WO2025170773A1

WO2025170773A1 - Tam-family degraders and uses thereof

Info

Publication number: WO2025170773A1
Application number: PCT/US2025/012993
Authority: WO
Inventors: Xiaodong Wang; Kaikai LYU
Original assignee: University of North Carolina at Chapel Hill
Current assignee: University of North Carolina at Chapel Hill
Priority date: 2024-01-26
Filing date: 2025-01-24
Publication date: 2025-08-14
Anticipated expiration: 2026-07-26

Abstract

The subject matter described herein is directed to degraders having the formula: and pharmaceutically acceptable salts thereof, and compositions thereof, including pharmaceutical compositions, and methods of treating disorders associated with TAM receptor tyrosine kinases and/or TYRO3.

Description

TAM-FAMILY DEGRADERS AND USES THEREOF

BACKGROUND

[0001] The TAM-family (TYRO3, AXL, and MER) tyrosine kinases are expressed on macrophages, dendritic cells, monocyte-derived suppressor cells (MDSCs) and other innate immune cells. These receptors are activated by ligands complexed with phosphatidylserine (PtdSer) on the surface of apoptotic and virus-infected cells. In macrophages, ligand binding triggers apoptotic cell engulfment and activates expression of an anti-inflammatory cytokine profile and immune checkpoint pathway components, leading to immune suppression.

[0002] Cancer cells hijack this system to suppress anti-tumor immunity and thereby promote tumor growth and progression. Conversely, TAM kinase inhibitors can promote anti-tumor immunity and studies demonstrating the potential of TAM kinases as immuno-oncology targets have been increasingly reported in recent years. First-in-class MERTK or AXL-selective inhibitors have been developed and advanced to early-stage clinical trials, yet there remains a need for TYRO3- selective inhibitors. Furthermore, methods of targeting TAM kinases beyond kinase inhibition are needed as TAM kinases likely have kinase-independent functions. The subject matter described herein addresses this need.

[0003] Ubiquitin-Proteasome Pathway (UPP) is a pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation. Bifunctional compounds composed of a target protein- binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins. [0004] It would be beneficial to have more useful compounds that utilize the UPP. The present application relates to novel bifunctional compounds, which function to recruit TAM receptor kinases to E3 Ubiquitin Ligase for degradation, and methods of preparation and uses thereof.

BRIEF SUMMARY

[0005] Described are TAM degraders comprising: a residue of a compound of Formula A, I,

II, or III; a Linking Group (L), and a E3 ubiquitin binding group (UBG); having the structure:

— Linking Group —

[0006] In certain embodiments, the compound is of Formula I: wherein:

U is N or CH; X is N or C; Y is N or C, and A is N or CH, wherein two or three of U, X, Y and A is N, and at least one of U and X is N;

D is selected from the group consisting of a bond, (CH₂)_m, -O-, -CO-, -N(H)- and -S(O₂)-;

E is a residue of a moiety to which L is covalently attached, and is selected from the group consisting of:

-NR^E1R^E2, wherein R^E1 is hydrogen or C₁-C₆ alkyl, and R^E2 is substituted or unsubstituted

C₁-C₆ alkyl; and, X¹ is CH or N;

X² is CH₂, 0, S, or N-R⁶, wherein R⁶ is hydrogen, substituted or unsubstituted C₁-C₆ alkyl, or C₃-C₉ cycloalkyl;

Q is selected from the group consisting of:

K, if present, is 0 or CR⁷R⁸, wherein R⁷ and R⁸ are independently selected from C₁-C₆ alkylhydroxy, or R⁷ and R⁸ together with the carbon to which each is attached form a carbonyl or a 5-6 membered heterocycloalkyl (spiro); m is 0, 1, or 2; j is 0, 1, 2, or 3; p is 0 or 1; q is 0 or 1; t is 1 or 2;

R¹ is selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, nitro, C₁-C₆-haloalkyl, cyano, and N(R^4a)₂, wherein each R^4a is independently selected from the group consisting of hydrogen, and C₁-C₆-alkyl;

R² and R³ are each independently selected from the group consisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, nitro, C₁-C₆-haloalkyl, cyano, and N(R^4b)₂, wherein each R^4b is independently selected from the group consisting of hydrogen and C₁-C₆-alkyl; or, R¹ and R² or R² and R³ together with the carbon to which each is attached form a ring selected from the group consisting of substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted C3-C₈ aryl, and substituted or unsubstituted C₃-C₈ heteroaryl, wherein the heteroatom is 0, N, or S; and,

R⁵ is selected from the group consisting of hydroxy, cyano, halogen, amino, C₁-C₆ alkyl,

C₁-C₆ alkoxy, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, N-alkoxycarbonyl and C₁-C₆ alkylhydroxy; or a pharmaceutically acceptable salt thereof

[0007] In certain embodiments, the compound is of Formula II: wherein,

N* is the point of attachment to L;

K, if present, is 0 or CR⁷R⁸, wherein R⁷ and R⁸ are independently selected from C₁-C₆ alkylhydroxy, or R⁷ and R⁸ together with the carbon to which each is attached form a carbonyl or a 5-6 membered heterocycloalkyl (spiro); p is 0 or 1; q is 0 or 1; t is 1 or 2; and, R⁵ is selected from the group consisting of hydroxy, cyano, halogen, amino, C₁-C₆ alkyl,

[0008] In certain embodiments, the compound is of Formula III: wherein,

N* is the point of attachment to L;

K, if present, is 0 or CR⁷R⁸, wherein R⁷ and R⁸ are independently selected from C₁-C₆ alkylhydroxy, or R⁷ and R⁸ together with the carbon to which each is attached form a carbonyl or a 5-6 membered heterocycloalkyl (spiro); p is 0 or 1; q is 0 or 1; t is 1 or 2; and,

C₁-C₆ alkoxy, mono(C₁-C₆)alkylamino, di( C₁-C₆)alkylamino, N-alkoxycarbonyl and C₁-C₆ alkylhydroxy; or a pharmaceutically acceptable salt thereof

[0009] In certain embodiments, the UBG is a VHL E3 ligase. In certain embodiments, the UBG is a cereblon E3 ligase.

[0010] In certain embodiments, L is a bifunctional linker selected from the group consisting wherein La is an integer from 1 to 12;

, wherein Lv is 0, -N(H)-, a 4-7 member heterocyclyl (including bicyclic), a C₆ aryl, a 5-6 member heteroaryl, or -O-(4-7 member heterocyclyl (including bicyclic))-; Le is an integer from 1 to 12; and Lf is an integer selected from 0 to 12; , wherein L_zi, L_z2 and L_z3 are each independently selected from the group consisting of 0, carbonyl, -N(H)-, amide, a 4-7 member heterocyclyl (including bicyclic), a C₆ aryl, a 5-6 member heteroaryl (such as triazole), an alkylenyl bond, and an alkynyl bond; wherein Lb and Lc, in each instance is independently an integer selected from 0 to 12; Ld is an integer selected from 0 to 12; Le is an integer from 0 to 12; Lh is an integer from 0 to 12; Lo, Lh and Lw are each independently 0 or 1, wherein at least one of Lo, Lh and Lw is 1; , wherein Lg, Lh and Li, in each instance is independently an integer selected from 0 to 12; and, , wherein Lv is 0, -N(H)-, amide, a 4-7 member heterocyclyl (including bicyclic), a C₆ aryl, a 5-6 member heteroaryl (such as triazole) or an alkynyl bond; wherein Lb and Lc, in each instance is independently an integer selected from 0 to 12; Ld is an integer selected from 1 to 12; Le is an integer from 0 to 12; Lh is an integer from 0 to 12; Lo and Lw are each independently 0 or 1, wherein both Lo and Lw cannot be 0; where in every instance, one is a point of attachment to a residue of a compound of

Formula A, I, II or III, and the other is a point of attachment to UBG.

[0011] Also described are methods for the treatment of disorders associated with TAM receptor tyrosine kinases, the method comprising the step of administering to the subject an effective amount of a TAM degrader disclosed herein.

DETAILED DESCRIPTION

[0012] The present disclosure describes bifunctional compounds which function to recruit endogenous proteins to an E3 Ubiquitin Ligase for degradation, and methods of using the same. In particular, the present disclosure provides bifunctional degrader compounds that are modulators of targeted ubiquitination of a variety of polypeptides and other proteins, 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 targeted polypeptides from virtually any protein class or family. In addition, the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition.

[0013] Specifically, the present disclosure application relates to novel bifunctional compounds, which function to recruit TAM receptor kinases to E3 Ubiquitin Ligase for degradation, and methods of preparation and uses thereof. In particular, the present disclosure provides bifunctional compounds that are modulators of targeted ubiquitination of Tyro3, Axl, and/or MerTK, which are then degraded and/or otherwise inhibited by the bifunctional compounds as described herein. The present application further relates to bifunctional molecules, including bifunctional molecules that link a cereblon-, VHL-, IAP-, MDM2-, RNF114-, RNF4-, DCAF16-, DCAF15-, DCAF11-, KEAP1-, FEM1B-, or AhR-binding moiety to a ligand that binds Tyro3, Axl, and/or MerTK that are effective for the modulation of targeted ubiquitination. Such compounds have the general structure: — Linking Group —

[0014] The presently disclosed subject matter will now be described more fully hereinafter. However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented herein. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subj ect matter described herein covers all alternatives, modifications, and equivalents. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in this field. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

I. Definitions

[0015] “Alkyl” as used herein alone or as part of another group, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3 -methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. The term “alkyl” is intended to include both substituted and unsubstituted alkyl unless otherwise indicated and these groups may be substituted with groups selected from halo (e.g., haloalkyl), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl (including spiroalkyl, e.g., C2, C3, or C4 spiroalkyl), cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy (thereby creating a polyalkoxy such as polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, amino, carboxy, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, ester, amide, sulfonamide, nitro or cyano.

[0016] “Cycloalkyl” as used herein alone or as part of another group, refers to a saturated or partially unsaturated cyclic hydrocarbon group containing from 3, 4 or 5 to 6, 7 or 8 carbons (which carbons may be replaced in a heterocyclic group as discussed below) and includes spirocyclics. Representative examples of cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. These rings may be optionally substituted with additional substituents as described herein such as halo or loweralkyl. The term “cycloalkyl” is generic and intended to include heterocyclic groups as discussed below unless specified otherwise.

[0017] “Heterocyclic group” or “heterocycloalkyl” as used herein alone or as part of another group, refers to an aliphatic (e.g., fully or partially saturated heterocycloalkyl) or aromatic (e.g., heteroaryl) monocyclic- or a bicyclic-ring system. Monocyclic ring systems are exemplified by any 5- or 6-membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. The 5 membered ring has from 0-2 double bonds and the 6 membered ring has from 0-3 double bonds. A heterocycloalkyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=0) or N-oxide (N-O’) moieties. Representative examples of monocyclic ring systems that are heterocycloalkyls include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3- dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadi azole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like. These rings may be optionally substituted with groups selected from halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, amino, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, ester, amide, sulfonamide, nitro or cyano.

[0018] “Aryl” as used herein alone or as part of another group, refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like. The term “aryl” is intended to include both substituted and unsubstituted aryl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl above.

[0019] “Arylalkyl” as used herein alone or as part of another group, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3- phenylpropyl, 2-naphth-2-ylethyl, and the like.

[0020] “Heteroaryl” as used herein is as described in connection with heterocycloalkyl above. [0021] “Alkoxy” as used herein alone or as part of another group, refers to an alkyl group, as defined herein (and thus including substituted versions such as polyalkoxy), appended to the parent molecular moiety through an oxy group, -O- Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

[0022] “Halo” or “halogen” as used herein refers to any suitable halogen, including F, Cl, Br, and I.

[0023] “Cyano” as used herein refers to a -CN group. [0024] “Hydroxyl” as used herein refers to an -OH group.

[0025] “Amino” as used herein means the radical -NH2.

[0026] “Alkylamino” as used herein alone or as part of another group means the radical -NHR, where R is an alkyl group.

[0027] “Disubstituted-amino” as used herein alone or as part of another group means the radical -NR^aR^b, where R^a and R^b are independently selected from the group alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.

[0028] “Ester” as used herein alone or as part of another group refers to a -C(O)OR radical, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

[0029] “Amide” as used herein alone or as part of another group refers to a -C(O)NR^aR^b radical, where R^aand R^b are any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

[0030] As used herein, the notation “+/+” refers to genetically unmodified or wildtype alleles. As used herein, the notation refers to genetically silenced, deleted or “knocked out” alleles. The notation refers to a complete knock-out of that specific allele.

[0031] As used herein, the term “residue” or “residue of’ a chemical moiety refers to a chemical moiety that is bound to a molecule, whereby through the binding, at least one covalent bond has replaced at least one atom of the original chemical moiety, resulting in a residue of the chemical moiety in the molecule.

[0032] The compounds of the present disclosure may have asymmetric centers. Compounds of the present disclosure containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, all mixtures of chiral or diastereomeric forms and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. It will also be well recognized by a person skilled in the art that when a bond is drawn from an optically active center, that a “flat” bond ( - ) represents and encompasses both the “wedge” bond and the “dashed” bond

( nil) each representing the (R) or (S) stereoisomer. It will also be understood by a person of ordinary skill in the art that when a compound is denoted as (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity i.e., the (S) stereoisomer in less than about 5%, preferably 2% by wt. and then it is denoted as a mixture of R and S isomers, the amounts of R or S isomer in the mixture is greater than about 5%, preferably 2% w/w.

[0033] The compounds of Formula A, I, II or III as described herein can exist as cis and trans isomers, for example, when the compound contains a cyclohexyl ring, such as

This flat structure depicts all ring conformations. Specific cis or trans conformations are depicted with bold and dashed bonds:

[0034] The term “Linker,” “Linking Unit,” and the like are used herein to mean a chemical moiety comprising a chain of atoms that covalently attaches a compound of Formula A, I, II or III to a U group. In various embodiments, a linker is a divalent radical, specified as “L.”

[0035] As used herein, the term “physiological conditions” refers to the range of conditions of temperature, pH, and tonicity (or osmolality) normally encountered within tissues in the body of a living human.

[0036] The term “in vitro” refers to artificial environments and to processes or reactions that occur within an artificial environment (e.g., a test tube).

[0037] The term “in vivo” refers to natural environments (e.g., a cell or organism or body) and to processes or reactions that occur within a natural environment.

[0038] “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “heterocyclyl group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with alkyl.

[0039] A “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees and apes, and, in particular, humans. In some embodiments, the subject can be human. In some embodiments, the subject can be a human child and/or a human infant, for example, a child or infant with a fever. In other embodiments, the subject can be a human adult.

[0040] “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[0041] A “therapeutically effective amount” means the amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof that, elicits the biological or medicinal response indicated. For example, when administered to a subject for treating a disease, the therapeutically effective amount of a compound is sufficient to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The “therapeutically effective amount” of the compounds disclosed herein will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated. Designation of a range of values includes all integers within or defining the range, and all subranges defined by integers within the range. [0042] Unless otherwise apparent from the context, the term “about” encompasses values within a standard margin of error of measurement (e.g., SEM) of a stated value or variations ± 0.5%, 1%, 5%, or 10% from a specified value.

[0043] Compositions or methods “comprising” or “including” one or more recited elements may include other elements not specifically recited. For example, a composition that “comprises” or “includes” a protein may contain the protein alone or in combination with other ingredients.

[0044] The singular forms of the articles “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “an antigen” or “at least one antigen” can include a plurality of antigens, including mixtures thereof.

[0045] Statistically significant means p <0.05.

II. Degraders

[0046] The degraders described herein comprise a residue of a compound of Formula A, I, II or III, a ubiquitin binding group (UBG) and a linker (L) that is covalently linked to the compound and to UBG. a. Compounds of Formulae A, I, II and III

[0047] In certain embodiments, the subject matter described herein is directed to compounds of Formula A: wherein:

D is selected from the group consisting of a bond, (CH₂)_m, (CD₂)_m, (CHD)_m, (CF₂)_m, (CHF)_m, -O-, -CO-, -N(H)- and -S(O₂)-; E is selected from the group consisting of:

-NR^E1R^E2, wherein R^E1 is hydrogen, deuterium or C₁-C₆ alkyl, and R^E2 is substituted or unsubstituted C₁-C₆ alkyl; and, , wherein:

X¹ isCH or N;

X³ and X⁴ are independently selected from hydrogen and halogen;

X⁵ is CH orN;

Q is selected from the group consisting of:

K, if present, is 0 or CR⁷R⁸, wherein R⁷ and R⁸ are independently selected from C₁-C₆ alkylhydroxy, or R⁷ and R⁸ together with the carbon to which each is attached form a carbonyl or a 5-6 membered heterocycloalkyl; m is 0, 1, or 2; j is 0, 1, 2, or 3; p is 0 or 1; t is 1 or 2; q is 0 or 1; R¹ is selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, nitro, C₁-C₆-haloalkyl, cyano, and N(R^4a)₂, wherein each R^4a is independently selected from the group consisting of hydrogen, and C₁-C₆-alkyl;

R² and R³ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, nitro, C₁-C₆-haloalkyl, cyano, and N(R^4b)₂, wherein each R^4b is independently selected from the group consisting of hydrogen and C₁-C₆-alkyl; or,

R¹ and R² or R² and R³ together with the carbon to which each is attached form a ring selected from the group consisting of substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted C₃-C₈ aryl, and substituted or unsubstituted C₃-C₈ heteroaryl, wherein the heteroatom is 0, N, or S; and,

C₁-C₆ alkoxy, mono(C₁-C₆)alkylamino di(C₁-C₆)alkylamino, N-alkoxycarbonyl, and C₁-C₆ alkylhydroxy; or a pharmaceutically acceptable salt thereof; wherein the circle inside a ring depicts single or double bonds, aromatic and non-aromatic, as appropriate for the value of U, X, Y and A.

[0048] In certain embodiments, the subject matter described herein is directed to compounds of Formula A-l:

A-l

[0049] In certain embodiments, the subject matter described herein is directed to compounds of Formula A-2:

[0050] In certain embodiments, the subject matter described herein is directed to compounds of Formula A-3:

[0051] In certain embodiments, the subject matter described herein is directed to compounds of Formula A-4:

[0052] In certain embodiments, the subject matter described herein is directed to compounds of Formula A-5:

[0053] In certain embodiments, the subject matter described herein is directed to compounds of Formula A-6:

A-6

[0054] In certain embodiments, the subject matter described herein is directed to compounds of Formula A-7:

A-7

[0055] In certain embodiments, the subject matter described herein is directed to compounds of Formula I:

wherein:

D is selected from the group consisting of a bond, (CH₂)_m, (CD2)_m, (CHD)_m, (CF₂)_m, (CHF)_m, -O-, -CO-, -N(H)- and -S(O₂)-;

E is selected from the group consisting of:

-NR^E1R^E2, wherein R^E1 is hydrogen or C₁-C₆ alkyl, and R^E2 is substituted or unsubstituted C₁-C₆ alkyl; and,

XUs CH or N;

Q is selected from the group consisting of: wherein, G is S, 0 or N; m is 0, 1, or 2; j is 0, 1, 2, or 3; p is 0 or 1; q is 0 or 1;

R¹ is selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, nitro, C₁-C₆-haloalkyl, cyano, and N(R^4a)2, wherein each R^4a is independently selected from the group consisting of hydrogen, and C₁-C₆-alkyl;

R² and R³ are each independently selected from the group consisting of hydrogen, halogen,

C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, nitro, C₁-C₆-haloalkyl, cyano, and N(R^4b)2, wherein each R^4b is independently selected from the group consisting of hydrogen and C₁-C₆-alkyl; or,

C₁-C₆ alkoxy, mono(C₁-C₆)alkylamino and di(C₁-C₆)alkylamino; or R⁵ is selected from the group consisting of hydroxy, cyano, halogen, amino, C₁-C₆ alkyl, C₁-C₆ alkoxy, mono(C₁-C₆)alkylamino and di(C₁-C₆)alkylamino, N-alkoxycarbonyl, C₁-C₆ alkylhydroxy; or a pharmaceutically acceptable salt thereof; wherein the circle inside a ring depicts single or double bonds, aromatic and non-aromatic, as appropriate for the value of U, X, Y and A.

