14 (m, 4H), 2.90 – 2.73 (m, 2H), 2.34 – 2.25 (m, 1H), 2.18 – 2.11 (m, 1H), 1.81 – 1.74 (m, 1H), 1.53 – 1.44 (m, 2H), 1.24 (s, 3H), 0.99 – 0.93 (m, 6H). LC / MS (ESI) m / z 781.4 [M+H]+. xlvii. 5-(4-(4-(4-((5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'- YL)AMINO)PHENYL)PIPERIDINE-1-CARBONYL)PIPERIDIN-1-YL)-2- (2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE (COMPOUND 40)

[0430] Compound 40 was synthesized from I-E. 1H NMR (600 MHz, Chloroform-d) δ 8.28(d, J = 5.3 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.51 – 7.46 (m, 1H), 7.39 – 7.32 (m, 3H), 7.27 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 5.4, 1.5 Hz, 1H), 7.19 – 7.14 (m, 2H), 7.11 – 7.02 (m, 2H), 6.83 (t, J = 54.1 Hz, 1H), 4.94 (dd, J = 12.4, 5.4 Hz, 1H), 4.80 (d, J = 13.1 Hz, 1H), 4.06 (d, J = 13.2 Hz, 1H), 4.01 – 3.92 (m, 2H), 3.87 – 3.81 (m, 2H), 3.25 – 3.14 (m, 1H), 3.10 – 3.00 (m, 2H), 2.92 – 2.62 (m, 6H), 2.15 – 2.09 (m, 1H), 1.99 – 1.86 (m, 6H), 1.82 – 1.76 (m, 1H), 1.66 – 1.58 (m, 2H), 1.55 – 1.47 (m, 2H), 1.26 (s, 3H), 1.02 – 0.94 (m, 6H). LC / MS (ESI) m / z 877.4 [M+H]+. xlviii. 5-(4-(4-((5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'-YL)AMINO)BENZOYL)PIPERAZIN-1-YL)-2-(2,6-DIOXOPIPERIDIN-3- YL)ISOINDOLINE-1,3-DIONE (COMPOUND 41)

[0431] Compound 41 was synthesized from I-F. 1H NMR (600 MHz, Chloroform-d) δ 8.28(d, J = 5.3 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.56 – 7.48 (m, 3H), 7.44 – 7.40 (m, 2H), 7.38 (d, J = 8.7 Hz, 1H), 7.28 (dd, J = 5.4, 1.5 Hz, 1H), 7.27 – 7.25 (m, 2H), 7.04 (dd, J = 8.6, 2.3 Hz, 1H), 6.83 (t, J = 54.1 Hz, 1H), 4.92 (dd, J = 12.4, 5.4 Hz, 1H), 3.93 – 3.67 (m, 6H), 3.47 – 3.40 (m, 3H), 2.88 – 2.66 (m, 3H), 2.12 – 2.08 (m, 2H), 1.79 – 1.70 (m, 1H), 1.55 – 1.44 (m, 2H), 1.24 (s, 3H), 1.00 – 0.92 (m, 6H). LC / MS (ESI) m / z 795.3 [M+H]+. xlix. (S)-1-(5-(4-(4-((5-((2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'- YL)AMINO)BENZOYL)PIPERAZINE-1-CARBONYL)-2- METHOXYPHENYL)DIHYDROPYRIMIDINE-2,4(1H,3H)-DIONE (COMPOUND 51)

[0432] Compound 51 was synthesized from I-F. 1H NMR (600 MHz, Chloroform-d) δ 8.31(d, J = 5.3 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.53 (s, 1H), 7.51 – 7.46 (m, 2H), 7.45 (dd, J = 8.5, 2.2 Hz, 1H), 7.43 – 7.39 (m, 3H), 7.37 (d, J = 8.7 Hz, 1H), 7.33 – 7.27 (m, 2H), 7.01 (d, J = 8.6 Hz, 1H), 6.86 (t, J = 54.1 Hz, 1H), 3.89 (s, 3H), 3.88 – 3.84 (m, 2H), 3.80 – 3.54 (m, 10H), 2.81 (t, J = 6.6 Hz, 2H), 1.81 – 1.77 (m, 1H), 1.56 – 1.48 (m, 2H), 1.27 (s, 3H), 1.01 – 0.96 (m, 6H). LC / MS (ESI) m / z 785.3 [M+H]+.l. 3-(4-(4-(4-((5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'- YL)AMINO)BENZOYL)PIPERAZIN-1-YL)PHENYL)PIPERIDINE-2,6- DIONE (COMPOUND 52)

[0433] Compound 52 was synthesized from I-F. 1H NMR (600 MHz, Chloroform-d) δ 8.22(d, J = 5.4 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.53 – 7.44 (m, 3H), 7.40 – 7.33 (m, 3H), 7.26 – 7.23 (m, 1H), 7.09 – 7.01 (m, 2H), 6.90 – 6.67 (m, 3H), 3.89 – 3.60 (m, 7H), 3.15 – 3.15 (m, 4H), 2.68 – 2.51 (m, 2H), 2.26 – 2.09 (m, 2H), 1.76 – 1.66 (m, 1H), 1.53 – 1.40 (m, 2H), 1.21 (s, 3H), 0.96 – 0.88 (m, 6H). LC / MS (ESI) m / z 726.3 [M+H]+. li. (S)-1-(4-(4-(4-((5-((2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'- YL)AMINO)BENZOYL)PIPERAZIN-1- YL)PHENYL)DIHYDROPYRIMIDINE-2,4(1H,3H)-DIONE (COMPOUND 53)

