WO2023055952A1

WO2023055952A1 - Neurotrophic tyrosine receptor kinase (ntrk) degrading compounds

Info

Publication number: WO2023055952A1
Application number: PCT/US2022/045257
Authority: WO
Inventors: James A. Henderson; Corey Don Anderson
Original assignee: C4 Therapeutics, Inc.
Priority date: 2021-09-29
Filing date: 2022-09-29
Publication date: 2023-04-06

Abstract

Compounds that degrade one or more neurotrophic tyrosine receptor kinase (NTRK) proteins for the treatment of NTRK mediated disorders are provided.

Description

NEUROTROPHIC TYROSINE RECEPTOR KINASE (NTRK) DEGRADING COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application 63/250,078 filed September 29, 2021, the entirety of which is incorporated by reference for all purposes.

FIELD OF THE INVENTION

This invention provides advantageous compounds that degrade one or more neurotrophic tyrosine receptor kinase (NTRK) proteins for the treatment of NTRK mediated disorders such as cancer.

BACKGROUND

Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, biogenesis of organelles, cell cycling, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscular degeneration, morphogenesis of neural networks, modulation of cell surface receptors, ion channels and the secretory pathway, the response to stress and extracellular modulators, ribosome biogenesis and viral infection.

Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitin ligase to a terminal lysine residue marks the protein for proteasome degradation, where the protein is digested into small peptides and eventually into its constituent amino acids that serve as building blocks for new proteins. Defective proteasomal degradation has been linked to a variety of disorders including cancer and others.

Thalidomide and its analogues have been found to bind to the ubiquitin ligase cereblon and redirect its ubiquitination activity (see Ito, T. et al. “Identification of a primary target of thalidomide teratogenicity” Science, 2010, 327: 1345). Cereblon forms part of an E3 ubiquitin ligase complex which interacts with damaged DNA binding protein 1, forming an E3 ubiquitin ligase complex with Cullin 4 and the E2-binding protein ROC1 (known as RBX1) where it functions as a substrate receptor to select proteins for ubiquitination. The binding of lenalidomide to cereblon facilitates subsequent binding of cereblon to Ikaros and Aiolos, leading to their ubiquitination and degradation by the proteasome (see Lu, G. et al. “The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins” Science, 2014, 343:305-309; Krönke, J. et al. “Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells” Science, 2014, 343:301-305).

Patent applications filed by C4 Therapeutics, Inc., that describe compounds capable of binding to an E3 ubiquitin ligase and a target protein for degradation include: WO 2022/032026 titled “Advantageous Therapies For Disorders Mediated By Ikaros or Aiolos”; WO 2022/081925 titled “Tricyclic Ligands for Degradation of IKZF2 or IKZF4”; WO 2022/081927 titled “Tricyclic Compounds to Degrade Neosubstrates for Medical Use”; WO 2022/081928 titled “Tricyclic Heterobifunctional Compounds for Degradation of Targeted Proteins”; WO 2021/255212 titled “BRAF Degraders”; WO 2021/255213 titled “Heterobifunctional Compounds as Degraders of BRAF”; WO 2021/178920 titled “Compounds for Targeted Degradation of BRD9”; WO 2021/127561 titled “Isoindolinone And Indazole Compounds For The Degradation Of EGFR”; WO 2021/086785 titled “Bifunctional Compounds”; WO 2021/083949 titled “Bifunctional Compounds for the Treatment of Cancer”; WO 2020/210630 titled “Tricyclic Degraders of Ikaros and Aiolos”; WO 2020/181232 titled “Heterocyclic Compounds for Medical Treatment”; WO 2020/132561 titled “Targeted Protein Degradation”; WO 2019/236483 titled “Spirocyclic Compounds”; WO 2020/051235 titled “Compounds for the degradation of BRD9 or MTH1”; WO 2019/191112 titled “Cereblon binders for the Degradation of Ikaros”; WO 2019/204354 titled “Spirocyclic Compounds”; WO 2019/099868 titled “Degraders and Degrons for Targeted Protein Degradation”; WO 2018/237026 titled “N/O-Linked Degrons and Degronimers for Protein Degradation”; WO 2017/197051 titled “Amine-Linked C3-Glutarimide Degronimers for Target Protein Degradation”; WO 2017/197055 titled “Heterocyclic Degronimers for Target Protein Degradation”; WO 2017/197036 titled “Spirocyclic Degronimers for Target Protein Degradation”; WO 2017/197046 titled “C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation”; and WO 2017/197056 titled “Bromodomain Targeting Degronimers for Target Protein Degradation.”