[0056] In certain embodiments, the subject matter described herein is directed to compounds of Formula I, wherein:

U is N; X is C; Y is N; and A is CH, the compound having a structure of Formula 1-1:

U is N; X is C; Y is N; and A is N, the compound having a structure of Formula 1-2.

U is N; X is N; Y is C; and A is N, the compound having a structure of Formula 1-3 : U is N; X is N; Y is C; and A is CH, the compound having a structure of Formula 1-4:

U is CH; X is N; Y is C; and A is N, the compound having a structure of Formula 1-5: or a pharmaceutically acceptable salt thereof.

[0057] In certain embodiments, the compounds are of Formula 1-1 or 1-2, having a structure of

Formula la:

or a pharmaceutically acceptable salt thereof.

[0058] In certain embodiments, the compounds are of Formula 1-3, 1-4 or 1-5, having a structure of Formula lb: or a pharmaceutically acceptable salt thereof.

[0059] In the above embodiments, compounds include those wherein E is

[0060] In the above embodiments, compounds include those wherein Q is selected from the group consisting of:

[0061] In the above embodiments, compounds include those wherein Q is

[0062] In the above embodiments, compounds include those wherein

R¹ is selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, nitro, C₁-C₆-haloalkyl, cyano, and N(R^4a)2, wherein each R^4a is independently selected from the group consisting of hydrogen, and C₁-C₆-alkyl; and,

C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, nitro, C₁-C₆-haloalkyl, cyano, and N(R^4b)2, wherein each R^4b is independently selected from the group consisting of hydrogen and C₁-C₆-alkyl.

[0063] In the above embodiments, compounds include those of Formula la-1 :

[0064] In the above embodiments, compounds include those of Formula Ib-1 or Ib-1 ’ :

[0065] In the above embodiments, compounds include those wherein q is 0.

[0066] In the above embodiments, compounds include those wherein p is 1.

[0067] In the above embodiments, compounds include those wherein D is (CH₂)_m, -O- or -N(H)-.

[0068] In the above embodiments, compounds include those wherein R⁵ is selected from the group consisting of hydroxy, halogen, amino, C₁-C₆ alkyl, and C₁-C₆ alkoxy. In the above embodiments, compounds include those wherein R⁵ is selected from the group consisting of hydroxy, amino, methoxy, ethoxy, methyl and ethyl. In the above embodiments, compounds include those wherein R⁵ is hydroxy, methoxy, or ethoxy. In the above embodiments, compounds include those wherein R⁵ is hydroxy.

[0069] In the above embodiments, compounds include those of Formula la-2:

[0070] In the above embodiments, compounds include those having a structure of Formula Ib-2 or Ib-2’:

[0071] In the above embodiments, compounds include those wherein X¹ is N.

[0072] In the above embodiments, compounds include those wherein, X² is S or N-R⁶, wherein R⁶ is hydrogen or a substituted or unsubstituted C₁-C₆ alkyl, or a C₃-C₉ cycloalkyl.

[0073] In the above embodiments, compounds include those wherein X¹ is N, and X² is S or N-R⁶, wherein R⁶ is hydrogen or a substituted or unsubstituted C₁-C₆ alkyl.

[0074] In the above embodiments, compounds include those wherein j is 1 or 2.

[0075] In the above embodiments, compounds include those wherein D is -N(H)- or O.

[0076] In the above embodiments, compounds include those wherein E is wherein X¹ is CH.

[0077] In the above embodiments, compounds include those wherein D is (CH₂)_m.

[0078] In the above embodiments, compounds include those wherein E is wherein X¹ is N.

[0079] In the above embodiments, compounds include those wherein A is N.

[0080] In the above embodiments, compounds include those of Formula la-3, Ib-3 or Ib-3 ’ :

[0081] In the above embodiments, compounds include those wherein A is CH.

[0082] In the above embodiments, compounds include those of Formula la-4 or Ib-4 :

[0083] In the above embodiments, compounds include those having a structure of Formula la-5:

[0084] In the above embodiments, compounds include those having a structure of Formula la-6:

[0085] In the above embodiments, compounds include those wherein D is CH₂; and E is -NR^E1R^E2, wherein R^E1 is hydrogen, and R^E2 is C₁-C₆ alkyl substituted once with mono(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, or a 5-7 member heterocyclyl.

[0086] In the above embodiments, compounds include those wherein -D-E is selected from the group consisting of

[0087] In the above embodiments, compounds include those of Formula Ic:

[0088] In the above embodiments, compounds include those of Formula Ic-1 :

[0089] In the above embodiments, compounds include those of Formula Ic-2:

[0090] In the above embodiments, compounds include those of Formula Ic-3:

[0091] In the above embodiments, compounds include those wherein X² is S.

[0092] In the above embodiments, compounds include those wherein X² is N-R⁶, wherein R⁶ is

C₁-C₆ alkyl.

[0093] In the above embodiments, compounds include those wherein R⁶ is methyl.

[0094] In the above embodiments, compounds include those wherein

R¹ is selected from the group consisting of halogen, C₁-C₆ haloalkyl and C₁-C₆ alkoxy; and,

R³ is selected from the group consisting of halogen, C₁-C₆ haloalkyl and C₁-C₆ alkoxy. [0095] In the above embodiments, compounds include those wherein

R¹ is selected from the group consisting of fluoro, -CF₃ and methoxy; and, [0096] R³ is selected from the group consisting of chloro, -CF₃ and methoxy. [0097] In the above embodiments, compounds include those where X³ is selected from the group consisting of H, F, Cl, and Br. In certain embodiments, X³ is F.

[0098] In the above embodiments, compounds include those where X⁴ is selected from the group consisting of H, F, Cl, and Br. In certain embodiments, X⁴ is F.

[0099] In the above embodiments, compounds include those where X⁵ is CH. [0100] In the above embodiments, compounds include those where X⁵ is N.

[0101] In the above embodiments, compounds include those wherein Q is

[0102] In the above embodiments, compounds include those wherein Q is

[0103] In the above embodiments, compounds include those wherein

[0104] In the above embodiments, compounds include those of Formula I, wherein R⁵ is

[0105] In certain embodiments, a C₁-C₆ alkylhydroxy is -CH₂OH.

[0106] In the above embodiments, compounds include those of Formula A-l, wherein R⁷ and R⁸ are -CH₂OH.

[0107] In certain embodiments, the subject matter described herein is directed to degraders that comprise a compound of Formula II:

wherein,

N* is the point of attachment to L;

C₁-C₆ alkoxy, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, N-alkoxycarbonyl and C₁-C₆ alkylhydroxy; or a pharmaceutically acceptable salt thereof, wherein the circle inside a ring depicts single or double bonds, aromatic and non-aromatic, as appropriate for the value of U, X, Y and A. [0108] In certain embodiments, the subject matter described herein is directed to degraders that comprise a compound of Formula II-A: wherein, M is as described above.

[0109] In certain embodiments of Formula II-A, M is wherein, p is 0 or 1; q is 0 or 1; and,

[0110] In certain embodiments of Formula II-A, compounds are of the structure Formula II-B or II-C: wherein, R⁵ is as described above.

[0111] In all embodiments, a particularly useful value of R⁵ is hydroxyl.

[0112] In certain embodiments, the subject matter described herein is directed to degraders that comprise a compound of Formula III: wherein,

N* is the point of attachment to L;

C₁-C₆ alkoxy, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, N-alkoxycarbonyl and C₁-C₆ alkylhydroxy; or a pharmaceutically acceptable salt thereof, wherein the circle inside a ring depicts single or double bonds, aromatic and non-aromatic, as appropriate for the value of U, X, Y and A. [0113] In certain embodiments, compounds of Formula III include compounds of Formula III’ : wherein, U, X, Y, A and M are as described above.

[0114] In certain embodiments of Formulae III and III’, M is wherein, p is 0 or 1; q is 0 or 1; and,

[0115] In certain embodiments of Formulae III and III’, compounds are of the structure Formula

III-B or ni-C: III-B ni-c

[0116] In certain embodiments of Formulae III and III’, R¹ is C₁-C₆ alkoxy. In certain embodiments of Formulae III and III’, R¹ is methoxy.

[0117] In all embodiments, a particularly useful value of R⁵ is hydroxyl. b. Linkers

[0118] As used herein, the linking group “L” can be any linking group that covalently links a residue of a compound of Formula A, I, II or III, or any sub-formulae described herein to the E3 ubiquitin binding group, UBG. Non-limiting examples of linking groups are disclosed in US2015/0291562, US2014/0356322, US2016/0045607, US2016/0058872; WO2014/063061; WO2013/106643; US7, 7208, 157; W02020/010210; W02021/011871, each of which is incorporated by reference in its entirety.

[0119] In certain embodiments, L is a bifunctional linker selected from the group consisting of , wherein La is an integer from 1 to 12; , wherein Lv is 0, -N(H)-, amide, a 4-7 member heterocyclyl (including bicyclic), a C₆ aryl, a 5-6 member heteroaryl, or -O-(4-7 member heterocyclyl (including bicyclic))-; Le is an integer from 1 to 12; and Lf is an integer selected from 0 to 12; , wherein Lz1, Lz2 and Lz3 are each independently selected from the group consisting of 0, carbonyl, -N(H)-, amide, a 4-7 member heterocyclyl (including bicyclic), a C₆ aryl, a 5-6 member heteroaryl (such as triazole), an alkylenyl bond, and an alkynyl bond; wherein Lb and Lc, in each instance is independently an integer selected from 0 to 12; Ld is an integer selected from 0 to 12; Le is an integer from 0 to 12; Lh is an integer from 0 to 12; Lo, Lh and Lw are each independently 0 or 1, wherein at least one of Lo, Lh and Lw is 1; , wherein Lg, Lh and Li, in each instance is independently an integer selected from 0 to 12; , wherein Lv is 0, -N(H)-, amide, a

4-7 member heterocyclyl (including bicyclic), a C6 aryl, a 5-6 member heteroaryl (such as triazole) or an alkynyl bond; wherein Lb and Lc, in each instance is independently an integer selected from 0 to 12; Ld is an integer selected from 1 to 12; Le is an integer from 0 to 12; Lh is an integer from 0 to 12; Lo and Lw are each independently 0 or 1, wherein both Lo and Lw cannot be 0; where in every instance, one a point of attachment to a residue of a compound of

Formula A, I, II or III, and the other a point of attachment to UBG. c. E3 Ubiquitin Binding Groups (UBG)

[0120] There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo. In the degraders described herein, UBG can be the residue of any E3 ubiquitin binding group.

[0121] One example of a E3 ubiquitin ligase is cereblon is a protein that in humans is encoded by the CRBN gene. CRBN orthologs are highly conserved from plants to humans, which underscores its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, cereblon ubquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates a number of developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryos. In the absence of cereblon, DDB1 forms a complex with DDB2 that functions as a DNA damage-binding protein.

[0122] Another E3 ligase with therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor, the substrate recognition subunit of the E3 ligase complex VCB, which also consists of elongins B and C, Cul2 and Rbxl. The primary substrate of VHL is Hypoxia Inducible Factor 1α (HIF-1α), a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the red blood cell inducing cytokine erythropoietin in response to low oxygen levels. The first small molecule ligands of Von Hippel Lindau (VHL) to the substrate recognition subunit of the E3 ligase were generated, and crystal structures were obtained confirming that the compound mimics the binding mode of the transcription factor HIF-la, the major substrate of VHL.

[0123] Other reported E3 ligases include IAP, MDM2, RNF114, RNF4, DCAF16, DCAF15, DCAF11, KEAP1, FEM1B, or AhR.

[0124] Exemplary E3 ubiquitin binding groups are disclosed in WO2013/106643;

WO2021/011871; US2015/0291562; W02017/030814; US2017/003004 and US2017/0008904, each of which is incorporated by reference in its entirety. [0125] In certain embodiments, UBG is an E3 ubiquitin binding group selected from the group consisting of:

[0126] The subject, mater described herein includes, but is not limited to, the degraders shown in Table 1.

IV. Pharmaceutical compositions

[0127] In certain embodiments, described herein are pharmaceutical compositions comprising at least one degrader as described herein, and a pharmaceutically acceptable excipient or carrier.

[0128] A “pharmaceutically acceptable excipient” refers to a vehicle for containing a functionalized cell or an acellular extracellular matrix that can be introduced into a subject without significant adverse effects and without having deleterious effects on the functionalized cell or acellular extracellular matrix. That is, “pharmaceutically acceptable” in the context of a formulation refers to any formulation which is safe and provides the appropriate delivery for the desired route of administration of an effective amount of at least one functionalized cell or acellular extracellular matrix for use in the methods disclosed herein. Pharmaceutically acceptable carriers or vehicles or excipients are well known. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington ’s Pharmaceutical Sciences, 18th ed., 1990, herein incorporated by reference in its entirety for all purposes. Such carriers can be suitable for any route of administration (e.g., parenteral, enteral (e.g., oral), or topical application). Such pharmaceutical compositions can be buffered, for example, wherein the pH is maintained at a particular desired value, ranging from pH 4.0 to pH 9.0, in accordance with the stability of the functionalized cell or acellular extracellular matrix and route of administration.

[0129] Suitable pharmaceutically acceptable carriers include, for example, sterile water, salt solutions such as saline, glucose, buffered solutions such as phosphate buffered solutions or bicarbonate buffered solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates (e.g., lactose, amylose or starch), magnesium stearate, talc, silicic acid, viscous paraffin, white paraffin, glycerol, alginates, hyaluronic acid, collagen, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, and the like. Pharmaceutical compositions or vaccines may also include auxiliary agents including, for example, diluents, stabilizers (e.g., sugars and amino acids), preservatives, wetting agents, emulsifiers, pH buffering agents, viscosity enhancing additives, lubricants, salts for influencing osmotic pressure, buffers, vitamins, coloring, flavoring, aromatic substances, and the like which do not deleteriously react with a functionalized cell or an acellular extracellular matrix.

[0130] For liquid formulations, for example, pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, emulsions, or oils. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous carriers include, for example, water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Examples of oils include those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil. Solid carriers/diluents include, for example, a gum, a starch (e.g., com starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, or dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.

[0131] Optionally, sustained or directed release pharmaceutical compositions or vaccines can be formulated. This can be accomplished, for example, through use of liposomes or compositions wherein the active compound is protected with differentially degradable coatings (e.g., by microencapsulation, multiple coatings, and so forth). Such compositions may be formulated for immediate or slow release. It is also possible to freeze-dry the compositions and use the lyophilisates obtained (e.g., for the preparation of products for injection).

V. Therapeutic Methods

[0132] In certain embodiments, the subject matter described herein is directed to methods of treating disorders associated with TAM receptor tyrosine kinases, the method comprising the step of administering to a subject an effective amount of at least one degrader or pharmaceutical composition comprising a degrader.

[0133] In certain embodiments, the method comprises treatment of a disorder associated with TYRO3 or Mer tyrosine kinases.

[0134] In certain embodiments, the method comprises treatment of a disorder associated with TYRO3 and Mer tyrosine kinases.

[0135] In certain embodiments, the method comprises treatment of a disorder associated with TYRO3 tyrosine kinases.

[0136] In certain embodiments described herein, the disorder is a cancer, an infection, a fibrosis, a thrombotic disorder, a clotting disorder, or a disorder associated with an immunosuppressed microenvironment surrounding diseased tissue.

[0137] In certain embodiments, the disorder is cancer.

[0138] In certain embodiments, the cancer is selected from the group consisting of breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, bladder cancer, hematologic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma), and myeloid leukemia. [0139] In certain embodiments, the cancer is TYRO3 and/or MerTK +/+.

[0140] In certain embodiments, the cancer is TYRO3 and/or MerTK -/-.

[0141] In embodiments described herein, the disorder is a thrombotic disorder or a clotting disorder.

[0142] In certain embodiments, the thrombotic disorder or clotting disorder involves ischemic heart disease, stroke, or acute myocardial infarction.

[0143] In certain embodiments described herein, the disorder is an infection. In certain aspects of these embodiments, the infection is viral. In certain aspects of these embodiments, the infection is bacterial.

[0144] In certain embodiments described herein, the disorder is fibrosis.

[0145] In certain embodiments, the method of treatment further comprises administering an additional active agent, such as an active agent useful in the treatment of cancer. The additional compounds may optionally be administered concurrently. As used herein, the word “concurrently” means sufficiently close in time to produce a combined effect (that is, concurrently may be simultaneously, or it may be two or more events occurring within a short time period before or after each other).

[0146] Degraders may optionally be administered in conjunction with other compounds useful in the treatment of blood clot formation in a subject in need thereof (e.g., a subject afflicted with coronary artery disease, peripheral vascular disease, or cerebrovascular disease, or prior to any medical or surgical procedure in which diminished coagulation potential is desirable, a non- limiting example of which is pulmonary vein ablation).

[0147] The present subj ect matter is primarily concerned with the treatment of human subj ects, but the invention may also be carried out on animal subjects, particularly mammalian subjects such as mice, rats, dogs, cats, livestock and horses for veterinary purposes, and for drug screening and drug development purposes. Subjects may be of any age, including infant, juvenile, adolescent, adult, and geriatric subjects.

[0148] As noted above, the subject matter provides pharmaceutical formulations comprising the compounds of Formula I (including the pharmaceutically acceptable salts thereof), in pharmaceutically acceptable carriers for oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, or intravenous, and transdermal administration. [0149] The therapeutically effective dosage of any specific compound can vary somewhat from compound to compound, and patient to patient, and will depend upon the condition of the patient and the route of delivery. As a general proposition, a dosage from about 0.1 to about 50 mg/kg will have therapeutic efficacy, with all weights being calculated based upon the weight of the active compound, including the cases where a salt is employed. Toxicity concerns at the higher level may restrict intravenous dosages to a lower level such as up to about 10 mg/kg, with all weights being calculated based upon the weight of the active base, including the cases where a salt is employed. A dosage from about 10 mg/kg to about 50 mg/kg may be employed for oral administration. In some embodiments, a dosage from about 0.5 mg/kg to 5 mg/kg may be employed for intramuscular injection. In some embodiments, dosages are 1 μmol/kg to 50 μmol/kg, and more preferably 22 μmol/kg and 33 μmol/kg of the compound for intravenous or oral administration. The duration of the treatment can be once per day for a period of two to three weeks or until the condition is essentially controlled.

[0150] In certain embodiments, the subject matter described herein is directed to methods of inhibiting TAM receptor kinases, in at least one cell, the method comprising the step of contacting the at least once cell with an effective amount of at least one degrader. In certain aspects of these embodiments, the method comprises inhibiting TYRO3 or Mer tyrosine kinases. In certain aspects of these embodiments, the method comprises inhibiting TYRO3 and Mer tyrosine kinases. In certain aspects of these embodiments, the method comprises inhibiting TYRO3 tyrosine kinase alone.

[0151] In embodiments described herein, the cell has been isolated from a mammal prior to the contacting step.

[0152] In embodiments described herein, the mammal has been diagnosed with a need for treatment of a disorder related to the TAM receptor tyrosine kinases, prior to the administering step.

[0153] In certain embodiments, the mammal has been diagnosed with a need for treatment of a disorder related to TYRO3 or Mer tyrosine kinases, prior to the administering step.

[0154] In certain embodiments, the mammal has been diagnosed with a need for treatment of a disorder related to TYRO3 and Mer tyrosine kinases, prior to the administering step. [0155] In certain embodiments, the mammal has been diagnosed with a need for treatment of a disorder related to TYRO3 tyrosine kinase, prior to the administering step.