[0434] Compound 53 was synthesized from I-F. 1H NMR (600 MHz, Chloroform-d) δ 8.23(d, J = 5.4 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.54 – 7.45 (m, 3H), 7.40 – 7.32 (m, 3H), 7.26 – 7.24 (m, 1H), 7.16 – 7.09 (m, 2H), 6.93 – 6.66 (m, 3H), 3.98 – 3.61 (m, 8H), 3.17 – 3.16 (m, 4H), 2.74 (t, J = 6.7 Hz, 2H), 1.75 – 1.67 (m, 1H), 1.51 (dd, J = 14.3, 5.6 Hz, 1H), 1.44 (dd, J = 14.3, 5.7 Hz, 1H), 1.21 (s, 3H), 0.98 – 0.88 (m, 6H). LC / MS (ESI) m / z 727.3 [M+H]+.lii. 3-((4-(4-(4-((5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'- YL)AMINO)BENZOYL)PIPERAZIN-1-YL)-3- FLUOROPHENYL)AMINO)PIPERIDINE-2,6-DIONE (COMPOUND 54)

[0435] Compound 54 was synthesized from I-F. 1H NMR (600 MHz, Chloroform-d) δ 8.27 –8.17 (m, 1H), 7.85 – 7.75 (m, 1H), 7.55 – 7.43 (m, 3H), 7.41 – 7.32 (m, 3H), 7.27 – 7.25 (m, 1H), 6.93 – 6.66 (m, 2H), 6.44 – 6.31 (m, 2H), 3.98 – 3.92 (m, 1H), 3.89 – 3.60 (m, 6H), 3.02 – 2.82 (m, 4H), 2.80 – 2.64 (m, 2H), 2.46 – 2.36 (m, 1H), 1.92 – 1.79 (m, 1H), 1.75 – 1.67 (m, 1H), 1.54 – 1.49 (m, 1H), 1.48 – 1.42 (m, 1H), 1.22 (s, 3H), 0.97 – 0.89 (m, 6H). LC / MS (ESI) m / z 759.3 [M+H]+. liii. 3-((4-(1-(4-((5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'- YL)AMINO)BENZOYL)PIPERIDIN-4-YL)-3- FLUOROPHENYL)AMINO)PIPERIDINE-2,6-DIONE (COMPOUND 55)

[0436] Compound 55 was synthesized from I-F. 1H NMR (600 MHz, Chloroform-d) δ 8.21(d, J = 5.4 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.51 – 7.43 (m, 3H), 7.40 – 7.31 (m, 3H), 7.25 (dd, J = 5.4, 1.6 Hz, 1H), 6.97 (t, J = 8.4 Hz, 1H), 6.78 (t, J = 54.1 Hz, 1H), 6.39 (dd, J = 8.4, 2.5 Hz, 1H), 6.31 (dd, J = 12.6, 2.5 Hz, 1H), 4.73 (s, 1H), 3.98 (dd, J = 12.3, 4.9 Hz, 2H), 3.87 – 3.75 (m, 2H), 3.04 – 2.61 (m, 5H), 2.47 – 2.36 (m, 1H), 1.91 – 1.55 (m, 6H), 1.52 – 1.40 (m, 2H), 1.21 (s, 3H), 0.97 – 0.88 (m, 6H). LC / MS (ESI) m / z 758.3 [M+H]+.liv. 5-(4-(4-(4-(5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)PYRIDIN-2-YL)-9H-PYRIDO[2,3-B]INDOL-6- YL)-1,2,3,6-TETRAHYDROPYRIDINE-1-CARBONYL)PIPERIDIN-1- YL)-2-(2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE (COMPOUND 58)

[0437] Compound 58 was synthesized from I-J. 1H NMR (600 MHz, DMSO-d6) δ 12.04 (d,J = 5.2 Hz, 1H), 11.07 (s, 1H), 8.50 (d, J = 5.0 Hz, 1H), 8.10 – 8.03 (m, 1H), 8.01 – 7.89 (m, 2H), 7.71 – 7.64 (m, 1H), 7.64 – 7.54 (m, 1H), 7.52 – 7.47 (m, 1H), 7.45 – 7.21 (m, 4H), 6.05 (d, J = 28.0 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.26 (s, 1H), 4.12 – 4.03 (m, 5H), 3.77 – 3.65 (m, 2H), 3.15 – 3.02 (m, 3H), 2.93 – 2.83 (m, 1H), 2.62 – 2.53 (m, 3H), 2.41 – 2.34 (m, 1H), 2.04 – 1.97 (m, 1H), 1.87 – 1.79 (m, 1H), 1.78 – 1.70 (m, 2H), 1.70 – 1.61 (m, 2H), 1.60 – 1.55 (m, 1H), 1.52 – 1.47 (m, 1H), 1.26 (s, 3H), 0.97 – 0.91 (m, 6H). LC / MS (ESI) m / z 873.4 [M+H]+. lv. 5-(4-(4-(4-(5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)PYRIDIN-2-YL)-9H-PYRIDO[2,3-B]INDOL-6-YL)PIPERIDINE-1-CARBONYL)PIPERIDIN-1-YL)-2-(2,6- DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE (COMPOUND 61)

[0438] Compound 61 was synthesized from I-K. 1H NMR (600 MHz, Methanol-d4) δ 8.41(d, J = 5.1 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.86 – 7.79 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.36 – 7.31 (m, 2H), 7.28 (d, J = 5.1 Hz, 1H), 7.23 – 7.00 (m, 2H), 5.03 (dd, J = 12.6, 5.5 Hz, 1H), 4.71 – 4.64 (m, 1H), 4.22 – 4.07 (m, 3H), 4.07 – 3.98 (m, 2H), 3.27 – 3.16 (m, 1H), 3.13 – 3.02 (m, 2H), 3.02 – 2.92 (m, 1H), 2.91 – 2.66 (m, 5H), 2.16 – 2.07 (m, 1H), 1.98 (d, J = 13.4 Hz, 1H), 1.92 – 1.81 (m, 6H), 1.73 – 1.67 (m, 1H), 1.65 – 1.56 (m, 3H), 1.39 (s, 3H), 1.05 – 0.99 (m, 6H). LC / MS (ESI) m / z 875.4 [M+H]+. lvi. 3-(5-(4-(4-(7-(5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)PYRIDIN-2-YL)PYRAZOLO[1,5-A]PYRIMIDIN- 2-YL)-1,2,3,6-TETRAHYDROPYRIDINE-1-CARBONYL)PIPERIDIN-1- YL)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE (COMPOUND 64)