Other patent applications that describe protein degrading compounds include: WO 2015/160845; WO 2016/105518; WO 2016/118666; WO 2016/149668; WO 2016/197032;

WO 2016/197114; WO 2017/007612; WO 2017/011371; WO 2017/011590; WO 2017/030814;

WO 2017/046036; WO 2017/176708; WO 2017/176957; WO 2017/180417; WO 2018/053354;

WO 2018/071606; WO 2018/102067; WO 2018/102725; WO 2018/118598; WO 2018/119357;

WO 2018/119441; WO 2018/119448; WO 2018/140809; WO2018/144649; WO 2018/119448; WO 2018/226542; WO 2019/023553; WO 2019/195201; WO2019/199816; WO 2019/099926; WO 2019/195609; WO 2020/041331; WO 2020/051564; WO 2020/023851; and W02021/011634.

Neurotrophic tyrosine receptor kinase (NTRK) is a family of genes encoding tyrosine receptor kinases that help regulate cell signaling and function for healthy cells. NTRK1, NTRK2, and NTRK3 encode tropomyosin receptor kinase A (TRKA), TRKB, and TRKC respectively. Rearrangements and fusions of the NTRK genes can result in the production of altered tyrosine receptor kinase proteins that may lead to uncontrolled cell growth. These oncogenic fusions can occur on either the NTRK1, NTRK2, and/or NTRK3 genes. Fusions of NTRK1, NTRK2, and/or NTRK3 drive several different adult and pediatric tumor types. Emiliano Cocco et al., Nature Reviews Clinical Oncology, 15, 731-747 2018. Non-limiting examples of cancers that can be driven by NTRK fusion include various solid tumors such as breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma, and thyroid cancers. NTRK fusions can also drive CNS cancers particularly in children such as gliomas, soft-tissue sarcomas, inflammatory myofibroblastic tumors, congenital infantile fibrosarcoma, and mesoblastic nephroma.

Examples of NTRK inhibitors include larotrectinib, entrectinib, repotrectinib, and LOXO- 195. Drillon et al., AACR Cancer Discovery, 10/2018, 1227; Menichincheri et al., J. Med. Chem. 2016, 59, 7, 3392. These NTRK inhibitors have varying degrees of selectivity for NTRK1, NTRK2, and/or NTRK3 as well as mutants thereof. For example, G595R and G667C mutations of NTRK1 cause a greater than 50-fold loss in potency for Larotrectinib. Drillon et al., AACR Cancer Discovery, 09/2017, 0F1. Additional examples of NTRK ligands include those described in W02020/243021, W02020/114499, WO2019/206069, WO2014/071358, and W02009/140128.

NTRK degrading compounds are described in patent applications W02020/038415 and W02021/170109 filed by Cullgen Inc. which describe the use of select NTRK targeting ligands linked to E3 Ligase ligands for the degradation of NTRK. Additional NTRK degraders are described in a paper titled “Discovery of First-In-Class Potent and Selective Tropomyosin Receptor Kinase Degraders” by Chen et al., J. Med. Chem. 2020, 63, 14562-14575.

Despite these efforts, there remains a need for new NTRK degraders to treat disorders mediated by NTRK in hosts in need thereof, including humans.

SUMMARY OF THE INVENTION

Compounds and their compositions, uses and manufacture are provided that cause degradation of one or more proteins encoded by a neurotrophic tyrosine receptor kinase (NTRK) gene, for example tropomyosin receptor kinase A (TRKA), TRKB, and/or TRKC, encoded by NTRK1, NTRK2, and NTRK3 respectively. By degrading a NTRK encoded protein a compound of the present invention can be used to treat a patient with a NTRK mediated disorder.