[0156] The disclosed subject matter is further described in the following non-limiting Examples. It should be understood that these Examples, while indicating preferred embodiments of the invention, are given by way of illustration only.

EXAMPLES

Materials and Methods

[0157] All solvents were purchased from Sigma- Aldrich (anhydrous grade), VWR International, or Fisher Scientific. All non-aqueous reactions were performed in flame-dried or oven dried round-bottomed flasks under an atmosphere of nitrogen or argon. Reaction temperatures were controlled using a thermocouple thermometer and analog hotplate stirrer. Reactions were conducted at room temperature (RT; approximately 23 °C) unless otherwise noted. Analytical thin-layer chromatography (TLC) was performed on E. Merck silica gel 60 F254 plates and visualized using UV, ceric ammonium molybdate, potassium permanganate, and anisaldehyde stains. Yields were reported as isolated, spectroscopically pure compounds.

[0158] 'H NMR spectra were recorded on Varian 400 MHz or 850 MHz spectrometers and are reported relative to deuterated solvent signals. Data for 'H NMR spectra are reported as follows: chemical shift (8 ppm), multiplicity (s= singlet, d = doublet, t = triple, dd = double of doublets, dt = doublet of triplets, q = quartet, m = multiplet, br = broad, app = apparent), coupling constants (Hz), and integration. LC/MS was conducted and recorded on an Agilent Technologies 6110 Quadrupole instrument.

Example 1 — Syntheses of Intermediates

Intermediate B: trans-4-( 2-(( 3-methoxyphenyl)amino)-5-(piperidin-4-yl)- 7H-pyrrolo[ 2,3- d]pyrimidin-7-yl)cyclohexan-l-ol

[0159] To a solution of yl)cyclohexan-l-ol (5.0 g, 15,1 mmol) and terLbutyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-3,6-dihydropyridine-l(2//)-carboxylate (5.14 g, 16.6 mmol) in EtOH (150 mL) and water (50 mL) was added (3.21 g, 30.2 mmol). The mixture was degassed and charged by nitrogen for three cycles. Then Pd2(dba)3 (69.2 mg, 75.6 μmoL) was added. The reaction mixture was degassed, heated under nitrogen atmosphere at 60 °C for 24 h, and then filtered through a short pad of celite while hot. The dark brown filtrate was concentrated under reduced pressure to remove ethanol. A dark grey solid was precipitated to afford the first crop of product. The filtrate was then quenched brine (50 mL). The aqueous phase was separated and extracted with CH₂CI2 (20 mL, 3x). The combined organic phase was concentrated under reduced pressure and the residue was purified by an ISCO silica gel column to afford the second crop of product. In total, terLbutyl 4-(2-chloro-7-(trans -4-hydroxycyclohexyl)-7H-pyrrolo[2,3- -3,6-dihydropyridine-l(2//)-carboxylate (6.09 g, 14.1 mmol, 93%) was obtained as an off-white solid. ¹HNMR (400 MHz, CDCI3) 5 8.96 (s, 1H), 7.17 (s, 1H), 6.11 (s, 1H), 4.71 (ddd, J= 12.1, 8.1, 3.9 Hz, 1H), 4.13 (d, J= 3.0 Hz, 2H), 3.80-3.72 (m, 1H), 3.66 (t, J = 5.7 Hz, 2H), 2.50 (s, 2H), 2.20-2.04 (m, 4H), 1.89-1.74 (m, 3H), 1.60 (dt, J= 13.0, 10.0 Hz, 2H), 1.49 (s, 9H); MS (ESI) for [M+H]⁺ calcd. m/z 433.20, found m/z 433.20; LC-MS: 95% purity. [0160] To a solution of tert-butyl 4-(2-chloro-7-(trans -4-hydroxycyclohexyl)- pyrrolo[2,3-J]pyrimidin-5-yl)-3,6-dihydropyridine-l(2/7)-carboxylate (1.50 g, 3.5 mmol) and Xantphos (80.2 mg, 0.10 mmol) in 1,4-dioxane (35 mL) was added 3 -methoxy aniline (428 μL, 3.8 mmol) and (1.69 g, 5.2 mmol). The mixture was degassed and charged by nitrogen for three cycles. Then Pd2(dba)3 (63.5 mg, 69.3 μmoL) was added. The resulting solution was degassed, heated under nitrogen atmosphere at 90 °C for 24 h and then filtered through a short pad of celite while hot. The dark brown filtrate was quenched with brine and extracted with EtOAc (3x), The combined organic phase was washed with thiourea aq. and brine. The resulting organic phase was dried and concentrated under reduced pressure. The residue was purified by a reverse ISCO silica gel column to afford tert-butyl 4-(7-(tram^,-4- hydroxycyclohexyl)-2-((3-methoxyphenyl)amino)-7rt-pyrrolo[2,3-J]pyrimidin-5-yl)-3,6- dihydropyridine- -carboxylate (701.0 mg, 1.4 mmol, 39%) as a light pink solid. 'H NMR (400 MHz, CDCI₃) δ 8.84 (s, 1H), 7.61 (t, J= 2.3 Hz, 1H), 7.23 (t, J= 8.2 Hz, 1H), 7.17 (s, 1H), 7.12 (ddd, J= 8.2, 2.1, 0.9 Hz, 1H), 6.92 (s, 1H), 6.58 (ddd, J= 8.1, 2.5, 0.9 Hz, 1H), 6.09 (s, 1H), 4.56 (tt, J= 12.0, 3.9 Hz, 1H), 4.13 (d, J= 3.2 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 1H), 3.66 (t, J = 5.7 Hz, 2H), 2.50 (s, 2H), 2.15 (t, J= 16.7 Hz, 4H), 1.98-1.85 (m, 2H), 1.59-1.51 (m, 2H), 1.50 (s, 9H); MS (ESI) for [M+H]⁺ ( : calcd. m/z 520.29, found m/z 520.35; LC- MS: 95% purity.

[0161] To a solution of tert-butyl methoxyphenyl)amino)-7H -pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-l(2//)- carboxylate (698 mg, 1.3 mmol) in MeOH (60 mL) and EtOAc (60 mL) was added 10% Pd/C (286 mg). The mixture was degassed, heated at 55 °C for 48 h, and then filtered through a short pad celite. The filtrate was concentrated under reduced pressure. The residue was purified by an ISCO silica gel column gradient) to afford tert-butyl 4-(l -(trans-4- hydroxycyclohexyl)-2-((3-methoxyphenyl)amino)-7rt-pyrrolo[2,3-J]pyrimidin-5-yl)piperidine- 1 -carboxylate (652 mg, 1.3 mmol, 93%) as an off-white solid. MS (ESI) for [M+H]⁺ : calcd. m/z 522.31, found m/z 522.30; LC-MS: 98% purity.

[0162] To a solution of tert-buty methoxyphenyl)amino mmol) in EtOAc (25 mL) was added Smopex 234 (65.0 mg). The suspension was stirred at 50 °C for 3 h and filtered at rt. The solvent was removed under reduced pressure. The residue was dissolved in (6 mL) and was added a 4.0 N solution of HC1 in 1,4-dioxane (3.1 mL, 12.5 mmol). The reaction mixture was stirred at rt for 15 h. The precipitate was filtered and washed with CH₂CI2. The filter cake was dissolved in miliQ water and lyophilized to afford HC1 salt of intermediate B (600 mg, 1.2 mmol, 97%) as a pale white solid. ^JH NMR (400 MHz, (s, 1H), 7.33 (d, J= 1.1 Hz, 1H), 7.27 (t, 2.3 Hz, 1H), 7.14 (t, J= 8.2 Hz, 1H), 6.83 (ddd, J=

8.0, 2.1, 0.8 Hz, 1H), 6.55-6.49 (m, 1H), 4.20 (tt, J= 10.4, 5.2 Hz, 1H), 3.74 (dt, J= 10.2, 4.0 Hz, 1H), 3.65 (s, 3H), 3.62-3.53 (m, 2H), 3.20 (td, J= 13.0, 2.9 Hz, 2H), 3.15-3.03 (m, 1H), 2.24 (d, J= 13.6 Hz, 2H), 2.04 (d, J= 12.3 Hz, 2H), 1.87 (pd, J= 13.4, 3.7 Hz, 6H), 1.36 (qd, J = 12.0, 4.8 Hz, 2H); ¹³C NMR (101 MHz, D2O) 159.06, 151.97, 147.19, 138.26, 138.06, 129.91, 125.94, 119.97, 112.25, 111.51, 108.96, 105.50, 68.74, 55.14, 53.97, 43.84, 32.98, 30.35, 29.00, 28.65; MS (ESI) for [M+H]⁺ : calcd. m/z 422.26, found m/z 422.30; LC-MS: 98% purity.

[0163] To a solution of Zrans-4-(5-bromo-2-chloro-7H -pyrrolo[2,3-6Qpyrimidin-7- yl)cyclohexan-l-ol (8.27 g, 25 mmol) in dimethyl sulfoxide (50 mL) was added 2-ethylbutan-l- amine (6.5 mL, 50 mmol) and (10.4 g, 75 mmol). The reaction mixture was purged with nitrogen, sealed in a sealed tube, and heated at 120 °C for 36 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (3x). The combined organic phase was washed with brine (2x), dried and concentrated under reduced pressure. The residue was dissolved in the minimum amount of hot EtOAc and saturated by hexane. After cooling to rt, the precipitate was collected as an off-white solid (8.08 g, 20.4 mmol). The filtrate was concentrated under reduced pressure. The residue was recrystallized in EtOAc/hexane to afford the second crop of product (1.13 g, 2.9 mmol). In total, -(5-bromo-2-((2-ethylbutyl)amino)-77/- pyrrolo[2,3-</]pyrimidin-7-yl)cyclohexan-l-ol was obtained (9.21 g, 23.3 mmol, 93%) as an off- white solid. ¹H NMR (400 MHz 8.38 (s, 1H), 6.82 (s, 1H), 5.11 (t, J= 6.0 Hz, 1H), 4.49 (tt, J= 12.0, 3.9 Hz, 1H), 3.73 (tt, J= 11.0, 4.3 Hz, 1H), 3.40 (t, J= 6.0 Hz, 2H), 2.18-2.01 (m, 4H), 1.93 (s, 1H), 1.78 (qd, J= 12.9, 3.2 Hz, 2H), 1.53 (tdd, J= 15.1, 8.5, 2.7 Hz, 3H), 1.45- 1.32 (m, 4H), 0.94 (t, ./ = 7.4 Hz, 6H); MS (ESI) for [M+H]⁺ calcd. m/z 395.14, found ; LC-MS: 95% purity.

[0164] To a solution of ( -2- cyclohexan-l-ol (4.47 g, 11.3 mmol) and fert-butyl 4-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzyl)piperazine-l-carboxylate (5.0 g, 12.4 mmol) in 1,4-dioxane (33 mL) and water (11 mL) was added (3.13 g, 22.6 mmol). The mixture was degassed and was added Pd(PPh3)₄ (131.0 mg, 0.1 mmol). The reaction mixture was degassed and heated at 90 °C for 20 h. Then the reaction mixture was poured onto brine (120 mL) and extracted with ethyl acetate (30 mL, 3x). The combined organic phase was washed with brine, dried

(Na₂SO₄) and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column to afford an orange solid which was recrystallized from a mixture of EtOAc and hexane to afford -7-(trans -4-hydroxycyclohexyl) 7]pyrimidin-5-yl)benzyl)piperazine-l-carboxylate (2.92 g, 5 mmol, 44%) as an off- white solid. MS (ESI) for [M+H]⁺ ): calcd. m/z 591.40, found m/z 591.40; LC-MS: 97% purity.

[0165] To a solution of tert-butyl 4-(4-(2-((2-ethylbutyl)amino)-7-(trara-4- hydroxycyclohexyl)-77/-pyrrolo[2,3-6/]pyrimidin-5-yl)benzyl)piperazine- l -carboxylate (200 mg, 0.3 mmol) in MeOH (6.7 mL) was added a 4.0 N solution of HC1 in 1,4-dioxane (0.90 mL, 3.4 mmol). The reaction mixture was stirred at rt for 4.0 h, then concentrated under reduced pressure. The residue was triturated with Et20 to form an off-white precipitate. The product was filtered and washed with Et₂O to afford HC1 salt of trans.s-4-(2-((2-ethylbutyl)amino)-5-(4- (piperazin-l-ylmethyl)phenyl)-7H -pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-l-ol (207 mg, 0.3 mmol, quantitative yield) as a yellow solid. 'H NMR (400 MHz, D2O) 8.67 (s, 1H), 7.79 (s, 1H), 7.71 (d, J= 8.3 Hz, 2H), 7.60 (d, J= 8.3 Hz, 2H), 4.52 (dd, J= 11.9, 4.0 Hz, 1H), 4.43 (s, 2H), 3.77 (td, J= 11.0, 5.4 Hz, 1H), 3.59 (s, 8H), 3.42 (d, J= 6.3 Hz, 2H), 2.11 (d, J= 12.2 Hz, 2H), 2.03 (d, J= 12.2 Hz, 2H), 1.99-1.87 (m, 2H), 1.60 (p, J = 6.3 Hz, 1H), 1.56-1.43 (m, 2H), 1.43-1.33 (m, 4H), 0.93 (t, J= 7.4 Hz, 6H); ¹³C NMR (101 MHz, 154.48, 150.84, 138.16, 133.67, 131.94, 127.13, 127.02, 126.86, 115.99, 109.72, 68.92, 60.43, 53.34, 47.95, 43.76, 40.86, 40.07, 32.92, 29.24, 23.27, 10.30; MS (ESI) for [M+H]⁺ calcd. m/z 491.35, found m/z 491.35; LC-MS: 99% purity.

[0166] To a solution of -4-(2-((2-ethylbutyl)amino)-5-(4-(piperazin-l-ylmethyl)phenyl)- 7rt-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan- l-ol trihydrochloride (300 mg, 1.0 Eq, 500 μmoL) in MeOH (15 mL) was added TEA (253 mg, 348 μL, 2.5 mmol) followed by acetic acid (150 mg, 143 μL, 2.5 mmol) and tert-butyl 4-oxopiperidine-l -carboxylate (398 mg, 2.0 mmol). The reaction mixture was stirred at rt for 1.0 h, then was added sodium triacetoxyborohydride (212 mg, 1000 The reaction mixture was heated at 55 °C for 15 h, and then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 10% MeOH/DCM) to afford tert-butyl 4-(4-(4-(2-((2-ethylbutyl)amino)-7-( trans -4- hydroxycyclohexyl)- -pyrrolo[2,3 -5-yl)benzyl)piperazin-l-yl)piperidine-l- carboxylate (235 mg, 349 μmoL, 69.7%) as a yellow solid. MS (ESI) for [M + H]⁺ : calcd m/z 674,47, found m/z 674.40; tR = 3.468 min.

[0167] To a solution of fert-butyl 4-(4-(4-(2-((2-ethylbutyl)amino)-7- hydroxycyclohexyl)-7H -pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperazin-l-yl)piperidine-l- carboxylate (235 mg, 3.5 mmol) in MeOH (15 mL) was added a 4.0 N solution of HC1 in 1,4- dioxane (106 mg, 146 μL, 1.0 mmol). The reaction mixture was stirred at rt for 15 h and then concentrated under reduced pressure. The residue was triturated in E₂O to form a yellow precipitate. The product was filtered and washed with E₂O to afford the hydrochloride salt of intermediate C, which was used in the next step without further purification. MS (ESI) for [M + H]⁺ ): calcd m/z 574.42, found m/z 574.30 = 2.834 min. Intermediate D: trans-4-( 2-(( 3-chloro-5-fluorophenyl)amino)-5-( 4-( ( 4-(piperidin-4-yl)piperazin-

[0168] To a solution of trans -4-(5-bromo-2-chloro-7H -pyrrol pyrimidin-7- yl)cyclohexan-l-ol (15.0 g, 145 mmol ) in a mixture of 1,4-dioxane (100 mL) and water (10 mL) were added tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)piperazine-l- carboxylate (20.1 g, 49.9 mmol) (988 mg, 1.4 mmol) and cesium carbonate (29.6 g, 90.7 mmol). The reaction mixture was heated under nitrogen atmosphere at 90 °C for 12 h, quenched with water at rt, and extracted with EtOAc (50 mL, 3x). The combined organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 15% MeOH/DCM) to afford tert-butyl 4-(4-(2-chloro-7-( trans -4-hydroxycyclohexyl) -pyrrolo[2,3- pyrimidin-5- yl)benzyl)piperazine-l -carboxylate (15.0 g, 28.5 mmol, 63%) as a light-yellow solid.

[0169] To a solution of fert-butyl 4-(4-(2-chloro-7-(trans -4-hydroxycyclohexyl pyrrolo[2 ]pyrimidin-5-yl)benzyl)piperazine-l-carboxylate (1.50 g, 2.9 mmol) and 3-chloro- 5 -fluoroaniline (1.20 g, 8.6 mmol) in 1,4-dioxane (30 mL) was added cesium carbonate (1.90 g, 5.7 mmol), BINAP (89.0 mg, 0.10 mmol) and palladium acetate (32.0 mg, 0.10 mmol). The reaction mixture was heated under nitrogen atmosphere at 90 °C for 18 h, then quenched with water. The mixture was extracted with EtOAc (30 mL, 3x). The combined organic layer was washed with water and brine, dried (Na₂SO₄), and concentrated. The residue was purified by an ISCO silica gel column (gradient elution, gradient 50 to 100% EtOAc/DCM) to afford tert-butyl

4-(4-(2-((3-chloro-5-fluorophenyl)amino)-7-( trans -4-hydroxycyclohexyl)-7H -pyrrolo[2,3- pyrimidin-5-yl)benzyl)piperazine-l-carboxylate (800 mg, 1.3 mmol, 44%) as a light-yellow solid. MS (ESI) for [M + H]⁺ calcd m/z 635.28, found m/z 635.20; t_R = 4.550 min. [0170] To a solution of tert-butyl 4-(4-(2-(('3-chloro-5-tluorophenyl)amino)-7-( trans -4- hydroxycyclohexyl) -pyrrolo[2,3-(7]pyrirnidin-5-yl)benzyl (piperazine-! -carboxylate (800 mg,

1.3 mmol) in dichloromethane (15 mL) was added a 4.0 N solution of HC1 in dioxane (1.6 mL,

6.3 mmol). The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was triturated in to form an off-white precipitate. The product was filtered and washed with E₂O to afford HC1 salt of trans -4-(2-((3-chloro-5-fluorophenyl)amino)-

5-(4-(piperazin-l-ylmethyl)phenyl)-7H -pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-l-ol, which was used in the next step without further purification. MS (ESI) for [M + H]⁺ (C29H33QFN6O ⁺): calcd m/z 535.23, found m/z 535.20; t_R = 3.511 min.

[0171] To a solution of tra«s-4-(2-((3-chloro-5-fluorophenyl)amino)-5-(4-(piperazin-l- ylmethyl)phenyl)- pyrrolo[2,3-J]pyrimidin-7-yl)cyclohexan-l-ol trihydrochloride (500 mg, 776 μmoL) in MeOH (15 mL) was added TEA (393 mg, 541 μL, 3.9 mmol) followed by acetic acid (186 mg, 177 μL, 3.1 mmol) and tert-butyl 4-oxopiperidine-l -carboxylate (618 mg, 3.1 mmol). The reaction mixture was stirred at rt for 1.0 h, then was added sodium triacetoxyborohydride (329 mg, 1.6 mmol). The reaction mixture was heated at 55 °C for 15 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 15% MeOH/DCM) to afford tert-butyl 4-(4-(4-(2-((3- chloro-5-fluorophenyl)amino)-7-(trans-4-hydroxycyclohexyl)- yrrolo[2,3-6 pyrimidin-5- yl)benzyl)piperazin-l-yl)piperidine-l -carboxylate (235 mg, 349 μmoL, 62.2%) as a light-yellow solid.