[0439] Compound 64 was synthesized from I-L. 1H NMR (600 MHz, Chloroform-d) δ 9.46(d, J = 8.9 Hz, 1H), 8.56 (d, J = 4.5 Hz, 1H), 7.85 – 7.77 (m, 1H), 7.72 (dd, J = 8.6, 2.7 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.05 – 6.53 (m, 5H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.40 (d, J =15.5 Hz, 1H), 4.37 – 4.29 (m, 2H), 4.25 (dd, J = 15.7, 2.8 Hz, 1H), 3.96 – 3.84 (m, 5H), 3.81 (t, J = 5.8 Hz, 1H), 2.99 – 2.91 (m, 2H), 2.89 – 2.78 (m, 4H), 2.38 – 2.28 (m, 1H), 2.23 – 2.17 (m, 1H), 2.04 – 1.97 (m, 2H), 1.91 – 1.86 (m, 2H), 1.83 – 1.77 (m, 2H), 1.57 – 1.50 (m, 2H), 1.28 (s, 3H), 1.03 – 0.97 (m, 6H). LC / MS (ESI) m / z 810.4 [M+H]+. lvii. PREPARATION OF 3-(5-(4-((4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN- 2-YL)AMINO)PHENYL)PIPERIDIN-1-YL)METHYL)PIPERIDIN-1-YL)- 1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE (COMPOUND 14)(a) STEP 1: SYNTHESIS OF TERT-BUTYL ((2S)-1-(4-(2-((4-(1-((1-(2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5- YL)PIPERIDIN-4-YL)METHYL)PIPERIDIN-4- YL)PHENYL)AMINO)PYRIDIN-4-YL)-2-(TRIFLUOROMETHYL)PHENOXY)-4-METHYLPENTAN-2- YL)CARBAMATE

[0440] A suspension of tert-butyl (S)-(4-methyl-1-(4-(2-((4-(piperidin-4- yl)phenyl)amino)pyridin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate (16.0 mg, 0.026 mmol), 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (10.2 mg, 0.029 mmol), and NaBH(OAc)3(27.8 mg, 0.130 mmol) in DCM (0.5 mL) and DMSO (0.5 mL) was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 15% of MeOH in DCM) to afford tert-butyl ((2S)-1-(4-(2-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyridin-4-yl)-2- (trifluoromethyl)phenoxy)-4-methylpentan-2-yl)carbamate (13.7 mg, 55% yield) as a white solid.1H NMR (600 MHz, CDCl3) δ 9.12 (s, 1H), 8.24 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.73 – 7.66 (m, 2H), 7.32 – 7.27 (m, 2H), 7.24 – 7.18 (m, 2H), 7.10 – 7.02 (m, 2H), 7.02 – 6.96 (m, 2H), 6.90 – 6.85 (m, 2H), 5.20 (dd, J = 13.3, 5.1 Hz, 1H), 4.72 (d, J = 8.8 Hz, 1H), 4.40 (d, J = 15.6 Hz, 1H), 4.24 (d, J = 15.6 Hz, 1H), 4.15 – 3.99 (m, 3H), 3.89 – 3.80 (m, 2H), 3.10 – 2.96 (m, 2H), 2.93 – 2.77 (m, 4H), 2.55 – 2.44 (m, 1H), 2.36 – 2.23 (m, 3H), 2.20 – 2.15 (m, 1H), 2.11 – 2.01 (m, 2H), 1.94 – 1.87 (m, 2H), 1.87 – 1.73 (m, 5H), 1.72 – 1.62 (m, 1H), 1.57 – 1.50 (m, 2H), 1.43 (s, 9H), 1.37 – 1.30 (m, 2H), 0.98 – 0.91 (m, 6H). LC / MS (ESI) m / z 952.4 [M+H]+. (b) STEP 2: SYNTHESIS OF 3-(5-(4-((4-(4-((4-(4-(((S)-2- AMINO-4-METHYLPENTYL)OXY)-3- (TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDIN-1-YL)METHYL)PIPERIDIN- 1-YL)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE (COMPOUND 14)

[0441] A solution of tert-butyl ((2S)-1-(4-(2-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyridin-4-yl)-2- (trifluoromethyl)phenoxy)-4-methylpentan-2-yl)carbamate (13.0 mg, 0.014 mmol) in DCM (1.5 mL) and TFA (0.5 mL) was stirred at room temperature for 1 hour. The mixture was quenched with sat. NaHCO3(aq.) and extracted with DCM. The combined organic layers were concentrated. The residue was purified by Pre-TLC (DCM : 0.5 M NH3in MeOH = 10 / 1) to afford 3-(5-(4-((4-(4-((4-(4-(((S)-2-amino-4-methylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)amino)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (compound 14) (8.3 mg, 72% yield) as a white solid.1H NMR (600 MHz, CDCl3) δ 8.24 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.3 Hz, 1H), 7.32 – 7.27 (m, 2H), 7.24 – 7.19 (m, 2H), 7.04 (d, J = 8.7 Hz, 1H), 7.01 – 6.97 (m, 2H), 6.93 (s, 1H), 6.90 – 6.86 (m, 2H), 5.20 (dd, J = 13.3, 5.1 Hz, 1H), 4.40 (d, J = 15.5 Hz, 1H), 4.24 (d, J = 15.6 Hz, 1H), 4.05 (dd, J = 8.7, 3.6 Hz, 1H), 3.89 – 3.78 (m, 3H), 3.34 – 3.27 (m, 1H), 3.02 (d, J = 10.8 Hz, 2H), 2.93 – 2.77 (m, 4H), 2.52 – 2.45 (m, 1H), 2.36 – 2.24 (m, 3H), 2.22 – 2.15 (m, 1H), 2.10 – 2.03 (m, 2H), 1.90 (d, J = 13.0 Hz, 2H), 1.84 – 1.76 (m, 6H), 1.38 – 1.30 (m, 4H), 0.99 – 0.92 (m, 6H). LC / MS (ESI) m / z 852.4 [M+H]+.