In certain embodiments a compound of the present invention is used to treat a cancer that is caused or mediated by NTRK for example a cancer associated with an NTRK mutation. In other embodiments a compound of the present invention is used to treat another disorder mediated by NTRK, for example a disorder related to pain, thermoregulation, movement, memory, mood, appetite, weight, sense of self-movement, and/or body position. In certain embodiments the disorder is related to pain and/or thermoregulation and the compound degrades NTRK1. In certain embodiments the disorder is related to movement, memory, mood, appetite, and/or weight and the compound degrades NTRK2. In certain embodiments the disorder is related to sense of selfmovement and/or body position and the compound degrades NTRK3.

The compounds of the present invention include a NTRK Targeting Ligand, a Linker, and a heterocyclic moiety.

In certain aspects a compound of Formula I or Formula II is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; wherein w is 0, 1, 2, or 3 and all other variables are as defined herein. In certain embodiments the compound of the present invention is selected from:

or a pharmaceutically acceptable salt thereof. In other embodiments the compound of the present invention is selected from:

or a pharmaceutically acceptable salt thereof.

Non-limiting examples of compounds of Formula I include:

. In certain embodiments a compound of Formula IA or Formula IB is provided:

or a pharmaceutically acceptable salt thereof.

In certain aspects a compound of the present invention selectively degrades NTRK1 and NTRK3 (for example the compound may be at least 10, 100, or 1000 times more active against NTRK1 or NTRK3 compared to NTRK2). In other aspects a compound of the present invention is a pan NTRK degrader.

In certain embodiments a compound of the present invention is used to degrade a mutant NTRK. Non-limiting examples of mutant NTRK’s include NTRK1 with one or more mutations selected form F589L, G595R, and G667C and NTRK3 with one or more mutations selected from F617L, G623R, and G696A.

In certain embodiments, the compound of the present invention provides multiple advantages over using a NTRK inhibitor, for example a NTRK degrading compound of the present invention may a) overcome resistance in certain cases; b) prolong the kinetics of drug effect by destroying the protein, thus requiring resynthesis of the protein even after the compound has been metabolized; c) target all functions of the protein at once rather than a specific catalytic activity or binding event; d) require a smaller dose; e) require less frequent dosing; f) require a shorter dosing period; g) cause fewer side effects; and/or h) have increased potency compared to the NTRK targeting ligand due to the possibility of the compound of the present invention acting catalytically.

Variables within the formulas described herein are typically selected such that the resulting compound is sufficiently stable to sustain a shelf life of at least two, three, four, or five months under ambient conditions. One of ordinary skill in the art is well aware of the stability of chemical moieties and can avoid those that are not stable or are too reactive under appropriate conditions. Also, all R groups, with or without optional substituents, should be interpreted in a manner that does not include redundancy (i.e., as known in the art, alkyl substituted with alkyl is redundant; however, for example, alkoxy substituted with alkoxy is not redundant and aryl substituted with aryl is also not redundant).

A compound of the present invention or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable composition thereof can be used to treat a NTRK mediated disorder such as cancer. Therefore, in some embodiments a method to treat a host with a NTRK mediated disorder is provided that includes administering an effective amount of the compound of the present invention or its pharmaceutically acceptable salt to a patient in need thereof, typically a human, optionally in a pharmaceutically acceptable composition.

In certain embodiments a compound of the present invention is used to treat a cancer selected from breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma, thyroid, glioma, soft-tissue sarcoma, inflammatory myofibroblastic tumor, congenital infantile fibrosarcoma, and mesoblastic nephroma.

In certain embodiments, a compound of the present invention has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound of the present invention includes a deuterium or multiple deuterium atoms.