[0172] To a solution of tert-butyl 4-(4-(4-(2-((3-chloro-5-fhiorophenyl)amino)-7-(trans-4- hydroxycyclohexyl)-7H -pyrrolo[2,3 pyrimidin-5-yl)benzyl)piperazin-l-yl)piperidine-l- carboxylate (235 mg, 327 μmoL) in dichloromethane (15 mL) was added a 4.0 N solution of HC1 in 1,4-di oxane (59.6 mg, 409 μL, 1.6 mmol). The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was triturated in Et₂O to form a yellow precipitate. The product was filtered and washed with Et₂O to afford HC1 salt of intermediate D, which was used in the next step without further purification. MS (ESI) for [M +

H]⁺ ( ): calcd m/z 618.31, found m/z 618.30; tR = 2.819 min.

Intermediate E: l-(4-(2-(( 3-chloro-5-fluorophenyl)amino)- 7 -(trans-4-hydr oxycyclohexyl) -7H-

[0173] To a solution of (/rans-4-(5-bromo-2-chloro-77/-pyrrolo[2,3-c/]pyrirnidin-7- yl)cyclohexan-l-ol (2.0 g, 6.1 mmol) and (4-formylphenyl)boronic acid (998 mg, 6.7 mmol) in a mixture of 1,4-dioxane (20 mL) and water (2.0 mL) was added (132 mg, 181 μmol) and (1.67 g, 12.1 mmol). The reaction mixture was heated under nitrogen atmosphere at 90 °C for 15 h, quenched with water at rt, and extracted with EtOAc (50 mL, 3x). The combined organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 15% MeOH/DCM) to afford 14-(2-chloro-7- -4-hydroxycyclohexyl)-7H -pyrrolo[2,3- pyrimidin-5-yl)benzaldehyde (1.50 g, 4.2 mmol, 70%) as a light-yellow solid. MS (ESI) for [M + H]⁺ : calcd m/z 356.11, found m/z 356.10; tR = 4.045 min.

[0174] To a solution of 4-(2-chloro-7-(trans-4-hydroxycyclohexyl)-7H -pyrrolo[2,3- t/]pyrimidin-5-yl)benzaldehyde (2.0 g, 5.6 mmol) in MeOH (30 mL) was added 4- (dimethoxymethyl)piperidine (2.69 g, 16.9 mmol) andacetic acid (675 mg, 644 μL, 11.2 mmol). After 1.0 h, sodium triacetoxyborohydride (2.38 g, 11.2 mmol) was added. The reaction mixture was heated at 55 °C for 15 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 15% MeOH/DCM) to afford trans- 4-(2-chloro-5-(4-((4-(dimethoxymethyl)piperidin-l-yl)methyl)phenyl)-7H -pyrrolo[2,3- pyrimidin-7-yl)cyclohexan-l-ol (2.0 g, 4.0 mmol, 71%) as a light-yellow solid. MS (ESI) for [M + H] 499.24, found m/z 499.20; t_R = 2.953 min.

[0175] To a solution of -4-(2-chloro-5-(4-((4-(dimethoxymethyl)piperidin-l- yl)methyl)phenyl)-7H -pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-l-ol (500 mg, 1.0 mmol) and 3- chl oro-5 -fluoroaniline (438 mg, 3.0 mmol) in 1,4-dioxane (15 mL) were added and cesium carbonate (653 mg, 2.0 mmol), BINAP (31.2 mg, 50.1 μmol) and palladium acetate (11.2 mg, 50.1 μmoL). The reaction mixture was heated under nitrogen atmosphere at 90 °C for 18 h, then quenched with water. The mixture was extracted with EtOAc (30 mL, 3x). The combined organic layer was washed with water and brine, dried (Na₂SO₄), and concentrated. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 15% MeOH/DCM) to afford trans-4-(2-((3-chloro-5-fluorophenyl)amino)-5-(4-((4-(dimethoxymethyl)piperidin-l- yl)methyl)phenyl)-7H -pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-l-ol (323.0 mg, 531 μmoL, 53.0%) as a light-yellow solid. MS (ESI) for [M + H]⁺ ( ): calcd m/z 625.28, found m/z 625.30; tR = 4.562 min.

[0176] To a solution of trans-4-(2-((3-chloro-5-fluorophenyl)amino)-5-(4-((4- (dimethoxymethyl)piperidin-l-yl)methyl)phenyl)-7H pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan- l-ol (323 mg, 531 μmol) in a mixture of CH3CN and water (5: 1 , v:v, 20 mL) was added 2,2- trifluoroacetaldehyde (260 mg, 2.7 mmol). The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was triturated in Et₂O to form a light-yellow precipitate. The product was filtered and washed with Et₂O to afford TFA salt of intermediate E, which was used in the next step without further purification. MS (ESI) for [M + H]⁺ ( calcd m/z 562.23, found m/z 562.20; t_R = 3.134 min.

Intermediate F: trans-4-(2-( ( 3, 5-bis( trifluoromethyl)phenyl)amino)-5-( 4-(piperazin-l- ylmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-l-ol

[0177] To a solution of tert-butyl 4-(4-(2-chloro-7-(trans -4-hydroxycyclohexyl)-7rt- pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperazine-l-carboxylate (6.0 g, 11.4 mmol) and 3,5- bis(trifluoromethyl)aniline (7.84 g, 34.2 mmol) in 1,4-dioxane (100 mL) were added (7.43 g, 22.8 mmol), BINAP (710.2 mg, 1.1 mmol) and palladium acetate (256 mg, 1.1 mmol). The reaction mixture was heated under nitrogen atmosphere at 90 °C for 18 h, then quenched with water. The mixture was extracted with EtOAc (100 mL, 3x). The combined organic layer was washed with water and brine, dried (Na₂SO₄), and concentrated. The residue was purified by an ISCO silica gel column (gradient elution, gradient 50 to 100% EtOAc/DCM) to afford tert- butyl 4-(4-(2-((3,5-bis(trifluoromethyl)phenyl)amino)-7-(tran5-4-hydroxycyclohexyl)-7H - pyrrolo[2,3-</]pyrimidin-5-yl)benzyl)piperazine-l-carboxylate (6.40 g, 8.9 mmol, 78%) as a light-yellow solid. MS (ESI) for [M + H]⁺ ( : calcd m/z 719.31, found m/z 719.30; tR = 4.307 min.

[0178] To a solution of tert-butyl 4-(4-(2-((3,5-bis(trifluoromethyl)phenyl)amino)-7-(trans- 4-hydroxycyclohexyl)-7H -pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperazine-l-carboxylate (3.0 g, 4.2 mmol) in dichloromethane (50 mL) was added a 4.0 N solution of HC1 in 1,4-dioxane (5.2 mL, 21 mmol). The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was triturated in Et₂O to form an off-white precipitate. The product was filtered and washed with Et₂O to afford HC1 salt of intermediate F, which was used in the next step without further purification. MS (ESI) for [M + H]⁺ : calcd m/z 619.25, found m/z 619.30; tR = 3.541 min.

Intermediate H: 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2, 6-dione

[0179] 4-B romo-2 -fluoro- 1 -nitrobenzene (100 mg, 0.50 mmol) was added a 2.0 M solution of CH3NH2 (2.3 mL, 4.6 mmol) in THF at rt. The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was suspended in water and centrifuged for 10 minutes. The liquid was removed and the solid was dried to yield 5-bromo-A-methyl-2- nitroaniline (100 mg, 95%) as a yellow solid, 'H NMR (400 MHz 8.24 (broad s, 1H), 7.98 (d, J= 9.0 Hz, 1H), 7.17 (d, J= 2.0 Hz, 1H), 6.83 (dd, J= 9.0, 2.0 Hz, 1H), 2.95 (d, J = 5.1 Hz, 3H)).

[0180] To a solution of 5-bromo- methyl-2-nitroaniline (21.0 g, 90.9 mmol) in EtOH (200 mL) was added aqueous ammonia chloride (19.5 g, 364 mmol) and iron (20.3 g, 364 mmol). The reaction mixture was stirred at 80 °C for 2 h, then filtered at rt. The filtrate was concentrated under reduced pressure. The residue was dissolved in water (500 mL) and extracted with EtOAc (500 mL, 2x). The combined organic layer was washed with brine (500 mL) and dried (Na₂SO₄), and concentrated to afford 5-bromo-Al -methylbenzene- 1,2-diamine as a brown solid, which was used in the next step without further purification, 'H NMR (400 MHz, 5 6.51 (dd, J = 7.8, 2.3 Hz, 1H), 6.44 (d, J= 7.8 Hz, 1H), 6.40 (d, J= 2.0 Hz, 1H), 4.67-4.61 (broad s, 2H), 2.68 (s, 3H)).

[0181] To a solution of 5-bromo- -methylbenzene- 1,2-diamine (0.71 g, 0.36 mmol) in THF (1.5 mL) was added GDI (0.070 g, 0.40 mmol) at rt. The reaction mixture was refluxed for 15 h, diluted with water (8.0 mL) at rt, and stirred for 30 minutes. The precipitated solids were collected by filtration and washed with water. The solid was dried under reduced pressure to afford 6-bromo-l-m ethyl- 1, 3 -dihydro-27/-benzo[d]imidazol -2-one as a white solid, which was used in the next step without further purification, 'H NMR (400 MHz, ) 10.97 (broad s, 1H), 7.34 (d, < , 1H), 7.13 (dd, J = 8.2, 2.0 Hz, 1H), 6.91 (d, .7= 8.2 Hz, 1H), 3.26 (s, 3H)).

[0182] To a solution of 6-bromo-l-methyl-l,3-dihydro-27/-benzo[d]imidazol-2-one (2.0 g, 8.8 mmol) in dry THF (50 mL) was added NaH (60% in mineral oil) (705 mg, 17.6 mmol) portion wise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then was added a solution of 3 -brom opiperidine-2, 6-dione (2.20 g, 11.5 mmol) in THF (10 mL) at 0 °C slowly. The reaction mixture was stirred for 15 h at 60 °C, quenched with saturated solution (1.0 mL) at 0 °C and then extracted with EtOAc (40 mL, 4x). The combined organic layer was washed with brine (50 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column to afford 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-l-yl)piperidine-2, 6-dione (1.80 g, 5.3 mmol, 60%) as an off-white solid. 'H NMR (400 MHz, 11.09 (s, 1H), 7.44 (d, J= 1.9 Hz, 1H), 7.19 (dd, J= 8.4, 1.9 Hz, 1H), 7.08 (d, J= 8.4 Hz, 1H), 5.35 (dd, J= 12.8, 5.3 Hz, 1H), 3.32 (s, 3H), 2.92-2.79 (m, 1H), 2.74-2.54 (m, 2H), 2.00 (dtd, J= 12.3, 6.2, 3.0 Hz, 1H).

[0183] To a solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-17/-benzo[d]imidazol-l- yl)piperidine-2, 6-dione (800 mg, 2.4 mmol) in a mixture of 1,4-dioxane (20 mL) and water (1.0 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine- l(2H)-carb oxy late (1.10 g, 3.5 mmol) (1.0 g, 4.7 mmol) and (186 mg, 236.6 μmol). The reaction mixture was stirred under nitrogen atmosphere at 80 °C for 4 h, quenched with water, and extracted with EtOAc (30 mL, 3x). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column to provide tert-butyl 4-(l-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-17/-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (600 mg, 1.4 mmol, 58%) as a white solid. MS (ESI) for [M + H]⁺ calcd m/z 441.21, found m/z 441.20; tR = 4.245 min.

[0184] To a solution of tert-butyl 4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-17/-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (600 mg, 1.4 mmol) in 1,4-di oxane (50 mL) was added 10% Pd/C (60.0 mg). The reaction mixture was heated under hydrogen atmosphere at 55 °C for 15 h. then filtered through a short pad celite. The filtrate was concentrated under reduced pressure. The residue was purified by an ISCO silica gel column gradient) to afford tert-butyl 4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperidine-l-carboxylate (550 mg, 1.2 mmol, 91%) as a white solid. MS (ESI) for [M + Na]⁺ ( ): calcd m/z 465.21, found m/z 465.20; tR = 4.276 min.

[0185] To a solution of tert-butyl 4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro- -benzo[d]imidazol-5-yl)piperidine-l-carboxylate (550 mg, 1.2 mmol) in dichloromethane (10 mL) was added a 4.0 N solution of HC1 in 1,4-dioxane (1.6 mL, 6.2 mmol). The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was triturated in Et₂O to form a white precipitate. The product was filtered and washed with Et₂O to afford HC1 salt of intermediate H as a white solid. MS (ESI) for [M + H]⁺ : calcd m/z 343.17, found m z 343.20; tR = 1.348 min.

Intermediate I: 5-( 3-( 1 -(2, 6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-

[0186] To a solution of 1,5 -pentanediol (7.0 g, 67 mmol) in dry THF (50 mL) was added

NaH (60% in mineral oil) (1.2 g, 31 mmol) under nitrogen atmosphere at rt. After 15 min, propargyl bromide (2.14 g) was added dropwise. The reaction mixture was stirred for 15 h, quenched with water (25 mL), and extracted with dichloromethane (25 mL, 4x). The combined organic layer was washed with brine (50 mL), dried and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (EtOAc: Hexane = 3\ 1) to yield 5-(prop-2-yn-l-yloxy)pentan-l-ol (1.41 g, 34%) as a liquid. [0187] To a solution of 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (3.0 g, 8.9 mmol) and 5-(prop-2-yn-l-yloxy)pentan-l-ol (3.8 g, 27.0 mmol)) in DMSO (10.0 mL) was added triethylamine (30 mL, 0.21 mol), copper(I) iodide (0.25 g, 1.3 mmol), and (0.80 g, 0.70 mmol) at rt. The reaction mixture was heated under nitrogen atmosphere at 85°C for 15 h, then quenched with water at rt, and extracted with dichloromethane (50 mL, 3x). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column chromatography (gradient elution, gradient 1 to 3% MeOH/DCM)) to afford 3-(5-(3-((5-hydroxypentyl)oxy)prop-l-yn-l-yl)-3- methyl-2-oxo-2, 3 -dihydro benzo[d]imidazol-l-yl)piperidine-2, 6-dione (710 mg, 1.78 mmol, 20 %) as a brown foam. MS (ESI) for [M + H]⁺ ): calcd m/z 400.18, found m/z 400.40; tR = 2.836 min.

[0188] To a solution of 3-(5-(3-((5-hydroxypentyl)oxy)prop-l-yn-l-yl)-3-methyl-2-oxo-2,3- dihydro-17/-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (167 mg, 1.0 eq, 418 μmol) in THF (20 mL) was added 10% Pd/C (10.0 mg) and 10% (10.0 mg). The reaction mixture was stirred under hydrogen atmosphere at rt for 18 h, then filtered. The filtrate was concentrated under reduced pressure to afford 3-(5-(3-((5-hydroxypentyl)oxy)propyl)-3-methyl-2-oxo-2,3- dihydro-17/-benzo ]imidazol-l-yl)piperidine-2, 6-dione as a brown solid which was used in the next step without further purification. MS (ESI) for [M + H]⁺ : calcd m/z 404.21, found m/z 404.20; tR = 2.833 min.

[0189] To a solution of 3-(5-(3-((5-hydroxypentyl)oxy)propyl)-3-methyl-2-oxo-2,3-dihydro- piperidine-2, 6-dione (100 mg, 248 mmol) in dichloromethane (10 mL) was added Dess-Martin Reagent (116 mg, 322 mmol). The reaction mixture was stirred at rt for 3.0 h, quenched with aqueous solution (1.0 mL), and extracted with dichloromethane (10 mL, 3x). The combined organic layer was washed with brine, dried (Na2SC>4), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 5% MeOH/DCM)) to afford intermediate I as a white foam solid (85.1 mg, 85.1%). MS (ESI) for [M + H]⁺ calcd m/z 402.20, found m/z 402.30; tR = 2.847 min.

Intermediate J: 3-( 1 -oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione

[0190] To a solution of 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (200 mg, 619 μmol) in 1,4-dioxane (6.0 mL) was added tert-butyl piperazine- 1 -carboxylate (150 mg, 805 μmol (605 mg, 1.9 mmol) and Pd-PEPPSI-IHeptCl (30.1 mg, 30.9 μmol). The reaction mixture was stirred under nitrogen atmosphere at 100 °C for 3 h, quenched with water, and extracted with EtOAc (30 mL, 3x). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column to provide tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazine- 1-carboxylate (100 mg, 233 μmol, 37.7%) as an off-white solid. MS (ESI) for [M + H]⁺ : calcd m/z 429.21, found m/z 429.30; t_R = 3.784 min.

[0191] To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperazine-l -carboxylate (700 mg, 1.6 mmol) in dichloromethane (20 mL) was added a 4.0 N solution of HC1 in 1,4-dioxane (2.0 mL, 8.2 mmol). The reaction mixture was stirred at rt for 15 h, then concentreated under reduced pressure. The residue was triturated in Et₂O to form a white precipitate. The product was filtered and washed with Et₂O to afford HC1 salt of intermediate J as a white solid. MS (ESI) for [M + H]⁺ : calcd m/z 329.15, found m/z 329.20; t_R = 0.687 min.

Intermediate K: 3-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)propoxy)propanal

[0192] To a solution of 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (350 mg, 1.1 mmol) and 3-(prop-2-yn-l-yloxy)propan-l-ol (371 mg, 3.2 mmol) in DMSO (5.0 mL) was added triethylamine (2.63 g, 3.6 mL, 26 mmol) followed by copper(I) iodide (20.6 mg, 108. μmol) and Pd(PPh3)4 (125 mg, 108 μmol). The mixture was heated under nitrogen atmosphere at 85°C for 15 h, then quenched with cold brine (20 mL) at rt, and extracted water with EtOAc (30 mL, 3x). Combined organic layer was washed with brine, dried , and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 3% MeOH/DCM)) to afford 3-(5-(3-(3-hydroxypropoxy)prop-l-yn-l-yl)-l-oxoisoindolin-2- yl)piperidine-2, 6-dione as a brown foam solid (200 mg, 561 μmol, 52%). MS (ESI) for [M + H]⁺ ( : calcd m/z 357.14, found m/z 357.20; t_R = 2.786 min.

[0193] To a solution of 3-(5-(3-(3-hydroxypropoxy)prop-l-yn-l-yl)-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (200 mg, 561 in THF (20 mL) was added 10% Pd/C (20.0 mg). The reaction mixture was stirred under hydrogen atmosphere at rt for 18 h. After filtration, and the solid was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford 3-(5-(3-(3-hydroxypropoxy)propyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione as a brown solid which was used in the next step without further purification. MS (ESI) for [M + H]⁺ : calcd m/z 361.17, found m/z 361.20; tR = 2.783 min.

[0194] To a solution of 3-(5-(3-(3-hydroxypropoxy)propyl)-l-oxoisoindolin-2-yl)piperidine- 2, 6-dione (348 mg, 966 μmol) in dichloromethane (30 mL) was added Dess-Martin reagent (532 mg, 1.3 mmol). The reaction mixture was stirred at rt for 3 h, quenched with water (20 mL), aqueous solution and aqueous solution, and extracted with EtOAc (30 mL, 3x). The combined organic layer was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 5% MeOH/DCM)) to intermediate K as a white foam solid (260 mg, 725 μmoL, 75%). MS (ESI) for [M + H]⁺ : calcd m/z 359.15, found m/z 359.20; t_R = 3.078 min.