[0442] The following compounds were prepared by following the similar proceduredescribed above for the synthesis of compound 14: lviii. 3-(5-(4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN-2-YL)AMINO)PHENYL)- [1,4'-BIPIPERIDIN]-1'-YL)-1-OXOISOINDOLIN-2-YL)PIPERIDINE- 2,6-DIONE (COMPOUND 17)

[0443] Compound 17 was synthesized from I-A and I-3. 1H NMR (600 MHz, CDCl3) δ 8.23(d, J = 5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.4 Hz, 1H), 7.32 – 7.27 (m, 2H), 7.24 – 7.19 (m, 2H), 7.04 (d, J = 8.7 Hz, 1H), 7.02 – 6.96 (m, 2H), 6.92 – 6.85 (m, 3H), 5.20 (dd, J = 13.3, 5.1 Hz, 1H), 4.40 (d, J = 15.6 Hz, 1H), 4.25 (d, J = 15.6 Hz, 1H), 4.05 (dd, J = 8.6, 3.5 Hz, 1H), 3.92 (d, J = 12.4 Hz, 2H), 3.82 (dd, J = 8.6, 7.2 Hz, 1H), 3.34 – 3.25 (m, 1H), 3.11 (d, J = 10.8 Hz, 2H), 2.93 – 2.78 (m, 4H), 2.63 – 2.47 (m, 2H), 2.42 – 2.27 (m, 3H), 2.23 – 2.14 (m, 1H), 2.00 (d, J = 12.2 Hz, 2H), 1.91 – 1.87 (m, 2H), 1.81 –1.69 (m, 5H), 1.36 (t, J = 7.0 Hz, 2H), 0.99 – 0.92 (m, 6H). LC / MS (ESI) m / z 838.4 [M+H]+.lix. 3-((4-(4-((4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDIN-1-YL)METHYL)PIPERIDIN-1-YL)-3- FLUOROPHENYL)AMINO)PIPERIDINE-2,6-DIONE (COMPOUND 18)

[0444] Compound 18 was synthesized from I-A and I-4. 1H NMR (600 MHz, CDCl3) δ 8.24(d, J = 5.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.7, 2.4 Hz, 1H), 7.32 – 7.27 (m, 2H), 7.25 – 7.20 (m, 2H), 7.04 (d, J = 8.7 Hz, 1H), 7.01 – 6.98 (m, 1H), 6.95 (s, 1H), 6.91 – 6.86 (m, 2H), 6.46 – 6.38 (m, 2H), 4.65 – 4.57 (m, 1H), 4.06 (dd, J = 8.6, 3.5 Hz, 1H), 4.02 – 3.95 (m, 1H), 3.87 – 3.78 (m, 1H), 3.34 – 3.26 (m, 3H), 3.12 – 3.00 (m, 2H), 2.91 – 2.81 (m, 1H), 2.79 – 2.69 (m, 1H), 2.65 – 2.57 (m, 2H), 2.57 – 2.45 (m, 2H), 2.37 – 2.23 (m, 2H), 2.14 – 2.01 (m, 2H), 1.89 – 1.77 (m, 7H), 1.73 – 1.60 (m, 2H), 1.49 – 1.41 (m, 2H), 1.36 (t, J = 7.0 Hz, 2H), 1.03 – 0.91 (m, 6H). LC / MS (ESI) m / z 830.5 [M+H]+. lx. 5-(4-((4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDIN-1-YL)METHYL)PIPERIDIN-1-YL)-N- ((S)-2,6-DIOXOPIPERIDIN-3-YL)PICOLINAMIDE (COMPOUND 19)

[0445] Compound 19 was synthesized from I-A and I-5. 1HNMR (600 MHz, CDCl3) δ 8.45(d, J = 6.8 Hz, 1H), 8.24 (d, J = 5.3 Hz, 1H), 8.21 (d, J = 2.9 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.6, 2.3 Hz, 1H), 7.33 – 7.28 (m, 2H), 7.24 – 7.18 (m, 3H), 7.04 (d, J = 8.7 Hz, 1H), 7.00 – 6.97 (m, 1H), 6.93 – 6.86 (m, 2H), 4.83 – 4.73 (m, 1H), 4.06 (dd, J = 8.7, 3.6 Hz, 1H), 3.91 – 3.79 (m, 3H), 3.35 – 3.27 (m, 1H), 3.12 – 2.98 (m, 2H),2.92 – 2.85 (m, 2H), 2.85 – 2.74 (m, 2H), 2.65 – 2.57 (m, 1H), 2.55 – 2.45 (m, 1H), 2.34 – 2.24 (m, 2H), 2.16 – 2.05 (m, 2H), 2.05 – 1.89 (m, 4H), 1.83 – 1.70 (m, 5H), 1.40 – 1.31 (m, 4H), 1.02 – 0.92 (m, 6H). LC / MS (ESI) m / z 841.4 [M+H]+. lxi. 2-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-5-(2-((4-(1-((1-(2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)PIPERIDIN-4- YL)METHYL)PIPERIDIN-4-YL)PHENYL)AMINO)PYRIDIN-4- YL)BENZONITRILE (COMPOUND 22)