In certain embodiments the NTRK Targeting Ligand is selected from:

In certain aspects a compound of Formula A or Formula B is provided:

or a pharmaceutically acceptable salt, A-oxide, isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; wherein:

Heterocyclic Moiety is selected from:

Heterocyclic Moiety^B is selected from:

Q is CH₂, NR², O, or S; X³, X⁴, X⁵, and X⁶ are independently selected from N, CH, and CR⁵, wherein one of X³, X⁴, X⁵, and X⁶ is a carbon atom that is attached to Linker, wherein typically no more than two of X³, X⁴, X⁵, and X⁶ are selected to be N; R¹, R³, R⁴, and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R³ and R⁴ together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group; or R¹ and R⁶ are combined together to form a 1 or 2-carbon bridge; for example

or R¹ and R³ are combined together to form a 3-6 membered fused ring; for example

each R² is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R⁹, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)₂R⁹, -SC(O)R⁹, -OS(O)₂R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, -NR⁷P(O)(R⁹)₂, -OP(O)(R⁹)₂, and oxo; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R¹⁶ is selected from:

and R¹², each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R^17A is selected from:

and

wherein the heterocycle is attached through a carbon-carbon bond; and wherein each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R¹⁷ is selected from:

and

each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R¹⁸ is selected from:

and

each of which is attached to the azaglutarimide moiety through a C-N bond and each of which R¹⁸ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; for example

includes

but does not include

Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with 1 R¹² substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with 1 R¹² substituent; R¹² is the attachment point to Linker; R⁷ and R⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R⁸, -OR⁷, and -SR⁷ each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, -OC(O)R¹⁴, -OC(S)R¹⁴, -OS(O)R¹⁴, -OS(O)₂R¹⁴, -NR¹¹C(O)R¹⁴, -NR¹¹C(S)R¹⁴, -NR¹¹S(O)R¹⁴, -NR¹¹S(O)₂R¹⁴, -P(O)(R¹⁴)₂, -NR¹¹P(O)(R¹⁴)₂, and -OP(O)(R¹⁴)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; R¹¹ and R¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂; Linker is a bivalent chemical group; NTRK Targeting Ligand is selected from:

NTRK Targeting Ligand^B is selected from:

X¹⁶ is selected from

and bond; each x is independently 0, 1, 2, 3, or 4; X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, and X¹⁵ are independently selected from N, CH, and CR³² wherein no more than 3 and typically no more than 2 of X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, and X¹⁵ are selected to be N; R²⁷ is selected from

, , , and

, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²⁹; R²⁸ is selected from

each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R³⁰; each R²⁹, R³⁰, R³¹, R³², and R³³ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)₂R⁹, -SC(O)R⁹, -OS(O)₂R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, -NR⁷P(O)(R⁹)₂, and -OP(O)(R⁹)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R³⁴ is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -C(O)R⁹, and -C(S)R⁹, each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R³⁵ is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -P(O)(R⁹)₂, and -alkyl-O-alkyl; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments Linker is selected from

wherein: X¹ and X² are independently at each occurrence selected from bond, heterocycle, NR², C(R²)₂, O, C(O), and S; R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO₂-, -S(O)-, -C(S)-, -C(O)NR²-, -NR²C(O)-, -O-, -S-, -NR²-, -C(R⁴⁰R⁴⁰)-, -P(O)(OR²⁶)O-, -P(O)(OR²⁶)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁰; R²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and R⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)₂, -NHSO₂(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO₂alkyl, -NHSO₂(aryl, heteroaryl or heterocycle), -N(alkyl)SO₂(aryl, heteroaryl or heterocycle), -NHSO₂alkenyl, -N(alkyl)SO₂alkenyl, -NHSO₂alkynyl, -N(alkyl)SO₂alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl. In other aspects a new NTRK Targeting Ligand which can act as an inhibitor is provided of Formula:

or a pharmaceutically acceptable salt thereof wherein all variables are as defined herein. In certain embodiments the new NTRK Targeting Ligand which can act as an inhibitor is selected from:

or a pharmaceutically acceptable salt thereof.

Other features and advantages of the present application will be apparent from the following detailed description and claims.