Intermediate L: 3-( 6-bromo-9H-pyrido[2, 3-b ]indol-9-yl)piperidine-2, 6-dione [0195] To a solution of pyrido[2,3-b]indole (500 mg, 3.0 mmol) in THF (20 mL) was added 1 -bromopyrrolidine-2, 5-dione (582 mg, 3.3 mmol). The reaction mixture was stirred at rt for 18 h, quenched with water and aqueous ₃ solution, and extracted with EtOAc (10 mL, 3x). The combined organic layer was concentrated and purified by silica gel column chromatography (gradient elution, gradient 0 to 50% EA/DCM)) to afford 6-bromo-9//- pyrido[2,3-b]indole (500 mg, 2.0 mmol, 68.1%) as a white solid. ^!H NMR (400 MHz, DMSO-AL) 11.93 (s, 1H), 8.54 (dd, J= 7.7, 1.6 Hz, 1H), 8.45-8.35 (m, 2H), 7.56 (dd, J= 8.6, 2.0 Hz, 1H), 7.45 (d, J= 8.6 Hz, 1H), 7.21 (dd, J= 7.7, 4.8 Hz, 1H).

[0196] To a solution of 6-bromo-9/7-pyrido[2,3-b]indole (2.0 g, 1 Eq, 8.1 mmol) in THF (30 mL) was added potassium tert-butoxide (1.82 g, 2 Eq, 16.2 mmol) at 0°C. The reaction was stirred for 1 hour at this temperature. Then, the THF (10 mL) solution of 3-bromo-l-(4- methoxybenzyl)piperidine-2, 6-dione (5.05 g, 2 Eq, 16.2 mmol) was added to the above mixture. The reaction was stirred for 15 h at 60°C. the reaction was quenched with saturated (1 mL) at 0°C and then extracted with EtOAc (30 mL, 2x). The combined organic layer was washed with brine (20 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column to afford 3-(6-bromo- /-pyrido[2,3 ]indol-9-yl)-l-(4- methoxybenzyl)piperidine-2, 6-dione (1.0 g, 2.0 mmol, 30%) as a white solid.

[0197] To a solution of 3-(6-bromo -pyrido[2,3 indol-9-yl)-l-(4- methoxybenzyl)piperidine-2, 6-dione (200 mg, 418 μmol) in toluene (10 mL) was added methane sulfonic acid (1.21 g, 815 μL, 12.5 mmol) at rt. The mixture was stirred at 90 °C for 15 h. After cooled to rt, the mixture was concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 50% EtOAc/n-hexane) to afford 3-(6- bromo pyrido[2,3 ]indol-9-yl)piperidine-2, 6-dione (50.0 mg, 140 μmol, 33%) as a white solid. MS (ESI) for [M + H]⁺ : calcd m/z 358.01, found m/z 358.10; t_R = 4.536 min.

Intermediate M: 5-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-l-yl)pentanal [0198] To a solution of 3-((4-(piperazin-l-yl)phenyl)amino)piperidine-2, 6-dione (250 mg, 867 μmoL) in MeCN (20 mL) was added A-ethyl-A-isopropylpropan-2-amine (560 mg, 755 μL, 4.3 mmol), 2-(4-bromobutyl)- 1,3 -di oxolane (272 mg, 1.3 mmol), and sodium iodide (13.0 mg, 86.7 μmol). The reaction mixture was stirred at 80 °C for 18 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 3% MeOH/DCM)) to afford 3-((4-(4-(4-(l,3-dioxolan-2-yl)butyl)piperazin-l- yl)phenyl)amino)piperidine-2, 6-dione (212 mg, 509 μmol, 59%) as a white solid. MS (ESI) for [M + H]⁺ : calcd m/z 417.24, found m/z 417.30; tR = 2.093 min.

[0199] To a solution of 3-((4-(4-(4-(l,3-dioxolan-2-yl)butyl)piperazin-l- yl)phenyl)amino)piperidine-2, 6-dione (212 mg, 0.50 mmol) in a mixture of 1,4-di oxane :water (5: 1, v:v, 20 mL) was added a 4.0 N solution of HC1 in 1,4-dioxane (636 μL, 2.5 mmol) at rt.

The reaction mixture was stirred at rt for 18 h, then concentrated under reduced pressure. The residue was used in the next step without further purification. MS (ESI) for [M + H]⁺ 7 calcd m/z 373.22, found m/z 373.20; tR = 1.669 min.

Intermediate N: 5-bromo-N-(2, 6-dioxopiperidin-3-yl)picolinamide

[0200] To a solution of 5-bromopicolinic acid (1.0 g, 5.0 mmol) in di chloromethane (20 mL) was added DIPEA (1.92 g, 2.6 mL, 14.8 mmol) and HATU (2.26 g, 5.9 mmol). After 1.0 h, 3- aminopiperidine-2, 6-dione hydrochloride (978 mg, 5.9 mmol) was added. The reaction mixture was stirred rt for 18 h, quenched with water, and extracted with EtOAc (30 mL, 2x). The combined organic layer was washed with brine (20 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column to afford intermediate N (1.0 g, 3.0 mmol, 60%) as a white solid. [0201] To a suspension of sodium hydride (60% in mineral oil) (27.0 mg, 0.70 mmol) in THF (3.0 mL) was added a solution of pentane 1,5-diol (71.0 mg, 0.70 mmol) in THF (2.0 mL) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then was added a solution of 3-(4-(bromomethyl)phenyl)-lH-benzo[f]chromen-l-one (50.0 mg, 0.1 mmol) in a mixture of THF (2.0 mL) and DMF (0.20 mL) slowly at 0 °C. The reaction mixture was warmed to rt and stirred for 5 h, quenched with MeOH (2 mL), diluted with water, and extracted with EtOAc (10 mL, 2x). The combined organic layer was dried (MgSCL) and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient 0-100% Hexane: EtOAc) to afford 3-(4-(((5-hydroxypentyl)oxy)methyl)phenyl)-l/Z-benzo[/]chromen-l-one (20.0 mg, 77%) as an off-white solid. ' H NMR (400 MHz, 10.09 (d, J= 9.1 Hz, 1H), 8.13 (d, J= 8.7 Hz, 1H), 7.96 (d, J= 8.2 Hz, 2H), 7.93 (d, J= 8.3 Hz, 1H), 7.77 (t, J= 8.2 Hz, 1H), 7.67- 7.52 (m, 2H), 7.52 (d, J= 8.2 Hz, 2H), 7.00 (s, 1H), 4.60 (s, 2H), 3.68 (t, J= 6.6 Hz, 2H), 3.54 (t, J= 6.6 Hz, 2H), 1.70 (quint, J= 7.2 Hz, 2H), 1.62 (quint, J= 7.2 Hz, 2H), 1.53-1.48 (m, 2H).

[0202] To a solution of 3-(4-(((5-hydroxypentyl)oxy)methyl)phenyl)-lH-benzo[/]chromen-l- one (57.0 mg, 0.20 mmol) in anhydrous dichloromethane (5.0 mL) was added the Dess-Martin periodinane (93.0 mg, 0.20 mmol). The reaction mixture was stirred at rt for 2 h, quenched with saturated sodium bicarbonate (5.0 mL), and extracted with EtOAc (10 mL, 3x). The combined organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient 0-100% Hexane: EtOAc) to afford intermediate O (48.0 mg, 85%) as an off-white solid which was used in the next step without further characterization.

Intermediate P: 6-((l-(2-chloroacetyl)-l , 2, 3, 4-tetrahydroquinolin-6-yl)oxy)hexanal

[0203] To a solution of l,2,3,4-tetrahydroquinolin-6-ol (500 mg, 3.25 mmol) in dichloromethane (10 mL) were added triethylamine (0.60 mL, 4.02 mmol) and Boc-anhydride (805 mg, 3.69 mmol). The reaction mixture was stirred at rt for 12 h, quenched with water (10 mL), and extracted with di chloromethane (10 mL, 3x). The combined organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 5% MeOH/DCM)) to afford 2- chloro- tert-butyl 6-hydroxy-3,4-dihydroquinoline-l(2//)-carboxylate (751 mg, 90%) as a white foam. MS (ESI) for [M + H]⁺ ( : calcd m/z 250.32, found m/z 250.30; tR = 4.562 min. [0204] To a solution of 2-chloro-l-(6-hydroxy-3,4-dihydroquinolin-l( -yl)ethan-l-onel (100 mg, 0.40 mmol) in DMF (5.0 mL) was added (153 mg, 0.80 mmol) and 6- bromohexan-l-ol (88.3 mg, 0.61 mmol). The reaction mixture was stirred at rt for 12 quenched with water (10 mL), and extracted with dichloromethane (10 mL, 3x). The combined organic layer was washed with brine, dried , and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 5% MeOH/DCM)) to afford 2-chloro-l-(6-((6-hydroxyhexyl)oxy)-3,4-dihydroquinolin-l( )- yl)ethan-l-one (110 mg, 77%) as a white foam. MS (ESI) for [M + H]⁺ ( : calcd m/z 350.48, found m/z 350.40; tR = 4.012 min.

[0205] To a solution of tert-butyl 6-((6-hydroxyhexyl)oxy)-3,4-dihydroquinoline-l( )- carboxylate (500 mg, 1.4 mmol) in dichloromethane (10 mL) was added a 4.0 N solution of HC1 1,4-dioxane (1.4 mL, 5.7 mmol). The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was triturated in to form a white precipitate. The product was filtered and washed with Et₂O to afford HC1 salt of 6-((l,2,3,4-tetrahydroquinolin-6- yl)oxy)hexan-l-ol as a white solid. MS (ESI) for [M + H]⁺ ( calcd m/z 250.36, found m/z 250.30; tR = 1.531 min.

[0206] To a solution of 6-((l,2,3,4-tetrahydroquinolin-6-yl)oxy)hexan-l-ol (400 mg, 1.6 mmol) in dichloromethane (10 mL) was added tri ethylamine (0.48 mL, 3.2 mmol) and chloroacetyl chloride (0.20 mL, xx mmol). The reaction mixture was stirred at rtfor 2 h, quenched with water (10 mL), and extracted with di chloromethane (10 mL, 3x). The combined organic layer was washed with brine, dried ( g ), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 5% MeOH/DCM)) to afford 2-chloro-l-(6-((6-hydroxyhexyl)oxy)-3,4-dihydroquinolin-l(2//)- yl)ethan-l-one (112 mg, 21%) as a white foam. MS (ESI) for [M + H]⁺ calcd m/z 326.84, found m/z 326.80; tR = 3.147 min.

[0207] To a solution of containing 6-((l-(2-chloroacetyl)-l,2,3,4-tetrahydroquinolin-6- yl)oxy)hexanol (30.0 mg, 0.10 mmol) in dichloromethane (10 mL) was added Dess-Martin Reagent (43.0 mg, 0.10 mmol). The reaction mixture was stirred at rt for 3 h, quenched with aqueous (1.0 mL) solution, and extracted with dichloromethane (10 mL, 3x). The combined organic layer was washed with brine, dried (MgSO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 5% MeOH/DCM)) to afford intermediate P (28.0 mg, 94%) as a white foam. MS (ESI) for [M + H]⁺ calcd m/z 324.82, found m/z 324.80; t_R = 2.847 min.

Intermediate Q: (E)-6-(2, 6-dimethoxy-4-(3-oxo-3-(6-oxo-3, 6-dihydropyridin-l(2H)-yl)prop-l- en-l-yl)phenoxy)hexanal

[0208] To a solution of (£)-l-(3-(4-hydroxy-3,5-dimethoxyphenyl)acryloyl)-5,6- dihydropyridin-2(1H)-one (50.0 mg, 0.20 mmol) in DMF (5.0 mL) were added (57.0 mg, 0.40 mmol) and 6-bromohexan-l-ol (32.8, 0.20 mmol). The reaction mixture was stirred at rt for 12 h, quenched with water (10 mL), and extracted with di chloromethane (10 mL, 3x). The combined organic layer was washed with brine, dried (MgSO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 5% MeOH/DCM)) to afford (E)-l-(3-(4-((6-hydroxyhexyl)oxy)-3,5-dimethoxyphenyl)acryloyl)- 5,6-dihydropyridin-2(17/)-one (53.0 mg, 80%) as a white foam. MS (ESI) for [M + H]⁺ ( calcd m/z 404.48, found m/z 404.40; t_R = 4.012 min.

[0209] To a solution of (£)-l-(3-(4-((6-hydroxyhexyl)oxy)-3,5-dimethoxyphenyl) acryloyl)- 5,6-dihydropyridin-2(17/)-one (45.0 mg, 0.10 mmol) in dichloromethane (10 mL) was added Dess-Martin Reagent (52.0 mg, 0.10 mmol). The reaction mixture was stirred atrt for 3 h, quenched with aqueou h solution (1.0 mL), and extracted with dichloromethane (10 mL, 3x). The combined organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 5% MeOH/DCM)) to afford intermediate Q (37.0 mg, 83%) as a white foam. MS (ESI) for [M + H]⁺ ( : calcd m/z 402.47, found m/z 402.40; t_R = 2.831 min.

Intermediate R: 3-(N-(3-cyano-4-methyl-lH-indol-7-yl)sidfamoyl)-N-(6-oxohexyl)benzamide

[0210] To a solution of 3-( (3-cyano-4-methyl- -indol-7-yl)sulfamoyl)benzoic acid (161 mg, 0.50 mmol) in DMF (2.0 mL) was added DIPEA (0.20 mL, 1.1 mmol) and HATU (189.5 mg, 0.50 mmol) under nitrogen atmosphere at rt. After 10 min, 6-aminohexan-l-ol (53.1 mg, xx mmol) was added. The reaction mixture was stirred at rt for 4 h, then concentrated under reduced pressure. The residue was purified by a reverse ISCo column (water/methanol) to afford 3- (3- cyano-4-methyl-1H-indol-7-yl)sulfamoyl)-A-(6-hydroxyhexyl)benzamide (181 mg, 88%) as a white solid. MS (ESI) for [M + H]⁺ ): calcd m/z 455.56, found m/z 455.50; tR = 2.321 min.

[0211] To a solution of 3-(A-(3-cyano-4-methyl- -indol-7-yl)sulfamoyl)-A-(6- hydroxyhexyl)benzamide (70.0 mg, 0.10 mmol) in dichloromethane (10 mL) was added Dess- Martin Reagent (78.4 mg, 0.20 mmol). The reaction mixture was stirred at rt for 3.0 h, quenched with aqueous solution (1.0 mL), and extracted with dichloromethane (10 mL, 3x). The combined organic layer was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 5% MeOH/DCM)) to afford intermediate R (43.0 mg, 62%) as a white foam. MS (ESI) for [M + H]⁺ : calcd m/z 453.54, found m/z 453.50; t_R = 2.847 min.

Intermediate S: 2-((2-(2, 6-dioxopiperidin-3-yl)-l, 3-dioxoisoindolin-4-yl)oxy)-N-(3-(2-(2-((6- iodohexy I) oxy) ethoxy) ethoxy )propy I) acetamide

[0212] To a solution of diethylene glycol (1.4 mL, 15 mmol) in DMSO (10 mL) was added KOH (844.0 mg in 5 mL water, 15 mmol). After 5 min, l-bromo-6-chlorohexane (1.5 mL, 10 mmol) was added dropwise. The reaction mixture was stirred at rt for 15 h, quenched with brine (30 mL), and extracted with ethyl acetate (30 mL, 3x). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by a revered ISCO column to afford 2-(2-((6-chlorohexyl)oxy)ethoxy)ethan-l-ol (876 mg, 3.9 mmol, 39%) as a colorless oil. NMR (400 MHz, 3.77-3.70 (m, 2H), 3.71-3.64 (m, 2H), 3.65-3.55 (m, 4H), 3.52 (t, J= 6.7 Hz, 2H), 3.47 (t, J= 6.7 Hz, 2H), 2.87 (s, 1H), 1.83-1.71 (m, 2H), 1.65-1.54 (m, 2H), 1.50-1.32 (m, 4H); MS (ESI) for [M+H]⁺ : calcd. m/z 225.13, found m/z 225.15.

[0213] To a solution of fert-butyl (3-bromopropyl)carbamate (453 mg, 1.9 mmol) and 2-(2- ((6-chlorohexyl)oxy)ethoxy)ethan-l-ol (285 mg, 1.3 mmol) in benzene (1.3 mL) was added 50% wt NaOH aq. (507 mg, 12.7 mmol) and tetrabutylammonium hydrogen sulfate (432 mg, 1.3 mmol) at 0 °C. The reaction mixture was vigorously stirred at rt for 24 h, quenched with water, and extracted with Et₂O. The organic layer was washed with water (2x), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (hexane gradient) to afford tert-butyl (3-(2-(2-((6- chlorohexyl)oxy)ethoxy)ethoxy)propyl)carbamate (337 mg, 0.9 mmol, 70%) as a white solid. [0214] To a solution of 4.0 N HC1 in 1,4-dioxane (1.5 mL, 6.1 mmol) was added tert-butyl (3-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)propyl)carbamate (235 mg, 0.60 mmol). The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was lyophilized to afford 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetic acid (137 mg, 0.40 mmol, 70%) as a white solid. 'H NMR (400 MHz, CDCh) 6 8.20 (s, 3H), 3.73-3.57 (m, 10H), 3.51 (dtd, J= 19.1, 6.8, 1.3 Hz, 4H), 3.24-3.16 (m, 2H), 2.04 (p, J= 5.6 Hz, 2H), 1.84-1.73 (m, 2H), 1.66-1.56 (m, 2H), 1.50-1.31 (m, 4H); ¹³C NMR (101 MHz, CDCh) 6 71.40, 70.52, 70.16, 70.15, 70.11, 45.23, 39.69, 39.53, 32.67, 29.51, 26.81, 26.66, 25.51; MS (ESI) for [M+H]⁺ : calcd. m/z 282.18, found m/z 282.20.

[0215] To a solution of 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetic acid (100 mg, 0.30 mmol) in DMF (1.0 mL) was added DIPEA (157 ph. 0.90 mmol) and HATU (228 mg, 0.60 mmol) at 0 °C. The solution was stirred at 0 °C for 5 min, then was added a solution of 3-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)propan-l-amine hydrochloride (95.8 mg, 0.30 mmol) in DMF (0.5 mL). The reaction mixture was stirred at rt for 12 h, quenched with water, and extracted with EtOAc (3x). The combined organic layer was washed with brine, dried (Na2SC>4), and concentrated under reduced pressure. The residue was purified by reverse ISCO silica gel column to afford A-(3-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)propyl)-2-((2-(2, 6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide (90.3 mg, 0.20 mmol, 50%) as a colorless oil. 'H NMR (400 MHz, 8.70 (s, 1H), 7.74 (dd, J= 8.4, 7.3 Hz, 1H), 7.55 (d, .7= 7.1 Hz, 1H), 7.54 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.95 (dd, ./ = 12.1, 5.4 Hz, 1H), 4.64 (d, J = 2.1 Hz, 2H), 3.69-3.40 (m, 14H), 2.94-2.67 (m, 3H), 2.21-2.11 (m, 1H), 1.87 (p, J= 6.5 Hz, 2H), 1.81-1.53 (m, 6H), 1.49-1.30 (m, 4H); MS (ESI) for [M+H]⁺ ( : calcd. m/z 596.24, found m/z 596.20; LC-MS: 98% purity.

[0216] To a solution of A-(3-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)propyl)-2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide (90.3 mg, 0.2 mmol) in acetone (7.5 mL) was added Nal (227 mg, 15.1 mmol). The reaction mixture was reflused for 30 h, then filtered at room temperature. The filtrate was concentrated under reduced pressure. The residue was purified by a reverse ISCO column to afford intermediate S (86.9 mg, 0.10 mmol, 83%) as a colorless oil. 'H NMR (400 MHz 8.80 (s, 1H), 7.73 (dd, J= 8.4, 7.3 Hz, 1H), 7.54 (d, .7= 7.3 Hz, 2H), 7.19 = 8.4 Hz, 1H), 4.95 (dd, J= 12.0, 5.4 Hz, 1H), 4.63 (d, J= 1.7 Hz, 2H), 3.68-3.53 (m, 10H), 3.45 (dt, J= 11.1, 6.3 Hz, 4H), 3.17 (t, J = 7.0 Hz, 2H), 2.93-2.69 (m, 3H), 2.19-2.11 (m, 1H), 1.83 (dp, 25.1, 6.8 Hz, 4H), 1.56 (p, J= 6.8 Hz, 2H), 1.45-1.29 (m, 4H); MS (ESI) for [M+H]⁺ calcd. m/z 688.17, found m/z 688.10; LC-MS: 98% purity.