[0446] Compound 22 was synthesized from I-B and I-1.(600 MHz, D2O) δ 8.12 (d,J = 2.4 Hz, 1H), 8.05 (dd, J = 8.9, 2.5 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 6.8 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 8.4, 2.1 Hz, 1H), 7.52 – 7.47 (m, 2H), 7.43 – 7.39 (m, 2H), 7.34 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 1.7 Hz, 1H), 7.26 (dd, J = 6.8, 1.8 Hz, 1H), 5.19 (dd, J = 13.3, 5.3 Hz, 1H), 4.68 (d, J = 18.0 Hz, 1H), 4.60 (d, J = 17.9 Hz, 1H), 4.51 (dd, J = 10.8, 3.1 Hz, 1H), 4.38 (dd, J = 10.7, 6.3 Hz, 1H), 3.94 – 3.85 (m, 3H), 3.85 – 3.77 (m, 2H), 3.73 – 3.65 (m, 2H), 3.30 – 3.19 (m, 4H), 3.10 – 3.02 (m, 1H), 2.99 – 2.86 (m, 2H), 2.61 – 2.45 (m, 2H), 2.32 – 2.20 (m, 5H), 2.12 – 2.02 (m, 2H), 1.93 – 1.83 (m, 2H), 1.81 – 1.66 (m, 3H), 1.00 – 0.96 (m, 6H). LC / MS (ESI) m / z 809.5 [M+H]+. lxii. 5-(4-((4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-CYANOPHENYL)PYRIDIN-2-YL)AMINO)PHENYL)PIPERIDIN-1- YL)METHYL)PIPERIDIN-1-YL)-N-((S)-2,6-DIOXOPIPERIDIN-3- YL)PICOLINAMIDE (COMPOUND 23)

[0447] Compound 23 was synthesized from I-B and I-5. 1H NMR (600 MHz, D2O) δ 8.36 (d,J = 2.9 Hz, 1H), 8.18 – 8.10 (m, 2H), 8.05 (dd, J = 9.0, 2.4 Hz, 1H), 7.89 (d, J = 6.8 Hz, 1H), 7.84 (dd, J = 9.3, 2.8 Hz, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 9.0 Hz, 1H), 7.30 (s, 1H), 7.26 (dd, J = 6.8, 1.7 Hz, 1H), 4.99 – 4.91 (m, 1H), 4.51 (dd, J = 10.9, 3.0 Hz, 1H), 4.38 (dd, J = 10.8, 6.3 Hz, 1H), 4.11 – 4.04 (m, 2H), 3.93 – 3.86 (m, 1H), 3.78 (d, J = 12.0 Hz, 2H), 3.27 – 3.10 (m, 6H), 3.09 – 3.01 (m, 1H), 2.94 – 2.79 (m, 2H), 2.41 – 2.28 (m, 3H), 2.25 – 2.19 (m, 2H), 2.10 – 2.03 (m, 2H), 2.01 – 1.94 (m, 2H), 1.82 – 1.65 (m, 3H), 1.54 – 1.43 (m, 2H), 1.04 – 0.95 (m, 6H). LC / MS (ESI) m / z 798.4 [M+H]+. lxiii. 3-(5-(4-((4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN-2-YL)AMINO)PIPERIDIN-1- YL)METHYL)PIPERIDIN-1-YL)-1-OXOISOINDOLIN-2- YL)PIPERIDINE-2,6-DIONE (COMPOUND 24)

[0448] Compound 24 was synthesized from I-C and I-1. 1H NMR (600 MHz, CDCl3) δ 8.13(d, J = 5.3 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.74 – 7.67 (m, 2H), 7.05 (d, J = 8.6 Hz, 1H), 6.99 (dd, J = 8.7, 2.2 Hz, 1H), 6.87 (d, J = 2.1 Hz, 1H), 6.72 (dd, J = 5.3, 1.5 Hz, 1H), 6.48 (d, J = 1.2 Hz, 1H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.73 (s, 1H), 4.40 (d, J = 15.5 Hz, 1H), 4.24 (d, J = 15.5 Hz, 1H), 4.06 (dd, J = 8.7, 3.6 Hz, 1H), 3.88 – 3.77 (m, 3H), 3.71 (s, 1H), 3.37 – 3.24 (m, 1H), 2.95 – 2.74 (m, 6H), 2.37 – 2.16 (m, 6H), 2.13 – 2.04 (m, 2H), 1.92 – 1.84 (m, 2H), 1.83 – 1.75 (m, 2H), 1.60 – 1.53 (m, 2H), 1.39 – 1.29 (m, 4H), 0.99 – 0.91 (m, 6H). LC / MS (ESI) m / z 775.8 [M+H]+. lxiv. 2-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-5-(2-((1-((1-(2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)PIPERIDIN-4-YL)METHYL)PIPERIDIN-4-YL)AMINO)PYRIDIN-4- YL)BENZONITRILE (COMPOUND 25)

[0449] Compound 25 was synthesized from I-D and I-1. 1H NMR (600 MHz, D2O) δ 8.09 –8.05 (m, 1H), 7.98 (dd, J = 9.0, 2.5 Hz, 1H), 7.90 – 7.79 (m, 2H), 7.69 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 8.5, 2.2 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 7.17 – 7.08 (m, 2H), 5.11 (dd, J = 13.3, 5.2 Hz, 1H), 4.59 (d, J = 17.8 Hz, 1H), 4.50 (d, J = 17.9 Hz, 1H), 4.44 (dd, J = 10.7, 3.0 Hz, 1H), 4.30 (dd, J = 10.7, 6.3 Hz, 1H), 4.01 – 3.93 (m, 1H), 3.85 – 3.70 (m, 5H), 3.56 – 3.46 (m, 2H), 3.20 – 3.09 (m, 3H), 2.91 – 2.78 (m, 2H), 2.52 – 2.42 (m, 1H), 2.39 – 2.30 (m, 3H), 2.28 – 2.09 (m, 4H), 1.99 – 1.87 (m, 2H), 1.79 – 1.57 (m, 5H), 0.91 (d, J = 5.9 Hz, 6H). LC / MS (ESI) m / z 733.4 [M+H]+. 5-(4-((4-((4-(4-(((S)-2-amino-4-methylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)amino)piperidin-1- yl)methyl)piperidin-1-yl)-N-((S)-2,6-dioxopiperidin-3-yl)picolinamide (compound 26)