The present invention thus includes at least the following features:

(a) A compound of the present invention or a pharmaceutically acceptable salt, isotopic derivative (including a deuterated derivative), or prodrug thereof;

(b) A compound of the present invention or a pharmaceutically acceptable salt, isotopic derivative (including a deuterated derivative), or prodrug thereof for the treatment of a disorder that is mediated by NTRK;

(c) A method of treating a disorder mediated by NTRK comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, isotopic derivative (including a deuterated derivative), or prodrug thereof to a patient in need thereof;

(d) Use of a compound of the present invention in an effective amount in the treatment of a patient, typically a human, with a disorder mediated by NTRK;

(e) Use of a compound of the present invention in an effective amount in the manufacture of a medicament to treat of a patient, typically a human, with a disorder mediated by NTRK; (f) A pharmaceutical composition comprising an effective host-treating amount of a compound of the present invention or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof together and a pharmaceutically acceptable carrier; (g) A compound of the present invention as a mixture of enantiomers or diastereomers (as relevant), including as a racemate; (h) A compound of the present invention in an enantiomerically or diastereomerically (as relevant) enriched form, including an isolated enantiomer or diastereomer (i.e., greater than 85, 90, 95, 97, or 99% pure); and (i) A process for the preparation of a therapeutic product that contains an effective amount of a compound of the present invention. BRIEF DESCRIPTION OF THE FIGURES FIG.1 depicts Formula I of the present invention. FIG.2 is a western blot showing the effect of Compound 57, Compound 64, Compound 81, Compound 105, Compound 149, and Compound 213 on NTRK degradation in AP1060 cells harboring the ETV6-NTRK3 fusion. The experimental procedure is provided in Example 135. FIG. 3 is a line graph showing the effect of various doses of Compound 98, Compound 145, and Compound 149 on tumor growth compared to vehicle, larotrectinib, and entrectinib. The y-axis is tumor size measured in mm³ and the x-axis is days of treatment. The experimental procedure is provided in Example 137 FIG. 4 is a line graph showing the effect of various doses of Compound 98, Compound 145, and Compound 149 on mouse body weight compared to vehicle, larotrectinib, and entrectinib. The y-axis is change in body weight measured in % and the x-axis is days of treatment. The experimental procedure is provided in Example 137. FIG.5 is a western blot showing the effect of Compound 145 at various doses on NTRK degradation in a KM12 xenograft model. The experimental procedure is provided in Example 138. FIG. 6 is a western blot showing the effect of Compound 98 at various doses on NTRK degradation in a KM12 xenograft model. The experimental procedure is provided in Example 138. FIG. 7 is a western blot showing the effect of Compound 98, Compound 145, and Compound 149 at various doses on NTRK degradation in a KM12 xenograft model. The experimental procedure is provided in Example 138. FIG.8 is a western blot showing the effect of Compound 149 dosed at 10 mg/kg p.o. once a day or twice a day at various times after dosing NTRK degradation in a KM12 xenograft model. The experimental procedure is provided in Example 139. FIG.9 is a western blot showing the effect of Compound 149 dosed at 100 mg/kg p.o. once a day at various times after dosing on NTRK degradation in a KM12 xenograft model. The experimental procedure is provided in Example 139. DETAILED DESCRIPTION OF THE INVENTION I. DEFINITIONS Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. The compounds in any of the Formulas described herein may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, isomer; such as rotamer, as if each is specifically described unless specifically excluded by context. The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item(s). The term “or” means “and/or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. The present invention includes a compound of the present invention with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, and ¹²⁵I respectively. In one non- limiting embodiment, isotopically labelled compounds can be used in metabolic studies (with, for example ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of the present invention. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within one or more groups selected from any of R’s or variables described herein, Linker, and NTRK Targeting Ligand. For example, when any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting embodiments, CDH₂, CD₂H, CD_3, CH₂CD₃, CD₂CD₃, CHDCH₂D, CH₂CD₃, CHDCHD₂, OCDH₂, OCD₂H, or OCD₃ etc.). In certain other embodiments, when two substituents are combined to form a cycle the unsubstituted carbons may be deuterated. The compound of the present invention may form a solvate with a solvent (including water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of the compound. The term "solvate" refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g., D₂O, d₆-acetone, d₆-DMSO (dimethyl sulfoxide). A solvate can be in a liquid or solid form. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH₂ is attached through carbon of the carbonyl (C=O) group. “Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group. In one non- limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, or C₁-C_6. The specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species. For example, the term C₁- C₆ alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and therefore each subset is considered separately disclosed. For example, the term C₁-C₄ alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2- dimethylbutane, and 2,3-dimethylbutane. In an alternative embodiment, the alkyl group is optionally substituted. The term “alkyl” also encompasses cycloalkyl or carbocyclic groups. For example, when a term is used that includes “alk” then “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example, and without limitation, the terms alkyl, alkoxy, haloalkyl, etc., can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context. In one embodiment “alkyl” is a C₁-C₁₀alkyl, C₁-C₉alkyl, C₁-C₈alkyl, C₁-C₇alkyl, C₁-C₆alkyl, C₁-C₅alkyl, C₁-C₄alkyl, C₁-C₃alkyl, or C₁-C₂alkyl. In one embodiment “alkyl” has one carbon. In one embodiment “alkyl” has two carbons. In one embodiment “alkyl” has three carbons. In one embodiment “alkyl” has four carbons. In one embodiment “alkyl” has five carbons. In one embodiment “alkyl” has six carbons. Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl. Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl. Additional non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl. Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl. Additional non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl. In an alternative embodiment “alkyl” is “optionally substituted” with 1, 2, 3, or 4 substituents. In one embodiment “cycloalkyl” is a C₃-C₈cycloalkyl, C₃-C₇cycloalkyl, C₃-C₆cycloalkyl, C₃-C₅cycloalkyl, C₃-C₄cycloalkyl, C₄-C₈cycloalkyl, C₅-C₈cycloalkyl, or C₆-C₈cycloalkyl. In one embodiment “cycloalkyl” has three carbons. In one embodiment “cycloalkyl” has four carbons. In one embodiment “cycloalkyl” has five carbons. In one embodiment “cycloalkyl” has six carbons. In one embodiment “cycloalkyl” has seven carbons. In one embodiment “cycloalkyl” has eight carbons. In one embodiment “cycloalkyl” has nine carbons. In one embodiment “cycloalkyl” has ten carbons. Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. Additional non-limiting examples of “cycloalkyl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the cycloalkyl ring. For example:

is an “cycloalkyl” group. However,

is an “aryl” group. In an alternative embodiment “cycloalkyl” is a “optionally substituted” with 1, 2, 3, or 4 substituents. “Alkenyl” is a linear or branched aliphatic hydrocarbon groups having one or more carbon- carbon double bonds that may occur at a stable point along the chain. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term “alkenyl” also embodies “cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z” alkenyl geometry. In an alternative embodiment, the alkenyl group is optionally substituted. The term “Alkenyl” also encompasses cycloalkyl or cycloalkyl groups possessing at least one point of unsaturation. In an alternative embodiment “alkenyl” is “optionally substituted” with 1, 2, 3, or 4 substituents. “Alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain. The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In an alternative embodiment, the alkynyl group is optionally substituted. The term “Alkynyl” also encompasses cycloalkyl or cycloalkyl groups possessing at least one triple bond. In an alternative embodiment “alkynyl” is “optionally substituted” with 1, 2, 3, or 4 substituents. “Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example, can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6-carbon moiety, or an indicated number of carbon atoms, for example C₁-C₂alkylene, C₁-C₃alkylene, C₁-C₄alkylene, C₁-C₅alkylene, or C₁-C₆alkylene. “Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6-carbon moiety, or an indicated number of carbon atoms, for example C₂-C₄alkenylene. “Alkynylene” is a bivalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, a 2 to 6-carbon moiety, or an indicated number of carbon atoms, for example C₂-C₄alkynylene. “Halo” and “Halogen” refers independently to fluorine, chlorine, bromine or iodine. “Haloalkyl” is a branched or straight-chain alkyl groups substituted with 1 or more halo atoms described above, up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Perhaloalkyl” means an alkyl group having all hydrogen atoms replaced with halogen atoms. Examples include but are not limited to, trifluoromethyl and pentafluoroethyl. In one embodiment “haloalkyl” is a C₁-C₁₀haloalkyl, C₁-C₉haloalkyl, C₁-C₈haloalkyl, C₁- C₇haloalkyl, C₁-C₆haloalkyl, C₁-C₅haloalkyl, C₁-C₄haloalkyl, C₁-C₃haloalkyl, and C₁- C₂haloalkyl. In one embodiment “haloalkyl” has one carbon. In one embodiment “haloalkyl” has one carbon and one halogen. In one embodiment “haloalkyl” has one carbon and two halogens. In one embodiment “haloalkyl” has one carbon and three halogens. In one embodiment “haloalkyl” has two carbons. In one embodiment “haloalkyl” has three carbons. In one embodiment “haloalkyl” has four carbons. In one embodiment “haloalkyl” has five carbons. In one embodiment “haloalkyl” has six carbons. Non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