Intermediate T: 2-(2, 6-dioxopiperidin-3-yl)-4-((3-(2-(2-((6- iodohexyl)oxy)ethoxy)ethoxy)propyl)amino)isoindoline-l, 3-dione

[0217] To a solution of 3-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)propan-l-amine hydrochloride (115 mg, 0.40 mmol) in DMF (1.2 mL) was added 2-(2, 6-dioxopiperi din-3 -yl)-4- fhioroisoindoline-1, 3-dione (100 mg, 0.40 mmol) and DIPEA (189 μL, 1.1 mmol). The reaction mixture was stirred at 80 °C for 24 h, quenched with brine at rt, and extracted with EtOAc (3x). The combined organic layer was washed with brine, dried (Na2SC>4), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column to afford 4-((3-(2-(2- ((6-chlorohexyl)oxy)ethoxy)ethoxy)propyl)amino)-2-(2, 6-dioxopiperi din-3 -yl)isoindoline- 1,3- dione (37.4 mg, 69.5 μmol, 19%) as a bright green gel. ^!H NMR (400 MHz, 8.00 (br, 1H), 7.49 (dd, ./ = 8.6, 7.1 Hz, 1H), 7.08 (d, J= 7.1 Hz, 1H), 6.94 (d, J= 8.5 Hz, 1H), 6.44 (t, ./ = 5.7 Hz, 1H), 4.91 (dd, J= 12.1, 5.3 Hz, 1H), 3.73-3.36 (m, 16H), 2.94-2.70 (m, 3H), 2.17-2.09 (m, 1H), 1.94 (h, .7= 6.2 Hz, 2H), 1.81-1.72 (m, 2H), 1.59 (p, J= 6.9 Hz, 2H), 1.49-1.31 (m, 4H); MS (ESI) for [M+H]⁺ calcd. m/z 538.23, found m/z 538.20; LC-MS: 95% purity.

[0218] To a solution of 4-((3-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)propyl)amino) -2- (2, 6-dioxopiperi din-3 -yl)isoindoline-l, 3-dione (56.4 mg, 0.10 mmol) in acetone (5.0 mL) was added Nal (157 mg, 1.1 mmol). The reaction mixture was refluxed for 30 h, then filtered at rt. The filtrate was concentrated under reduced pressure. The residue was purified by ISCO silica gel column to afford intermediate T (52.5 mg, 83.4 μmol, 80%) as a brown oil. 'H NMR (400 MHz, 8.20 (d, J = 23.0 Hz, 1H), 7.49 (dd, J= 8.5, 7.1 Hz, 1H), 7.08 (d, J= 7.0 Hz, 1H), 6.94 (d, J= 8.5 Hz, 1H), 6.43 (t, J= 5.8 Hz, 1H), 4.90 (dd, J= 12.0, 5.4 Hz, 1H), 3.73-3.54 (m, 10H), 3.42 (dt, J= 20.0, 6.5 Hz, 4H), 3.17 (t, J= 7.0 Hz, 2H), 2.93-2.67 (m, 3H), 2.12 (dp, J = 9.4, 2.9, 2.1 Hz, 1H), 1.92 (p, 6.2 Hz, 2H), 1.81 (p, 7.0 Hz, 2H), 1.58 (p, J= 6.7 Hz,

2H), 1.45-1.30 (m, 4H); MS (ESI) for [M+H]⁺ ( : calcd. m/z 630.17, found m/z

630.20; LC-MS: 95% purity.

Intermediate U: N-(2-(2, 6-dioxopiperidin-3-yl)-l, 3-dioxoisomdolm-4-yl)-6-(2-(2-( ( 6- iodohexyl) oxy) ethoxy) ethoxy)hexanamide

[0219] To a solution of 6-bromohexanoic acid (975 mg, 5.0 mmol), butyl alcohol (1.4 mL,

15 mmol), and DMAP (61.1 mg, 0.50 mmol) in (5.0 mL) was added DCC (1.13 g, 5.5 mmol) at 0 °C. The reaction mixture was slowly warmed up to rt, stirred for 48 h, and then filtered. The solid was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (0-15% EtOAc/hexane) to afford -butyl 6-bromohexanoate (1.05 g, 4.2 mmol, 84%) as a colorless oil.

[0220] To a solution of tert-butyl 6-bromohexanoate (264 mg, 1.1 mmol) and 2-(2-((6- chlorohexyl)oxy)ethoxy)ethan-l-ol (260 mg, 1.2 mmol) in toluene (1.0 mL) was added 50% wt NaOH aq. (420 mg, 10.5 mmol) and TBAHS (357 mg, 1.1 mmol) at 0 °C. The reaction mixture was vigorously stirred for 12 h, quenched with water, and extracted with Et₂O. The organic layer was washed with water (2x), dried and concentrated under reduced pressure. The residue was purified by ISCO column chromatography to afford tert-butyl 6-(2-(2-((6- chlorohexyl)oxy)ethoxy)ethoxy) hexanoate (235 mg, 0.60 mmol, 57%) as a colorless oil.

[0221] To a solution of tert-butyl 6-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy) hexanoate (517 mg, 1.3 mmol) in MeCN (6.5 mL) was added TFA (0.90 mL, 13.1 mmol). The reaction mixture was heated at 50 °C for 6 h, quenched with water at rt, and extracted with CH₂CI2 (3x). The combined organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column to afford 6-(2-(2-((6- chlorohexyl)oxy)ethoxy)ethoxy)hexanoic acid (179 mg, 0.50 mmol, 40%) as a white solid. LC- MS data: MS (ESI) for [M+Na]⁺ : calcd. m/z 361.19, found m/z 361.20; t_R = 4.57 min.

[0222] To a solution of 6-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)hexanoic acid (58.7 mg, 0.20 mmol), 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione (47.3 mg, 0.20 mmol), and NMI (48.3 μL, 0.60 mmol) in MeCN (0.90 mL) was added TCFH (58.1 mg, 0.20 mmol). The reaction mixture was heated at 60 °C for 40 h, then quenched with water at rt. The slurry was stirred for 15 min and filtered. The solid was washed with a mixture of MeCN and water (1 :2) to afford 6-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)-A-(2-(2,6-dioxopiperidin-3- yl)-l,3-dioxoisoindolin-4-yl)hexanamide (89.6 mg, 0.20 mmol, 87%) as a yellow solid which was used in the next step without further purification. LC-MS data: MS (ESI) for [M+H]⁺ calcd. m/z 594.25, found m/z 594.20; t_R= 5.07 min.

[0223] To a solution of 6-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy) V-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hexanamide (89.6 mg, 0.20 mmol) in acetone (7.5 mL) was added Nal (226 mg, 1.5 mmol). The reaction mixture was refluxed for 30 h, then filtered at rt. The filtrate was concentrated under reduced pressure. The residue was purified by ISCO column chromatography (50-70% EtOAc/hexane) to afford intermediate U (86.1 mg, 0.10 mmol, 83%) as a white wax-like solid. LC-MS data: MS (ESI) for [M+H]⁺ calcd. m/z 686.19, found m/z 686.20; t_R= 5.40 min.

Example 2 — Synthesis of 3-(5-(3-((5-(4-(4-(2-((2-Ethylbutyl)amino)-7-(trans-4- hydroxycyclohexyl)-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)benzyl)piperazm-l-yl)pentyl)oxy)propyl)- 3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione

[0224] To a solution of -4-(2-((2-ethylbutyl)amino)-5-(4-(piperazin-l-ylmethyl)phenyl)- 77/-pyrrolo[2,3-J]pyrimidin-7-yl)cyclohexan-l-ol (36.6 mg, 0.10 mmol) in dichloromethane (5.0 mL) was added potassium acetate (33.0 mg, 0.30 mmol) followed by 5-(3-(l-(2,6-dioxopiperidin-

3-yl)-3-methyl-2-oxo-2,3-dihydro benzo[<7]imidazol-5-yl)propoxy)pentanal (30.0 mg, 0.10 mmol). After 1.0 h, i (47.5 mg, 0.20 mmol) was added. The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 20% MeOH/DCM) and a reverse ISCO column (water + 0.1% HCl/MeCN) to afford 3-(5-(3-((5-(4-(4-(2-((2-ethylbutyl)amino)-7-

4-hydroxycyclohexyl) -pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperazin-l- yl)pentyl)oxy)propyl)-3-methyl-2-oxo-2,3-dihydro-l/f-benzo[d]imidazol-l-yl)piperidine-2,6- dione (25.2 mg, 39%) as a yellow solid. NMR (400 MHz, Methanol-6/4) 5 8.68 (s, 1H), 7.56 (d, J= 8.1 Hz, 2H), 7.37-7.29 (m, 3H), 7.01-6.89 (m, 3H), 5.28 (dd, J= 12.5, 5.4 Hz, 1H), 4.52 (tt, J = 10.3, 5.2 Hz, 1H), 3.68 (td, J= 10.7, 5.3 Hz, 1H), 3.44-3.33 (m, 9H), 2.93-2.68 (m, 5H), 2.52 (s, 6H), 2.40-2.33 (m, 2H), 2.16-2.05 (m, 3H), 2.01 (d, J= 4.4 Hz, 5H), 1.85 (dt, J= 13.2, 6.5 Hz, 2H), 1.62-1.32 (m, 14H), 0.97 (t, J = 7.4 Hz, 6H). MS (ESI) for [M+H]’ calcd. m/z 877.17, found m/z 877.10; LC-MS: >96% purity.

Example 3: Synthesis of 3-(5-(3-(2-(4-(4-(4-(2-((3-Chloro-5-fluorophenyl)amino)-7-(trans-4- hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperazin-l-yl)piperidin-l- yl)ethoxy)prop-l-yn-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine- 2, 6-dione

[0227] To a solution of 3-(5-(3-(2-hydroxyethoxy)prop-l-yn-l-yl)-3-methyl-2-oxo-2,3- dihydr /-benzo imidazol-l-yl)piperidine-2, 6-dione (200 mg, 560 μmol) in dichloromethane (20 mL) was added TEA (227 mg, 312 μL, 2.2 mmol) at rt and then added methane sulfonyl chloride (128 mg, 86.6 μL, 1.1 mmol) at -20 °C. The reaction mixture was stirred at -20 °C for 1 h, quenched with water, and extracted with EtOAc (30 mL, 3x). The combined organic layer was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 5% MeOH/DCM)) to afford 2-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5- yl)prop-2-yn-l-yl)oxy)ethyl methane sulfonate (189 mg, 434 μmoL, 77 %) as a white solid. [0228] To a solution of ((3-chloro-5-fluorophenyl)amino)-5-(4-((4-(piperidin-4- yl)piperazin-l-yl)methyl)phenyl)-7H -pyrrolo[2,3 pyrimidin-7-yl)cyclohexan-l-ol (50.0 mg, 80.9 μmol) and 2-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro benzo[d]imidazol-5-yl)prop-2-yn-l-yl)oxy)ethyl methanesulfonate (70.4 mg, 162 μmol) in DMF (10 mL) was added triethylamine (49.1 mg, 67.6 μL, 485 μmol). The reaction mixture was heated at 90 °C for 15 h, quenched with water, and extracted with EtOAc (30 mL, 3x). The combined organic layer was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 20% MeOH/DCM) and reverse ISCO (water + 0.1% HCl/MeCN) to afford the title compound (10.0 mg, 10.4 μmol, 13%) as a yellow solid NMR (400 MHz, 8.93 (s, 1H), 7.84-7.65 (m, 4H), 7.53-7.42 (m, 3H), 7.27-7.14 (m, 2H), 7.00 (d, J= 8.2 Hz, 1H), 6.92 (dt, J = 8.6, 2.1 Hz, 1H) 5.26-5.18 (m, 1H),4.56- 4.44 (m, 2H),4.39 (s, 2H), 3.90-3.80 (m, 2H), 3.75-3.56 (m, 3H), 3.32 (s, 3H), 3.30-3.15 (m, 6H), 3.00-2.50 (m, 10H), 2.23-1.95 (m, 10H), 1.82-1.64 (m, 2H), 1.54-1.40 (m, 2H). MS (ESI) for [M+H]⁺ calcd. m/z 956.43, found m/z

957.40; LC-MS: 97% purity.

Example 4: Synthesis of 3-(5-(3-((l-((l-(4-(2-((3-Chloro-5-fluorophenyl)amino)-7-(trans-4- hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperidin-4-yl)methyl)piperidin-4- yl)oxy)prop-l -yn- 1 -y l)-3 -methyl-2-oxo-2,3 -dihydro- lH-benzo[d]imidazol- 1 -yl)piperidine-2,6- dione [0229] To a solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-lrt-benzo[d]imidazol-l- yl)piperidine-2, 6-dione (180 mg, 532 and tert-butyl 4-(prop-2-yn-l-yloxy)piperidine-l- carboxylate (255 mg, 1.1 mmol) into DMF (5.0 mL) was added Cs2CO3 (347 mg, 1.1 mmol), copper(I) iodide (10.1 mg, 53.2 , and P (37.4 mg, 53.2 μmol). The reaction mixture was stirred under nitrogen atmosphere at 80 °C for 3 h, quenched with cold brine (20 mL) at rt, and extracted water with EtOAc (30 mL, 3x). The combined organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 to 5% MeOH/DCM)) to afford tert- butyl 4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- -benzo[t midazol-5- yl)prop-2-yn-l-yl)oxy)piperidine-l -carboxylate (194 mg, 39 , 74%) as a light-yellow solid. MS (ESI) for [M+H] calcd. m/z 497.23, found m/z 497.20; t_R = 4.489 min. [0230] To a solution of tert-butyl 4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-l-yl)oxy)piperidine-l-carboxylate (200 mg, 403 μmol) in dichloromethane (20 mL) was added TFA (184 mg, 123 μL, 1.6 mmol). The reaction mixture was stirred at rt for 3 h, then concentrated under reduced pressure. The residue was triturated in Et₂O to form a brown precipitate. The product was filtered and washed with Et₂O to afford HC1 salt of (2,2,2-trifluoroacetaldehyde-3-(3-methyl-2-oxo-5-(3-(piperidin-4-yloxy)prop- l-yn-l-yl)-2,3-dihydro-lrt-benzo[d] imidazol-l-yl)piperidine-2, 6-dione as a brown solid. MS (ESI) for [M+H]⁺ calcd. m/z 397.18, found m/z 397.20; t_R = 2.250 min.

[0231] To a solution of (2,2,2-trifluoroacetaldehyde-3-(3-methyl-2-oxo-5-(3-(piperidin-4- yloxy)prop- 1 -yn- 1 -yl)-2, 3 -dihydr -benzo[d]imidazol- 1 -yl)piperidine-2, 6-dione ( 1/1 ) (132 mg, 267 μmol) in a mixture of dichloromethane (10 mL) and MeOH (1.0 mL) was added potassium acetate (122 mg, 1.2 mmol) followed by l-(4-(2-((3-chloro-5- fluorophenyl)amino)- hydroxycyclohexyl)-7H -pyrrolo[2,3-d]pyrimidin-5- yl)benzyl)piperidine-4-carbaldehyde (100 mg, 178 μmol). After 1.0 h, NaBH(OAc)3 (75.4 mg, 356 μmoL) was added. The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 20% MeOH/DCM) and reverse ISCO (water + 0.1% HCl/MeCN) to afford 3-(5-(3- ((l-((l-(4-(2-((3-chloro-5-fluorophenyl)amino) -4-hydroxycyclohexyl)-7rt-pyrrolo[2,3- pyrimidin-5-yl)benzyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)prop-l-yn-l-yl)-3-methyl-2- oxo-2, 3-dihydro-1H-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (44.0 mg, 47 μmol, 26%) as a yellow solid. NMR (400 MHz 6 8.93 (s, 1H), 7.79 (s, 1H), 7.76-7.68 (m, 3H), 7.53 (d, J= 8.0 Hz, 2H), 7.45 (dt, J= 11.1, 2.2 Hz, 1H), 7.30-7.13 (m, 2H), 7.01-6.93 (m, 2H), 5.21 (dd, J= 13.0, 5.4 Hz, 1H), 4.52-4.44 (m, 1H), 4.42-4.36 (m, 2H), 4.23 (s, 3H), 3.86-3.74 (m, 1H), 3.72-3.64 (m, 1H), 3.56-3.40 (m, 3H), 3.36-3.30 (m, 4H), 3.18-3.04 (m, 2H), 3.01-2.86 (m, 5H), 2.85-2.79 (m, 1H), 2.77-2.69 (m, 1H), 2.68-2.59 (m, 1H), 2.27-2.18 (m, 1H), 2.17-1.96 (m, 11H), 1.78-1.64 (m, 1H), 1.56-1.38 (m, 4H). MS (ESI) for [M+H]⁺ calcd. m/z 942.42, found m/z 942.40; LC-MS: 99% purity.

Example 5: Synthesis of 3-(5-(5-(4-((4-(4-(2-((2-Ethylbutyl)amino)-7-(trans-4- hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperazin-l-yl)methyl)-lH-l,2,3- triazol-l-yl)pentyl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione

[0232] To a solution of Zr6/«_ls -ethylbutyl)amino)-5-(4-(piperazin-l- ylmethyl)phenyl)- pyrrolo[2,3 yrimidin-7-yl)cyclohexan-l-ol trihydrochloride (400 mg, 667 μmol) in THF (15 mL) was added TEA (337 mg, 465 μL, 3.3 mmol) and 3 -bromoprop- 1- yne (496 mg, 359 μL, 80% Wt, 3.3 mmol). The reaction mixture was stirred at rt for 18 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 1 tol0% MeOH/DCM) to afford 4-(2-((2-ethylbutyl)amino)-5- (4-((4-(prop-2-yn-l-yl)piperazin-l-yl)methyl)phenyl) -pyrrolo pyrimidin-7- yl)cyclohexan-l-ol (333 mg, 630 μmol, 95%) as a yellow solid. MS (ESI) for [M+H]⁺ : calcd. m/z 424.15, found m/z 424.30; tR = 3.058 min.

[0233] To a solution of 3-(5-(5-hydroxypentyl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[tZ]imidazol-l-yl)piperidine-2, 6-dione (351 mg, 1.0 mmol) in dichloromethane (10 mL) was added A-ethyl-A-isopropylpropan-2-amine (394 mg, 531 μL, 3.0 mmol), and methanesulfonyl chloride (175 mg, 118 μL, 1.5 mmol) at 0°C. The reaction mixture was stirred at 0 °C for 1, quenched with water, and extracted with di chloromethane (3x). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 6% methanol/DCM) to afford 5-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)pentyl methanesulfonate (42.0 mg, 99 μmol, 9.8%) as a white solid. [0234] To a solution of 5-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[fl/]imidazol-5-yl)pentyl methanesulfonate (500 mg, 1.2 mmol) in a mixture of di chloromethane (20 mL) and DMSO (5.0 mL) was added sodium azide (384 mg, 5.9 mmol). The reaction mixture was heated at 40 °C for 18 h, quenched with water, and extracted with dichloromethane (3x). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 6% methanol/DCM) to afford 3-(5-(5-azidopentyl)-3-methyl-2- oxo-2,3-dihydro-l/f-benzo[J]imidazol-l-yl)piperidine-2, 6-dione (200 mg, 540 μmol, 46%) as a white solid.