[0450] Compound 26 was synthesized from I-D and I-5. 1H NMR (600 MHz, D2O) δ 8.37 (d,J = 2.9 Hz, 1H), 8.20 – 8.14 (m, 2H), 8.11 – 8.05 (m, 1H), 7.95 – 7.83 (m, 2H), 7.36 (dd, J = 8.9, 2.3 Hz, 1H), 7.27 – 7.15 (m, 2H), 5.01 – 4.92 (m, 1H), 4.53 (dd, J = 10.8, 3.0 Hz, 1H), 4.39 (dd, J = 10.8, 6.3 Hz, 1H), 4.13 – 4.02 (m, 3H), 3.90 (tt, J = 7.0, 4.3 Hz, 1H), 3.83 – 3.75 (m, 2H), 3.27 – 3.13 (m, 6H), 2.96 – 2.85 (m, 2H), 2.43 – 2.16 (m, 6H), 2.01 – 1.95 (m, 3H), 1.84 – 1.74 (m, 2H), 1.73 – 1.65 (m, 1H), 1.52 – 1.41 (m, 2H), 1.00 (d, J = 5.9 Hz, 6H). LC / MS (ESI) m / z 722.5 [M+H]+. lxv. 3-(5-(4-((4-(4-((5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'-YL)AMINO)PHENYL)PIPERIDIN-1-YL)METHYL)PIPERIDIN-1-YL)-1- OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE (COMPOUND 27) ,(m, 1H), 2.10 – 2.04 (m, 2H), 1.94 – 1.88 (m, 2H), 1.85 – 1.76 (m, 6H), 1.55 – 1.45 (m, 2H), 1.37 – 1.29 (m, 2H), 1.25 (s, 3H), 1.01 – 0.95 (m, 6H). LC / MS (ESI) m / z 849.4 [M+H]+. lxvi. 3-((4-(4-((4-(4-((5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'- YL)AMINO)PHENYL)PIPERIDIN-1-YL)METHYL)PIPERIDIN-1-YL)-3- FLUOROPHENYL)AMINO)PIPERIDINE-2,6-DIONE (COMPOUND 29)

[0452] Compound 29 was synthesized from I-E and I-4. 1H NMR (600 MHz, CDCl3) δ 8.28(d, J = 5.3 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.51 – 7.45 (m, 1H), 7.38 – 7.29 (m, 3H), 7.26 – 7.20 (m, 3H), 6.97 – 6.70 (m, 3H), 6.46 – 6.37 (m, 2H), 4.68 – 4.52 (m, 1H), 3.99 (dd, J = 12.4, 4.8 Hz, 1H), 3.88 – 3.78 (m, 2H), 3.34 – 3.25 (m, 2H), 3.04 (d, J = 10.9 Hz, 2H), 2.91 – 2.81 (m, 1H), 2.78 – 2.70 (m, 1H), 2.65 – 2.57 (m, 2H), 2.56 – 2.46 (m, 2H), 2.29 (d, J = 7.1 Hz, 2H), 2.10 – 2.01 (m, 2H), 1.91 – 1.62 (m, 12H), 1.54 – 1.41 (m, 4H), 1.03 – 0.95 (m, 6H). LC / MS (ESI) m / z 827.4 [M+H]+.lxvii. 3-(5-(4-((4-(4-((4-(4-(((S)-2-AMINO-4-METHYLPENTYL)OXY)-3-(TRIFLUOROMETHYL)PHENYL)PYRIDIN-2- YL)AMINO)PHENYL)PIPERIDIN-1-YL)METHYL)PIPERIDIN-1-YL)-1- OXOISOINDOLIN-2-YL)-1-METHYLPIPERIDINE-2,6-DIONE (COMPOUND 37)

[0453] Compound 37 was synthesized from I-A and I-8. 1H NMR (600 MHz, DMSO-d6) δ9.42 (s, 1H), 9.23 (s, 1H), 8.18 (d, J = 5.5 Hz, 1H), 8.13 – 8.09 (m, 2H), 8.05 (dd, J = 8.6, 2.3 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.68 – 7.60 (m, 2H), 7.56 – 7.51 (m, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.22 – 7.17 (m, 2H), 7.17 – 7.15 (m, 1H), 7.11 – 7.07 (m, 2H), 5.11 (dd, J = 13.4, 5.1 Hz, 1H), 4.40 – 4.25 (m, 3H), 4.20 (d, J = 16.7 Hz, 1H), 3.98 – 3.88 (m, 2H), 3.69 – 3.55 (m, 3H), 3.12 – 3.01 (m, 4H), 3.01 – 2.94 (m, 4H), 2.91 – 2.85 (m, 2H), 2.82 – 2.72 (m, 2H), 2.43 – 2.29 (m, 1H), 2.17 – 2.08 (m, 1H), 2.03 – 1.91 (m, 5H), 1.89 – 1.83 (m, 2H), 1.79 – 1.71 (m, 1H), 1.67 – 1.61 (m, 1H), 1.59 – 1.52 (m, 1H), 1.39 – 1.28 (m, 2H), 0.95 – 0.89 (m, 6H). LC / MS (ESI) m / z 866.5 [M+H]+. lxviii. 4-(4-((4-(4-((5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'- YL)AMINO)PHENYL)PIPERIDIN-1-YL)METHYL)PIPERIDIN-1-YL)-2- (2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE (COMPOUND 43)

[0454] Compound 43 was synthesized from I-E. 1H NMR (600 MHz, Chloroform-d) δ 8.27(d, J = 5.3 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.56 (dd, J = 8.4, 7.1 Hz, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.39 – 7.30 (m, 4H), 7.26 – 7.15 (m, 4H), 6.98 – 6.70 (m, 2H), 4.96 (dd, J = 12.5, 5.4 Hz, 1H), 3.86 – 3.80 (m, 2H), 3.79 – 3.70 (m, 2H), 3.14 – 3.03 (m, 2H), 2.97 – 2.78 (m, 4H), 2.76 – 2.67 (m, 1H), 2.56 – 2.46 (m, 1H), 2.38 – 2.28 (m, 2H), 2.16 – 2.08 (m, 3H), 2.00 – 1.90 (m, 3H), 1.86 – 1.82 (m, 3H), 1.81 – 1.74 (m, 2H), 1.55 – 1.46 (m, 4H), 1.25 (s, 3H), 1.02 – 0.93 (m, 6H). LC / MS (ESI) m / z 863.3 [M+H]+. lxix. 5-(4-((4-(4-((5-(((S)-2-AMINO-2,4-DIMETHYLPENTYL)OXY)-6-(DIFLUOROMETHYL)-[2,4'-BIPYRIDIN]-2'- YL)AMINO)PHENYL)PIP...