. Additional non-limiting examples of “haloalkyl” include:

, , . Additional non-limiting examples of “haloalkyl” include:

, , “Chain” indicates a linear chain to which all other chains, long or short or both, may be regarded as being pendant. Where two or more chains could equally be considered to be the main chain, “chain” refers to the one which leads to the simplest representation of the molecule. “Haloalkoxy” indicates a haloalkyl group as described herein attached through an oxygen bridge (oxygen of an alcohol radical). “Heterocycloalkyl” is an alkyl group as described herein substituted with a heterocyclo group as described herein. “Arylalkyl” is an alkyl group as described herein substituted with an aryl group as described herein. Non-limiting examples of “arylalkyl” include:

In one embodiment “arylalkyl” is

In one embodiment the “arylalkyl” refers to a 2-carbon alkyl group substituted with an aryl group. Non-limiting examples of “arylalkyl” include:

In one embodiment the “arylalkyl” refers to a 3-carbon alkyl group substituted with an aryl group. “Heteroarylalkyl” is an alkyl group as described herein substituted with a heteroaryl group as described herein. As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C_6–14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1– naphthyl and 2–naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocycle groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. The one or more fused carbocyclyl or heterocycle groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocycle groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4- methylenedioxyphenyl group. In one non-limiting embodiment, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In an alternative embodiment, the aryl group is optionally substituted as described above. In certain embodiments, the aryl group is an unsubstituted C6–14 aryl. In certain embodiments, the aryl group is a substituted C6–14 aryl. An aryl group may be optionally substituted with one or more functional groups that include but are not limited to, halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo. In one embodiment “aryl” is a 6-carbon aromatic group (phenyl). In one embodiment “aryl” is a 10-carbon aromatic group (napthyl). In one embodiment “aryl” is a 6-carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring. For example,

is an “aryl” group. However,

is a “heterocycle” group. In one embodiment “aryl” is a 6-carbon aromatic group fused to a cycloalkyl wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the aromatic ring. For example,

is an “aryl” group. However,

is a “cycloalkyl” group. In an alternative embodiment “aryl” is “optionally substituted” with 1, 2, 3, or 4 substituents. The term “heterocyclyl”, “heterocycle”, and “heterocyclo” includes saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. This term should not be confused with the capitalized term “Heterocyclic Moiety” that is in the present invention and separately defined. Heterocyclic rings comprise monocyclic 3, 4, 5, 6, 7, 8, 9, or 10 membered rings, as well as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 membered bicyclic ring systems (which can include bridged fused and spiro- fused bicyclic ring systems). It does not include rings containing -O-O-.-O-S- or -S-S- portions. Said “heterocycle” group may be optionally substituted, for example, with 1, 2, 3, 4 or more substituents that include but are not limited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino. Examples of saturated heterocyclo groups include saturated 3, 4, 5, or 6-membered heteromonocyclic groups containing 1, 2, 3, or 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms [e.g., morpholinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclo groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro- benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4- tetrahydro-isoquinolyl, 1 ,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-lH-3-aza-fluorenyl, 5,6,7- trihydro-l,2,4- triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[l,4]oxazinyl, benzo[l,4]dioxanyl, 2,3- dihydro- lH-lλ’-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, , isoquinolin-1(2H)-onyl, benzo[d]oxazol-2(3H)-onyl, 1,3-dihydro-2H-benzo[d]midazol-2-onyl, benzo[d]thiazole-2(3H)- onyl, 1,2-dihydro-3H-pyrazol-3-onyl, 2(1H)-pyridinonyl, 2-piperazinonyl, indolinyl, and dihydrothiazolyl. The term “heterocyclyl”, “heterocycle”, and “heterocyclo” groups also include moieties where heterocycle radicals are fused/condensed with aryl or heteroaryl radicals: such as unsaturated condensed heterocycle group containing 1, 2, 3, 4, or 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocycle group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms, unsaturated condensed heterocycle group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocycle group containing 1 or 2 oxygen or sulfur atoms. In one embodiment “heterocycle” refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms. In one embodiment “heterocycle” refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In one embodiment “heterocycle” refers to a cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms. In one embodiment “heterocycle” refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In one embodiment “heterocycle” refers to a cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of “heterocycle” include aziridine, oxirane, thiirane, azetidine, 1,3- diazetidine, oxetane, and thietane. Additional non-limiting examples of “heterocycle” include pyrrolidine, 3-pyrroline, 2- pyrroline, pyrazolidine, and imidazolidine. Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane. Additional non-limiting examples of “heterocycle” include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine. Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring. For example,