[0235] To a solution of trans -4-(2-((2-ethylbutyl)amino)-5-(4-((4-(prop-2-yn-l-yl)piperazin- l-yl)methyl)phenyl) pyrrolo[2,3 pyrimidin- y )cyclohexan-l-ol (100 mg, 189 μmol) and 3-(5-(5-azidopentyl)-3-methyl-2-oxo-2,3-dihydro- -benz midazol- l -yl)piperidine-2,6- dione (186 mg, 502 μmol) in a mixture (16 mL) and (2.0 mL) was added (12.1 mg, 75.7 μmol) and sodium -l,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5- dihydrofuran-3-olate (30.0 mg, 151 μmol). The reaction mixture was stirred at rt for 18 h, quenched with water, and extracted with dichloromethane (3x). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 20% MeOH/DCM) and a reverse ISCO column (water + 0.1% HCl/MeCN) to afford the title compound (38.0 mg, 42 μmol, 22%) as a yellow solid. ' H NMR (400 MHz, Methanol- 8 8.80 (s, 1H), 8.11 (d, J= 27.9 Hz, 1H), 7.88 (s, 1H), 7.73 (d, J= 7.7 Hz, 2H), 7.67 (d, 7.7 Hz, 2H), 6.99-6.82 (m, 3H), 5.28

(dd, J= 12.6, 5.3 Hz, 1H),4.64- 4.54 (m, 1H), 4.46-4.33 (m, 6H), 3.76-3.65 (m, 1H), 3.64-3.42 (m, 10H), 3.39 (s, 3H), 2.86-2.71 (m, 2H), 2.68-2.60 (m,2H), 2.19-2.09 (m, 3H), 2.08-1.99 (m, 4H), 1.95-1.85 (m, 2H), 1.72-1.58 (m, 3H), 1.54-1.38(m, 6H), 1.32-1.24 (m, 3H), 0.99 (t, J= 7.4 Hz, 6H). MS (ESI) for [M+H]⁺ calcd. m/z 899.53, found m/z 899.50; LC-MS:> 97% purity.

Example 6: Synthesis of 3-(5-(4-((l-(4-(2-((3-Chloro-5-fluorophenyl)amino)-7-(trans-4- hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperidin-4-yl)methyl)piperazin-l- yl)- 1 -oxoisoindolin-2-yl)piperidine-2, 6-dione

[0236] To a solution of l-(4-(2-((3-chloro-5-fluorophenyl)amino)-7 hydroxycyclohexyl)-7H -pyrrolo[2,3 pyrimidin-5-yl)benzyl)piperidine-4-carbaldehyde (150 mg, 267 μmol) and 3-(l-oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione (87.6 mg, 266.9 μmol) in a mixture of di chloromethane (10 mL) and MeOH (1.0 mL) was added potassium acetate (183 mg, 1.9 mmol). After 1.0 h, ( ) (170 mg, 801 μmol) was added. The reaction mixture was stirred at rt for 18 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 20% MeOH/DCM) and a reverse ISCO column (water + 0.1% HCl/MeCN) to afford the title compound (36.0 mg, 41.2 μmol, 15%) as a yellow solid. 'H NMR (400 MHz, 8.97 (s, 1H), 7.84 (s, 1H), 7.77-7.71 (m, 3H), 7.67-7.65 (m, 1H), 7.59-7.56 (m, 2H), 7.48 (dt, J = 11.0, 2.2 Hz, 1H), 7.13-7.07 (m, 2H), 6.98 (dt, J = 8.6, 2.1 Hz, 1H), 5.01 (dd, J= 13.4, 5.2 Hz, 1H), 4.56-4.45 (m, 1H), 4.40-4.24 (m, 4H), 4.00-3.88 (m, 2H), 3.50-3.44 (m, 2H), 3.10-3.06 (m, 2H), 3.02-2.95 (m, 2H), 2.87-2.66 (m, 3H), 2.49-2.31 (m, 2H), 2.28-2.14 (m, 2H), 2.13-1.96 (m, 10H), 1.61-1.44 (m, 4H), 1.28-1.25 (m, 2H), 0.86-0.84 (m, 1H). MS (ESI) for [M+H]⁺ ( calcd. m/z 874.39, found m/z 874.40; LC-MS: 97% purity.

Example 7: Synthesis of 3-(5-((4-(4-(4-(2-((2-Ethylbutyl)amino)-7-(trans-4-hydroxycyclohexyl)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperazin- l-yl)piperi din-1 -yl)methyl)-3-methyl-2-oxo- 2,3 -dihydro- lH-benzo[d]imidazol- 1 -yl)piperidine-2, 6-dione

[0238] To a solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-17/-benzo[<7]imidazol-l- yl)piperidine-2, 6-dione (500 mg, 1.5 mmol) and 3-oxoben sothiazole-2(3 )-carbaldehyde 1,1-dioxide (625 mg, 3.0 mmol) in DMF (10 mL) was added 235 mg, 2.2 mmol), diacetoxypalladium (10.0 mg, 44.4 μmol), l,4-bis(diphenylphosphaneyl)butane (28.4 mg, 66.5 μmol), and tri ethylsilane (344 mg, 472 μL, 3.0 mmol). The reaction mixture was stirred under nitrogen atmosphere at rt for 10 min, heated at 75 °C for 15 h, quenched with water (20 mL), and extracted with EtOAc (30 mL, 3x). The combined organic layer was washed with brine, dried , and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 8% methanol/DCM) to afford l-(2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro benzo midazole-5-carbaldehyde (333 mg, 1.2 mmol, 78%) as a white solid. MS (ESI) for [M+H]⁺ calcd. 288.09, found m/z 288.10; tR = 2.663 min.

[0239] To a solution of (2-((2-ethylbutyl)amino)-5-(4-((4-(piperidin-4-yl)piperazin- l-yl)methyl)phenyl)-7H -pyrrolo[2, pyrimidin-7-yl)cyclohexan-l-ol (230 mg, 401 μmol) in DMF (10 mL) was added TEA (203 mg, 279 μL, 2.0 mmol), acetic acid (72.2 mg, 68.8 μL, 1.2 mmol), and l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro benzo ]imidazole-5- carbaldehyde (115 mg, 401 μmol). After 1.0 h, NaBH(OAc)3 (170 mg, 802 μmol) was added. The reaction mixture was stirred at rt for 18 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 20% MeOH/DCM) and a reverse ISCO column (water + 0.1% HCl/MeCN) to afford the title compound 115 (38.0 mg, 45 μmol, 11%) as a yellow solid. NMR (400 MHz, 8.81 (s, 1H), 7.92 (s, 1H), 7.75 (d, J= 8.0 Hz, 2H), 7.67 (d, J= 8.1 Hz, 2H), 7.41 (s, 1H), 7.29- 7.08 (m, 2H), 5.36 (dd, J= 12.3, 5.5 Hz, 1H),4.65- 4.52(m, 2H), 4.46-4.30 (m, 4H), 3.78-3.66 (m, 2H), 3.65-3.56 (m, 3H), 3.55-3.39 (m, 10H), 3.15-3.00 (m, 2H), 2.95-2.75 (m, 3H), 2.36- 2.22 (m, 2H), 2.18-1.98 (m, 9H), 1.63 (p, J= 6.3 Hz, 1H), 1.56-1.35 (m, 7H), 0.99 (t, J= 7.4 Hz, 6H). MS (ESI) for [M+H]⁺ calcd. m/z 845.51, found m/z 845.45; LC-MS: >95% purity.

Example 8: Synthesis of3-(5-((3-((4-((4-(4-(2-((3-Chloro-5-fluorophenyl)amino)-7-(trans-4- hydroxycyclohexyl)-7H-pyrrolo[2,3 -d]pyrimidin-5-yl)benzyl)piperazin- 1 -yl)methyl)piperidin- 1 - yl)methyl)azetidin-l-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2, 6-dione

[0240] To a solution of trans-4-(2-((3-chloro-5-fluorophenyl)amino)-5-(4-(piperazin-l- ylmethyl)phenyl)- pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-l-ol trihydrochloride (150 mg, 233 μmol) in MeOH (15 mL) was added TEA (94.2 mg, 130 μL, 931 μmol), acetic acid (55.9 mg, 53.2 μL, 931 μmol), and tert-butyl 4-formylpiperidine-l-carboxylate (199 mg, 931 μmol). After 1.0 h, sodium triacetoxyborohydride (98.7 mg, 466 μmol) was added. The reaction mixture was heated at 55 °C for 15 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 15% MeOH/DCM) to afford tert- butyl 4-((4-(4-(2-((3-chloro-5-fluorophenyl)amino)-7-(trans-4-hydroxycyclohexyl)-7H - pyrrolo[2,3 pyrimidin-5-yl)benzyl)piperazin-l-yl)methyl)piperidine-l-carboxylate (135 mg, 184 μmol, 79%) as a light-yellow solid.

[0241] To a solution of tert-butyl 4-((4-(4-(2-((3-chloro-5-fluorophenyl)amino)-7-(trans-4- hydroxycyclohexyl)-7H -pyrrol pyrimidin-5-yl)benzyl)piperazin-l-yl)methyl)piperidine- 1-carboxylate (235 mg, 321 μmol) in dichloromethane (15 mL) was added a 4.0 N solution of HC1 in 1,4-dioxane (325 μL, 1.3 mmol).The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was triturated in to form a yellow precipitate. The product was filtered and washed with Et₂O to afford HC1 salt of chloro-5-fluorophenyl)amino)-5-(4-((4-(piperidin-4-ylmethyl)piperazin-l-yl)methyl)phenyl)-7H - pyrrolo[2, pyrimidin-7-yl)cyclohexan-l-ol, which was used in the next step without further purification.

[0242] To a solution of trans -4-(2-((3-chloro-5-fluorophenyl)amino)-5-('4-((4-(piperidin-4- ylmethyl)piperazin-l-yl)methyl)phenyl) pyrrolo[2,3 pyrimidin-7-yl)cyclohexan-l-ol (100 mg, 158 μmol) in MeOH (15 mL) was added TEA (96.0 mg, 132 μL, 949 μmol), acetic acid (38.0 mg, 36.2 μL, 633 μmol), and tert-butyl 3 -formylazetidine- 1 -carboxylate (58.6 mg, 316 μmol). After 1.0 h, (67.0 mg, 316 μmol) was added. The reaction mixture was heated at 55 °C for 15 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 15% MeOH/DCM) to afford tert-butyl

3-((4-((4-(4-(2-((3-chloro-5-fluorophenyl)amino)-7-(/ra«5-4-hydroxycyclohexyl) pyrrolo[2, ]pyrimidin-5-yl)benzyl)piperazin-l-yl)methyl)piperidin-l-yl)methyl) azetidine-1- carboxylate (88.0 mg, 0.10 mmol, 69%) as a light-yellow solid. MS (ESI) for [M+H]⁺ : calcd. m/z 801.43, found m/z 801.40, tR = 3.291 min.

[0243] To a solution of tert-butyl 3-((4-((4-(4-(2-((3-chloro-5-fluorophenyl)amino)-7

4-hydroxycyclohexyl)-7H -pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperazin-l-yl)methyl)piperidin- l-yl)methyl)azetidine-l -carboxylate (88.0 mg, 110 μmol) in dichloromethane (15 mL) was added a 4.0 N solution of HC1 in 1,4-dioxane (137 μL, 549 μmol). The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was triturated in Et?O to form a yellow precipitate. The product was filtered and washed with to afford HC1 salt -(5-(4-((4-((l-(azetidin-3-ylmethyl)piperidin-4-yl)methyl)piperazin-l- yl)methyl)phenyl)-2-((3-chloro-5-fluorophenyl)arnino)-7H -pyrrolo[2,3-d]pyrimidin-7- yl)cyclohexan-l-ol, which was used in the next step without further purification.

[0244] To a solution of trans -4-(5-(4-((4-(( l-(azetidin-3-ylmethyl)piperidin-4- yl)methyl)piperazin-l-yl)methyl)phenyl)-2-((3-chloro-5-fluorophenyl)amino)-7H -pyrrolo[2,3- ]pyrimidin-7-yl)cyclohexan-l-ol (30.0 mg, 42.8 μmol) in DMF (10 mL) was added TEA (8.7 mg, 12.0 μL, 85.6 μmol), 1 -(2, 6-dioxopiperi din-3 -yl)-3 -methyl -2-oxo-2, 3 -dihydro- 1H- benzo imidazole-5-carbaldehyde (30.7 mg, 107 μmol), and acetic acid (10.3 mg, 9.8 μL, 171 μmol). After 1.0 h, 18.1 mg, 85.6 μmol) was added. The reaction mixture was stirred at rt for 18 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 20% MeOH/DCM) and a reverse ISCO column (water + 0.1% HCl/MeCN) to afford the title compound 116 (10.0 mg, 10.3 μmol, 24%) as a yellow solid. 'H NMR (400 MHz, C 1 (s, 1H), 7.82-7.75 (m, 2H), 7.71 (d, J= 8.1 Hz, 2H), 7.50 (d, J= 8.3 Hz, 2H), 7.44 (dt, J= 11.1, 2.2 Hz, 1H), 7.20 (s, 1H), 7.10 (q, J = 7.4 Hz, 2H), 6.96 (dt, J= 8.6, 2.1 Hz, 1H), 5.26 (dd, J= 13.1, 5.5 Hz, 1H), 4.54-4.34 (m, 3H), 4.20-4.06 (m, 4H), 3.97 (dd, J= 11.0, 7.0 Hz, 2H), 3.69 (ddt, J= 11.2, 8.0, 3.8 Hz, 1H), 3.54- 3.15 (m, 16H), 2.96-2.56 (m, 8H), 2.21-1.96 (m, 9H), 1.53-1.34 (m, 4H). MS (ESI) for [M+H]⁺ calcd. m/z 972.47, found m/z 972.40; LC-MS: 100% purity.

Example 9: Synthesis of 3-(5-((4-(3-(4-(4-(2-((2-Ethylbutyl)amino)-7-(trans-4- hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperazin-l-yl)propoxy)piperidin- l-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione

[0245] To a solution of utyl 4-(allyloxy)piperidine-l -carboxylate (4.50 g, 18.7 mmol) in THF (100 mL) was added 9-borabicyclo[3.3.1]nonane (3.40 g, 55.9 mL, 28 mmol) under nitrogen atmosphere at 0 °C. The reaction mixture was heated at 70 °C for 8 h, then added a 4.0 N aqueous solution of sodium hydroxide (3.58 g, 22.4 mL, 89.5 mmol), hydrogen peroxide (25.4 g, 22.9 mL, 30% Wt, 224 mmol), and EtOH (10 mL). The reaction was stirred at rt for 16 h, quenched water, and extracted with EtOAc. The combined organic layer was washed with brine, dried ( , and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 80% EtOAc/n-hexane) to afford tert-butyl 4-(3- hydroxypropoxy)piperidine-l -carboxylate (2.0 g, 7.7 mmol, 41%) as a colorless oil.

[0246] To a solution of l 4-(3-hydroxypropoxy)piperidine-l-carboxylate (200 mg, 771 μmol) in dichloromethane (5.0 mL) was added a 4.0 N solution of HC1 inl,4-dioxane (1.0 mL, 3.9 mmol). The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was used in the next step without further purification.

[0247] To a solution of 3-(piperidin-4-yloxy)propan-l-ol hydrochloride (372 mg, 1.9 mmol) in DMF (10 mL) was added TEA (256 mg, 353 μL, 2.5 mmol) followed by acetic acid (152 mg, 145 μL, 2.5 mmol) and l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-177- benzo[d]imidazole-5-carbaldehyde (364 mg, 1.3 mmol). After 1.0 h, NaBH(OAc)3 (537 mg, 2.5 mmol) was added. The reaction mixture was stirred at rt for 18 h, then concentrated under reduced pressure. The residue was purified by purified by an ISCO silica gel column (gradient elution, gradient 0 to 15% MeOH/DCM) to afford 3-(5-((4-(3-hydroxypropoxy)piperidin-l- yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (242 mg, 562 μmol, 44%) as a white solid. MS (ESI) for [M+H]⁺ : calcd. m/z 431.22, found m/z 431.20; tR = 1.821 min.

[0248] To a solution of 3-(5-((4-(3-hydroxypropoxy)piperidin-l-yl)methyl)-3-methyl-2-oxo- 2, 3 -dihydro- -benz ]imidazol-l-yl)piperidine-2, 6-dione (550 mg, 1.3 mmol) in di chloromethane (20 mL) was adde ethyl-A-isopropylpropan-2-amine (495 mg, 668 μL, 3.8 mmol) and methane sulfonyl chloride (220 mg, 148 μL, 1.9 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, quenched with water, and extracted with dichloromethane (3x). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 6% methanol/DCM) to afford 3-((l-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- -benzo[d]imidazol-5-yl)methyl)piperidin-4-yl)oxy)propyl methane sulfonate (498 mg, 979 μmol, 77%) as a white solid. MS (ESI) for [M+H]⁺ calcd. m/z 509.20, found m/z 509.20; tR = 2.390 min.

[0249] To a solution of trans -4-(2-((2-ethylbutyl)amino)-5-(4-(piperazin-l- ylmethyl)phenyl) -pyrrolo[2,3 pyrimidin-7-yl)cyclohexan-l-ol trihydrochloride (100 mg, 167 μmol) in DMF (10 mL) was added K2CO3 (69.1 mg, 500 μmol) and 3 -((1 -((1 -(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro -benzo[d]imidazol-5-yl)methyl)piperi din-4- yl)oxy)propyl methane sulfonate (170 mg, 333 μmol). The reaction mixture was stirred at 90 °C for 15 h, then concentrated under reduced pressure. The residue was purified by an silica gel column (gradient elution, gradient 0 to 20% MeOH/DCM) and a reverse ISCO column (water + 0.1% HCl/MeCN) to afford the title compound 117 (15 mg, 17 μmol, 10%) as a yellow NMR (400 MHz, 8.80 (s, 1H), 7.85 (s, 1H), 7.77-7.70 (m, 4H), 7.47-7.37 (m, 1H), 7.32-7.20 (m, 1H), 7.18-7.12 (m, 1H), 5.33 (dd, J= 12.3, 5.4 Hz, 1H), 4.64-4.53 (m, 1H), 4.52-4.42 (m, 2H), 4.40-4.30 (m, 2H), 3.88-3.53 (m, 12H), 3.51-3.36 (m, 6H), 3.27-3.14 (m, 2H), 3.08-2.96 (m, 1H), 2.92-2.84 (m, 1H), 2.84-2.73 (m, 2H), 2.29-1.86 (m, 12H),1.82- 1.70 (m, 1H), 1.66-1.56 (m, 1H), 1.56-1.36 (m, 7H), 1.34-1.22 (m, 1H), 0.98 (t, J= 7.4 Hz, 6H).MS (ESI) for [M+H]⁺ calcd. m/z 903.55, found m/z 903.50; LC-MS: >97% purity.

Example 10: Synthesis of 3-(5-(4-(5-(4-(4-(2-((3-Chloro-5-fluorophenyl)amino)-7-(trans-4- hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperazin-l-yl)-5- oxopentyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0250] To a solution of 3-(l-oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione (250 mg, 761 μmol) in MeCN (20 mL) was added 7V-ethyl-7V-isopropylpropan-2-amine (394 mg, 530 μL, 3.0 mmol), tert-butyl 5-bromopentanoate (361 mg, 1.5 mmol), and sodium iodide (11.4 mg, 76.1 μmol). The reaction mixture was heated at 80 °C for 18 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 10% MeOH/DCM)) to afford tert-butyl 5-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperazin-l-yl)pentanoate (200 mg, 413 μmol, 54%) as a white solid. MS (ESI) for [M+H]⁺ : calcd. m/z 485.27, found m/z 485.30; tR = 2.606 min.