Claims

1. CLAIMS What is claimed:

1. A compound having a structure represented by a formula:, wherein L is an E3 ligase binding ligand; wherein Q is selected from –N= and –CH=; wherein Z is a bifunctional linker; wherein R1is a structure selected from:wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein R3is selected from –CHF2, –CF3, and –CN, or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound has a structure represented by aformula:,wherein each of q, r, s, and t is independently selected from 0 and 1; wherein A1is selected from –O–, –NH–, –CF2–, –C≡C–, –CF2C≡C–, and – CF2C≡CCH2O–; wherein A2is a structure selected from: ,wherein X and Y are independently selected from –N= and –CH=; wherein A3is selected from –O–, –C(O)–, –C(O)(C1-C8 alkylene)–, – C(O)(CH2CH2O)n(C1-C4 alkylene)–, –(C1-C8 alkylene)–, –(C1-C8 alkylene)O–, and – CH2C≡C–; wherein n is selected from 1, 2, 3, and 4; wherein A4is a structure selected from:, , ,wherein A5is selected from –CH2– and –OCH2CH2–; wherein L is an E3 ligase binding ligand; wherein Q is selected from –wherein R1is a structure selected from:wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein R3is selected from –CHF2, –CF3, and –CN, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein each of q, r, s, and t is 0.

4. The compound of claim 2, wherein at least one of q, r, s, and t is 1.

5. The compound of claim 2, wherein each of q, r, and s is 1 and wherein t is 0.

6. The compound of claim 2, wherein q is 1.

7. The compound of claim 2, wherein r is 1.

8. The compound of claim 2, wherein s is 1.

9. The compound of any one of claims 2 to 8, wherein A1 is –NH–.

10. The compound of any one of claims 2 to 9, wherein A2 is a structure:.

11. The compound of any one of claims 2 to 9, wherein A2 is a structure:.

12. The compound of any one of claims 2 to 11, wherein A3 is selected from –, –C(O)–, –C(O)(C1-C8 alkylene)–, –C(O)(CH2CH2O)n(C1-C4 alkylene)–, and –(C1-C8 alkylene)–.

13. The compound of any one of claims 2 to 12, wherein A4 is a structure selected from:

14. The compound of any one of claims 2 to 12, wherein L is an E3 ligase binding ligandis selected from:,,,15. The compound of any one of claims 2 to 14, wherein Q is.

16. The compound of any one of claims 2 to 14, wherein Q is –CH=.

17. The compound of any one of claims 2 to 16, wherein R1 is a structure:.

18. The compound of any one of claims 2 to 17, wherein R2 is hydrogen.

19. The compound of any one of claims 2 to 17, wherein R2 is C1-C4 alkyl.

20. The compound of any one of claims 2 to 17, wherein R2 is methyl.

21. The compound of any one of claims 2 to 20, wherein R3 is selected from –CHF2 and –CF3. The compound of claim 2, wherein R3 is –CHF2.

23. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

24. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

25. The compound of claim 2, wherein the compound has a structure represented by aformula:,or a pharmaceutically acceptable salt thereof.

26. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

27. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

28. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

29. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

30. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

31. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

32. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

33. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

34. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

35. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

36. The compound of claim 2, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable salt thereof.

37. The compound of claim 2, wherein the compound is selected from:,,,,,,,, ,or a pharmaceutically acceptable salt thereof.

38. The compound of claim 2, wherein the compound is selected from:,,,,,, ,,,,,,, ,,, ,,or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising a therapeutically effective amount of thecompound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

40. A method of degrading a target protein in a cell, the method comprising contactingthe cell with an effective amount of the compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof.

41. The method of claim 40, wherein the target protein is AP2 associated kinase 1(AAK1).

42. The method of claim 40, wherein the cell is mammalian.

43. The method of claim 40, wherein the cell is human.

44. The method of claim 40, wherein the cell has been isolated from a mammal prior to thecontacting step.

45. The method of claim 40, wherein the contacting is ex vivo.

46. The method of claim 40, wherein the contacting is in vitro.

47. The method of claim 40, wherein contacting is via administration to a mammal.

48. The method of claim 47, wherein the mammal has been diagnosed with a need fordegrading the target protein prior to the administering step.

49. The method of claim 40, wherein the mammal has been diagnosed with a need fortreatment of a cancer related to activity of the target protein prior to the administering step.

50. A method of degrading a target protein in a subject, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof.

51. The method of claim 50, wherein the subject is a mammal.

52. The method of claim 50, wherein the subject is a human.

53. The method of claim 50, wherein the subject has been diagnosed with a need for degrading the target protein prior to the administering step.

54. The method of claim 50, further comprising identifying a subject in need of degradation of the target protein.

55. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the disorder is cancer, pain, a neurodegenerative disease, or a viral infection.

56. The method of claim 55, wherein the subject is a mammal.

57. The method of claim 55, wherein the subject is a human.

58. The method of claim 55, wherein the subject has been diagnosed with a need for treatment of the disorder prior to the administering step.

59. The method of claim 55, further comprising the step of identifying a subject in need of treatment of the disorder.

60. The method of claim 55, wherein the effective amount is a therapeutically effective amount.

61. The method of claim 55, wherein the effective amount is a prophylactically effective amount.

62. The method of claim 55, wherein the disorder is associated with activity of AP2 associated kinase 1 (AAK1).

63. The method of claim 55, wherein the disorder is cancer.

64. The method of claim 63, wherein the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

65. The method of claim 63, wherein the cancer is ovarian cancer.

66. The method of claim 55, wherein the disorder is pain.

67. The method of claim 55, wherein the disorder is a neurodegenerative disease.

68. The method of claim 67, wherein the neurodegenerative disease is selected from Alzheimer’s disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, and Lewy body disease.

69. The method of claim 55, wherein the disorder is a viral infection.

70. The method of claim 69, wherein the viral infection is selected from human immunodeficiency virus (HIV), human papillomavirus (HPV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), dengue (DENV), influenza, West Nile virus (WNV), and zika (ZIKV).

71. A kit comprising the compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent known to treat a disorder associated with activity of AP2 associated kinase 1 (AAK1);(b) instructions for administering the compound in connection with treating a disorder associated with activity of AP2 associated kinase 1 (AAK1); and (c) instructions for treating a disorder associated with activity of AP2 associated kinase 1 (AAK1)..

72. The kit of claim 71, wherein the disorder is selected from cancer, pain, a neurodegenerative disease, and a viral infection.

73. The kit of claim 71, wherein the agent is a chemotherapeutic agent.

74. The kit of claim 73, wherein the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, and an mTor inhibitor agent.

75. The kit of claim 74, wherein the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

76. The kit of claim 74, wherein the antimetabolite agent is selected from gemcitabine, 5- fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

77. The kit of claim 74, wherein the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

78. The kit of claim 74, wherein the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

79. The kit of claim 74, wherein the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

80. The kit of claim 71, wherein the agent is known to treat pain.

81. The kit of claim 80, wherein the agent is selected from a nonsteroidal anti- inflammatory drug (NSAID), an antimigraine agent, a COX-2 inhibitor, acetaminophen, ziconotide, a narcotic, and a salicylate.

82. The kit of claim 81, wherein the NSAID is selected from flurbiprofen, ketorolac, ketoprofen, tolmetin, aspirin, ibuprofen, naproxen, indomethacin, sulindac, piroxicam, mefenamic acid, meloxicam, diclofenac, celecoxib, etodolac, etoricoxib, lumiracoxib, and rofecoxib.

83. The kit of claim 81, wherein the antimigraine agent is selected from almotriptan, dihydroergotamine, eletriptan, ergotamine, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zomitriptan.

84. The kit of claim 81, wherein the COX-2 inhibitor is selected from celecoxib, rofecoxib, and valdecoxib.

85. The kit of claim 81, wherein the narcotic is selected from alfentanil, buprenorphine, butorphano, codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, propoxyphene, tramadol, and tapentadol.

86. The kit of claim 81, wherein the salicylate is selected form aspirin, diflunisal, magnesium salicylate, and salsalate.

87. The kit of claim 71, wherein the agent is known to treat a neurodegenerative disease.

88. The kit of claim 87, wherein the agent is selected from amantadine, apomorphine, baclofen, carbidopa, carbidopa / levodopa, dantrolene, donepiezil, entacapone, galantamine, levodopa, memantine, pramipexole, rasagiline, riluzole, rivastigmine, ropinirole, selegiline, tacrine, tetrabenazine, tizanidine, and tolcapone.

89. The kit of claim 71, wherein the agent is an antiviral agent.

90. The kit of claim 89, wherein the antiviral agent is selected from acemannan, acyclovir, acyclovir sodium, adamantanamine, adefovir, adenine arabinoside, alovudine, alvircept sudotox, amantadine hydrochloride, aranotin, arildone, atevirdine mesylate,avridine, cidofovir, cipamfylline, cytarabine hydrochloride, BMS 806, C31G, carrageenan, cellulose sulfate, cyclodextrins, dapivirine, delavirdine mesylate, desciclovir, dextrin 2- sulfate, didanosine, disoxaril, dolutegravir, edoxudine, enviradene, envirozime, etravirine, famciclovir, famotine hydrochloride, fiacitabine, fialuridine, fosarilate, foscarnet sodium, fosfonet sodium, FTC, ganciclovir, ganciclovir sodium, GSK 1265744, 9-2-hydroxy-ethoxy methylguanine, ibalizumab, idoxuridine, interferon, 5-iodo-2′-deoxyuridine, IQP-0528, kethoxal, lamivudine, lobucavir, maraviroc, memotine pirodavir, penciclovir, raltegravir, ribavirin, rimantadine hydrochloride, rilpivirine (TMC-278), saquinavir mesylate, SCH-C, SCH-D, somantadine hydrochloride, sorivudine, statolon, stavudine, T20, tilorone hydrochloride, TMC120, TMC125, trifluridine, trifluorothymidine, tenofovir, tenofovir alefenamide, tenofovir disoproxyl fumarate, prodrugs of tenofovir, UC-781, UK-427, UK- 857, valacyclovir, valacyclovir hydrochloride, vidarabine, vidarabine phosphate, vidarabine sodium phosphate, viroxime, zalcitabene, zidovudine, and zinviroxime.

91. The kit of claim 71, wherein the compound and the agent are co-packaged.

92. A compound selected from:,,,, ,,,or a pharmaceutically acceptable salt thereof.

93. A pharmaceutical composition comprising a therapeutically effective amount of thecompound of claim 92, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

94. A method of degrading a target protein in a cell, the method comprising contactingthe cell with an effective amount of the compound of claim 92, or a pharmaceutically acceptable salt thereof.

95. A method of degrading a target protein in a subject, the method comprisingadministering to the subject an effective amount of the compound of claim 92, or a pharmaceutically acceptable salt thereof.

96. A method of treating a disorder in a subject, the method comprising administering tothe subject an effective amount of the compound of claim 92, or a pharmaceutically acceptable salt thereof, wherein the disorder is cancer, pain, a neurodegenerative disease, or a viral infection.

97. A kit comprising the compound of claim 92, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent known to treat a disorder associated with activity of AP2 associated kinase 1 (AAK1); (b) instructions for administering the compound in connection with treating a cancer; and (c) instructions for treating a disorder associated with activity of AP2 associated kinase 1 (AAK1).

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