[0251] To a solution of tert-butyl 5-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperazin-l-yl)pentanoate (200 mg, 413 μmol) in di chloromethane (20 mL) was added 2,2,2- trifluoroacetaldehyde (202 mg, 2.1 mmol). The reaction mixture was stirred at rt for 18 h, then concentrated under reduced pressure. The residue was used in the next step without further purification. MS (ESI) for [M+H]⁺ calcd. m/z 429.21, found m/z 429.20; tR = 1.727 min.

[0252] To a solution of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l- yl)pentanoic acid (104 mg, 243 μmol) in DMF (10 mL) was added DIPEA (193 mg, 260 μL, 1.5 mmol) and HATU (114 mg, 299 μmol). After 1.0 h, trans -4-(2-((3-chloro-5- fluorophenyl)amino)-5-(4-(piperazin-l-ylmethyl)phenyl) -pyrrolo[2,3-J]pyrimidin-7- yl)cyclohexan-l-ol (100 mg, 187 μmol) was added. The reaction mixture was stirred at rt for 18 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 20% MeOH/DCM) and a reverse ISCO column (water + 0.1% HCl/MeCN) to afford the title compound (76.0 mg, 80 μmol, 43%) as a yellow solid. 'H NMR (400 MHz, C 8.95 (s, 1H), 7.80 (s, 1H), 7.78-7.71 (m, 3H), 7.68-7.63 (m, 1H), 7.55 (d, J= 8.3 Hz, 2H), 7.48 (t, J= 2.1 Hz, 1H), 7.09 (dd, J= 6.4, 2.4 Hz, 2H), 6.98-6.93 (m, 1H), 5.00 (dd, J= 13.4, 5.2 Hz, 1H), 4.56-4.44 (m, 2H), 4.38-4.25 (m, 4H), 3.95-3.88 (m, 4H), 3.72-3.62 (m, 2H), 3.61-3.50 (m, 3H), 3.21-2.99 (m, 8H), 2.91-2.67 (m, 3H), 2.50-2.35 (m, 3H), 2.15-1.98 (m, 7H), 1.76-1.67 (m, 2H), 1.57 (q, J= 7.4 Hz, 2H), 1.51-1.41 (m, 2H).MS (ESI) for [M+H]⁺ ( 7 calcd. m/z 945.43, found m/z 945.40; LC-MS: 98% purity.

Example 11 : Synthesis of 3-(5-(4-(3-(4-(4-(2-((3-Chloro-5-fluorophenyl)amino)-7-(trans-4- hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperazin-l-yl)propyl)piperazin-l- yl)- 1 -oxoisoindolin-2-yl)piperidine-2, 6-dione

[0253] To a solution of 3-(l-oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione (300 mg, 914 μmol) in MeCN (10 mL) was added ethyl-iV-isopropylpropan-2-amine (472 mg, 637 μL, 3.7 mmol), 3 -bromopropan- l-ol (381 mg, 2.7 mmol), and sodium iodide (13.7 mg, 91.4 μmol). The reaction mixture was heated at 80 °C for 18 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 10% MeOH/DCM)) to afford 3-(5-(4-(3-hydroxypropyl)piperazin-l-yl)-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (200 mg, 518 μmol, 57%) as a white solid.

[0254] To a solution of 3-(5-(4-(3-hydroxypropyl)piperazin-l-yl)-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (200 mg, 518 μmol) in a mixture of THF (10 mL) and DMF (1.0 mL) was added TEA (210 mg, 289 μL, 2.1 mmol), and methanesulfonyl chloride (119 mg, 80.1 μL, 1.0 mmol) at -20 °C. The reaction mixture was stirred at -20 °C for 1 h, quenched with water, and extracted with di chloromethane (3x). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 6% methanol/DCM) to afford 3-(4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)propyl methanesulfonate (164 mg, 353 μmol, 68%) as a white solid. MS (ESI) for [M+H]⁺ ): calcd. m/z 465.17, found m/z 465.20; tR = 1.810 min.

[0255] To a solution of trans-4-(2-((3-chloro-5-fluorophenyl)amino)-5-(4-(piperazin-l- ylrnethyl)phenyl)-7H -pyrrolo[2,3 pyrimidin-7-yl)cyclohexan-l-ol (140 mg, 262 μmol) in DMF (10 mL) was added TEA (181 mg, 249 μL, 1.3 mmol) and 3-(4-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)piperazin-l-yl)propyl methane sulfonate (158 mg, 340 μmol). The reaction mixture was heated at 90 °C for 18 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 20% MeOH/DCM) and a reverse ISCO column (water + 0.1% HCl/MeCN) to afford the title compound 124 (13.0 mg, 14 μmol, 5.5%) as a yellow solid. ^X R (400 MHz, 8.91 (s, 1H), 7.81 (s, 1H), 7.77-7.67 (m, 3H), 7,67-7,61 (m, 1H), 7.55-7.49 (m, 2H), 7.43 (dt, J= 11.0, 2.1 Hz, 1H), 7.12- 7.05 (m, 2H), 6.97 (dt, J= 8.6, 2.0 Hz, 1H), 4.99 (dd, J= 13.4, 5.2 Hz, 1H), 4.52-4.44 (m, 1H), 4.41-4.25 (m, 5H), 3.98-3.80 (m, 2H), 3.75-3.62 (m, 2H), 3.60-3.25 (m, 10H), 3.11 (dt, 32.1, 8.1 Hz, 6H), 2.84-2.69 (m, 2H), 2.40-2.31 (m, 1H), 2.18-1.95 (m, 9H), 1.52-1.38 (m 2H), 1.25- 1.10 (m, 1H). MS (ESI) for [M+H]⁺ ( calcd. m/z 903.42, found m/z 903.40; LC-MS: 97% purity.

Example 12: Synthesis of (2S,4R)-l-((S)-2-(7-(4-(4-(2-((3-Chloro-5-fluorophenyl)amino)-7- (trans-4-hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzyl)piperazin-l- yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

[025 6] To a solution o -4-(2-((3-chloro-5-fluorophenyl)amino)-5-(4-(piperazin-l- ylmethyl)phenyl)-7H -pyrrolo[2, pyrimidin-7-yl)cyclohexan-l-ol (250 mg, 467 μmol) in MeCN (25 mL) was added (194 mg, 1.4 mmol) and tert-butyl 7-bromoheptanoate (206 mg, 776 μmol). The reaction mixture was heated at 80 °C for 18 h, then concentrated under the reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 15% MeOH/DCM)) to afford te/7-butyl 7-(4-(4-(2-((3-chloro-5- fluorophenyl)amino) 7H -pyrrolo[2,3 pyrimidin-5- yl)benzyl)piperazin-l-yl)heptanoate (250 mg, 348 μmol, 90%) as a white solid.

[0257] To a solution of tert-butyl 7-(4-(4-(2 hydroxycyclohexyl)-7H -pyrrolo[2,3- pyrimidin-5-yl )benzyl)piperazin- l -yl)heptanoate (250 mg, 348 μmol) in dichloromethane (15 mL) was added 2,2,2-trifluoroacetic acid (198 mg, 1.7 mmol). The reaction mixture was stirred at rt for 18 h, then concentrated under reduced pressure. The residue was triturated with diethyl ether to obtain a yellow solid which was used in the next step without further purification.

[0258] To a solution of 7-(4-(4-(2-((3-chloro-5-fluorophenyl)amino)-7- hydroxycyclohexyl -pyrrolo[2,3-t/]pyrimidin-5-yl)benzyl)piperazin-l-yl)heptanoic acid (250 mg, 377 μmol) in DMF (10 mL) was added DIPEA (390 mg, 525 μL, 3.0 mmol) and HATU (172 mg, 452 μmol). After 1.0 h, HC1 salt of VHL ligand (202 mg, 432 μmol) was added. The reaction mixture was stirred at rt for 18 h, then concentrated under reduced pressure. The residue was purified by an ISCO silica gel column (gradient elution, gradient 0 to 20% MeOH/DCM) and a reverse ISCO column (water + 0.1% HCl/MeCN) to afford the title compound (77.0 mg, 72 μmol, 19 %) as a yellow solid. NMR (400 MHz 9.63 (s, 1H), 8.96 (s, 1H), 7.91 (s, 1H), 7.76-7.69 (m, 3H), 7.60 (d, J= 8.3 Hz, 2H), 7.47-7.36 (m, 5H), 7.05-7.00 (m, 1H), 4.52-4.41 (m, 6H), 4.32 (s, 2H), 3.87-3.77 (m, 2H), 3.74-3.43 (m, 10H), 3.17-3.11 (m, 2H), 2.59 (s, 1H), 2.50 (s, 3H), 2.23-2.18 (m, 2H), 2.09-1.97 (m, 6H), 1.68-1.61 (m, 2H), 1.53-1.41 (m, 4H), 1.31-1.22 (m, 4H), 0.89 (s, 9H). MS (ESI) for [M+H]⁺ calcd. m/z 1075.51, found m/z 1075.40; LC-MS: 97% purity.

Example 13: Synthesis of 2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-N-(3- (2-(2-((6-(4-(4-(2-((2-ethylbutyl)amino)-7-(trans-4-hydroxycyclohexyl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)benzyl)piperazin-l-yl)hexyl)oxy)ethoxy)ethoxy)propyl)acetamide [0259] To a solution of 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-A-(3- (2-(2-((6-iodohexyl)oxy)ethoxy)ethoxy)propyl)acetamide (15.0 mg, 21.8 μmol) in DMF (0.20 mL) was added 4-(2-((2-ethylbutyl)amino)-5-(4-(piperazin-l-ylmethyl)phenyl)-7H - pyrrolo[2,3 pyrimidin-7-yl)cyclohexan-l-ol (12.8 mg, 26.2 μmol) and DIPEA (9.50 μL, 54.5 μmol). The reaction mixture was heated at 75 °C for 4.0 h, then quenched with MeOH (3.0 mL). After addition of silica gel, the mixture was concentrated under reduced pressure. The residue was purified by ISCO silica gel column chromatography (20% gradient, 0.1% NH3) to afford the title compound (13.6 mg, 12.9 μmol, 59%) as an off-white solid. 'H NMR (400 MHz, ) .77 (s, 1H), 7.78-7.69 (m, 1H), 7.58-7.47 (m, 4H), 7.33 (d, J= 7.9 Hz, 2H), 7.19 (d, J= 8.4 Hz, 1H), 7.03 (s, 1H), 5.36 (s, 1H), 4.95 (dd, J= 12.3, 5.4 Hz, 1H), 4.63 (s, 2H), 4.54 (tt, J= 12.1, 3.8 Hz, 1H), 3.76 (tt, J= 11.0, 4.2 Hz, 1H), 3.69-3.36 (m, 18H), 2.97- 2.35 (m, 13H), 2.13 (td, J= 13.5, 4.1 Hz, 5H), 1.94-1.80 (m, 4H), 1.63-1.18 (m, 17H), 0.95 (t, J = 7.4 Hz, 6H); MS (ESI) for [M+H]⁺ : calcd. m/z 1050.60, found m/z 1050.60; LC-MS: 97% purity. [0260] 697 B-cell acute lymphoblastic leukemia cells were cultured in the presence of test compound at concentrations of 5 nM, 10 nM, 50 nM, 250 nM, 500 nM or 1000 nM for 16-24 hours. Controls were treated with an equivalent volume of vehicle. Cell lysates were prepared in 50 mM HEPES pH 7.5, 150 mM NaCl, 10 mM EDTA, 10% glycerol, and 1% Triton X-100, supplemented with protease inhibitors (Roche Molecular Biochemicals, #11836153001).

MERTK and TYRO3 proteins were detected by immunoblot using anti-MERTK (Abeam, #ab52968) or anti-TYRO3 (Cell Signaling, #5585) antibodies. GAPDH or tubulin were detected as loading controls.

[0261] Table 12 provides MERTK and TYRO3 degradation results for compounds 1-130 synthesized following procedures described in the Examples (Note: ++ means > 50% degradation below 250 nM; + means >50 % degradation above 250 nM; - means inactive.)

[0262] Many modifications and other embodiments of the inventions set forth herein will come to mind to one skilled in the art to which the inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the inventions are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

What is claimed is:

1. A TAM degrader comprising: a residue of a compound of Formula A, I, II, or III; a Linking Group (L), and a E3 ubiquitin binding group (UBG); and having the structure:

2. The degrader of claim 1, wherein the compound is of Formula I: wherein:

D is selected from the group consisting of a bond , -O-, -CO-, -N(H)- and -S(O₂)-; E is a residue of a moiety to which L is covalently attached, and is selected from the group consisting of:

-NR^E1R^E2, wherein R^E1 is hydrogen or C₁-C₆ alkyl, and R^E2 is substituted or unsubstituted C₁-C₆ alkyl; and, XHs CH or N;

Q is selected from the group consisting of:

C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, nitro, C₁-C₆-haloalkyl, cyano, and N(R^4b)2, wherein each R^4b is independently selected from the group consisting of hydrogen and C₁-C₆-alkyl; R¹ and R² or R² and R³ together with the carbon to which each is attached form a ring selected from the group consisting of substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted C₃-C₈ aryl, and substituted or unsubstituted C₃-C₈ heteroaryl, wherein the heteroatom is 0, N, or S; and,

C₁-C₆ alkoxy, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, N-alkoxycarbonyl and C₁-C₆ alkylhydroxy; or a pharmaceutically acceptable salt thereof.

3. The degrader of claim 2, wherein the compound is of Formula I’ : wherein:

D is selected from the group consisting of a bond, (CH₂)_m, -0-, -CO-, -N(H)- and -S(02)-;

-NR^E1R^E2, wherein R^E1 is hydrogen or C₁-C₆ alkyl, and R^E2 is substituted or unsubstituted C₁-C₆ alkyl; and, X² is CH₂, 0, S, or N-R⁶, wherein R⁶ is hydrogen, substituted or unsubstituted C₁-C₆ alkyl, or C₃-C₉ cycloalkyl;

Q is selected from the group consisting of wherein, G is S, 0 or N; m is 0, 1, or 2; j is 0, 1, 2, or 3; p is 0 or 1; q is 0 or 1;

C₁-C₆ alkoxy, mono(C₁-C₆)alkylamino and di(C₁-C₆)alkylamino; or a pharmaceutically acceptable salt thereof.

4. The degrader of claim 1, wherein, UisN;

XisC;

Y is N; and

A is CH, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula 1-1:

5. The degrader of claim 1, wherein,

UisN;

XisC;

Y is N; and

AisN, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula 1-2:

6. The degrader of claim 1, wherein,

UisN;

XisN;

Y is C; and

AisN, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula 1-3:

7. The degrader of claim 1, wherein, UisN;

XisN; Y is C; and

A is CH, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of

Formula 1-4:

8. The degrader of claim 1, having a structure of Formula la: or a pharmaceutically acceptable salt thereof.

9. The degrader of claim 1, having a structure of Formula lb:

or a pharmaceutically acceptable salt thereof.

10. The degrader of claim 1, having a structure of Formula la-3, or Ib-3 :

or a pharmaceutically acceptable salt thereof.

11. The degrader of claim 1, having a structure of Formula la-4: or a pharmaceutically acceptable salt thereof.

12. The degrader of claim 1, having a structure of Formula la-5 or la-6:

or a pharmaceutically acceptable salt thereof.

13. The degrader of claim 1 , having a structure of F ormula Ic-2 or Ic-3 :

or a pharmaceutically acceptable salt thereof.

14. The degrader of any one of claims 10-13, wherein X² is N*, wherein N* is the point of attachment to L.

15. The degrader of any one of claims 1-14, wherein

R³ is selected from the group consisting of halogen, C₁-C₆ haloalkyl and C₁-C₆ alkoxy.

16. The degrader of claim 15, wherein R¹ and R³ are each halogen, or CF₃.

17. The degrader of claim 1, wherein the compound is of Formula II: wherein,

N* is the point of attachment to L;

18. The degrader of claim 17, wherein the compound is of Formula II-B or II-C:

or a pharmaceutically acceptable salt thereof.

19. The degrader of claim 17 or 18, wherein R⁵ is hydroxyl.

20. The degrader of claim 1, wherein the compound is of Formula III: wherein,

N* is the point of attachment to L; U is N or CH; X is N or C; Y is N or C, and A is N or CH, wherein two or three of U, X, Y and A is N, and at least one of U and X is N;

21. The degrader of claim 20, wherein the compound is of Formula III-B or III-C:

III-B III-C or a pharmaceutically acceptable salt thereof.

22. The degrader of claim 21, wherein R¹ is methoxy.

23. The degrader of claim 21 or 22, wherein R⁵ is hydroxyl.

24. The degrader of any one of claims 1-23, wherein the UBG is a VHL E3 ligase.

25. The degrader of any one of claims 1-23, wherein the UBG is a cereblon E3 ligase.

26. The degrader of claim 1, wherein the UBG is selected from the group consisting of:

27. The degrader of any one of claims 1-26, wherein L is a bifunctional linker selected from the group consisting of: wherein La is an integer from 1 to 12; , wherein Lv is 0, -N(H)-, a 4-7 member heterocyclyl (including bicyclic), a CL aryl, a 5-6 member heteroaryl, or -O-(4-7 member heterocyclyl (including bicyclic))-; Le is an integer from 1 to 12; and Lf is an integer selected from 0 to 12; , wherein are each independently selected from the group consisting of 0, carbonyl, -N(H)-, amide, a 4-7 member heterocyclyl (including bicyclic), a CL aryl, a 5-6 member heteroaryl (such as triazole), an alkylenyl bond, and an alkynyl bond; wherein Lb and Lc, in each instance is independently an integer selected from 0 to 12; Ld is an integer selected from 0 to 12; Le is an integer from 0 to 12; Lh is an integer from 0 to 12; Lo, Lh and Lw are each independently 0 or 1, wherein at least one of Lo, Lh and Lw is 1; , wherein Lg, Lh and Li, in each instance is independently an integer selected from 0 to 12; and, , wherein Lv is 0, -N(H)-, amide, a 4-7 member heterocyclyl (including bicyclic), a C6 aryl, a 5-6 member heteroaryl (such as triazole) or an alkynyl bond; wherein Lb and Lc, in each instance is independently an integer selected from 0 to 12; Ld is an integer selected from 1 to 12; Le is an integer from 0 to 12; Lh is an integer from 0 to 12; Lo and Lw are each independently 0 or 1, wherein both Lo and Lw cannot be 0; where in every instance, one a point of attachment to a residue of a compound of Formula

A, I, II or III, and the other a point of attachment to UBG.

28. The degrader of claim 1 as depicted in Table 1.

29. A pharmaceutical composition comprising a degrader of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

30. A method for the treatment of a disorder associated with TAM receptor tyrosine kinases, the method comprising the step of administering to the subject an effective amount of a degrader of any one of claims 1-28, or the pharmaceutical composition of claim 29.

31. The method of claim 30, wherein the method comprises treatment of a disorder associated with TYRO3 or Mer tyrosine kinases.

32. The method of claim 30, wherein the method comprises treatment of a disorder associated with TYRO3 and Mer tyrosine kinases.

33. The method of claim 30, wherein the method comprises treatment of a disorder associated with TYRO3 tyrosine kinase.

34. The method of any one of claims 30-33, wherein the disorder is a cancer, an infection, a fibrosis, a thrombotic disorder, or a clotting disorder.

35. The method of claim 34, wherein the disorder is a cancer.

36. The method of claim 35, wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, bladder cancer, hematologic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma).

37. The method of claim 36, wherein the cancer is TYRO3 and/or MerTK +/+.

38. The method of claim 36, wherein the cancer is TYR03 and/or MerTK

39. The method of claim 34, wherein the disorder is a thrombotic disorder or clotting disorder.

40. The method of claim 39, wherein the thrombotic disorder or clotting disorder involves ischemic heart disease, stroke, or acute myocardial infarction.

41. The method of claim 34, wherein the disorder is an infection.

42. The method of claim 41, wherein the infection is viral.

43. The method of claim 34, wherein the disorder is fibrosis.

44. The method of claim 30, further comprising administering an additional active agent.