is a “heterocycle” group. However,

is an “aryl” group. Non-limiting examples of “heterocycle” also include:

. Additional non-limiting examples of “heterocycle” include:

. Additional non-limiting examples of “heterocycle” include:

. Non-limiting examples of “heterocycle” also include:

Non-limiting examples of “heterocycle” also include:

Additional non-limiting examples of “heterocycle” include:

. Additional non-limiting examples of “heterocycle” include:

In an alternative embodiment “heterocycle” is “optionally substituted” with 1, 2, 3, or 4 substituents. The term “heteroaryl” denotes a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) and 1, 2, 3, 4, 5, or 6, heteroatoms independently selected from O, N, and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized. Examples include, but are not limited to, unsaturated 5 to 6 membered heteromonocyclyl groups containing 1, 2, 3, or 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1 ,2,3-triazolyl, 2H-1,2,3- triazolyl]; unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl]; unsaturated 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. Additional examples include 8-, 9-, or 10-membered heteroaryl bicyclic groups such as indazolyl, indolyl, imidazo[1,5-a]pyridinyl, benzimidazolyl, 4(3H)-quinazolinonyl, quinolinyl, isoquinolinyl, isoindolyl, thienothienyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl, and triazolopyridinyl. In one embodiment “heteroaryl” is a 5 membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms. Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

Additional non-limiting examples of 5 membered “heteroaryl” groups include:

In one embodiment “heteroaryl” is a 6 membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include:

In one embodiment “heteroaryl” is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole.

Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:

. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:

. In one embodiment “heteroaryl” is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:

. In an alternative embodiment “heteroaryl” is “optionally substituted” with 1, 2, 3, or 4 substituents. The term “bicycle” refers to a ring system wherein two rings are fused together and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Non-limiting examples of bicycle groups include: ,

When the term “bicycle” is used in the context of a bivalent residue such as Linker the attachment points can be on separate rings or on the same ring. In certain embodiments both attachment points are on the same ring. In certain embodiments both attachment points are on different rings. Non-limiting examples of bivalent bicycle groups include:

. In an alternative embodiment “bicycle” is “optionally substituted” with 1, 2, 3, or 4 substituents. The term “optionally substituted” denotes the substitution of a group herein by a moiety including, but not limited to, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₂ cycloalkyl, C₃- C₁₂ cycloalkenyl, C₁–C₁₂ heterocycloalkyl, C₃-C₁₂ heterocycloalkenyl, C₁-C₁₀ alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C₁-C₁₀ alkylamino, C₁–C₁₀ dialkylamino, arylamino, diarylamino, C₁-C₁₀ alkylsulfonamino, arylsulfonamino, C₁-C₁₀ alkylimino, arylimino, C₁-C₁₀ alkylsulfonimino, arylsulfonimino, hydroxyl, halo, thio, C₁-C₁₀ alkylthio, arylthio, C₁-C₁₀ alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester. In one alternative embodiment any suitable group may be present on a “substituted” or “optionally substituted” position if indicated that forms a stable molecule and meets the desired purpose of the invention and includes, but is not limited to, e.g., halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C₂-C₆ alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having more than one N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either substituted or unsubstituted); arylalkyl having for example, 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, for example, having 1 to 3 separate or fused rings with benzyloxy being an exemplary arylalkoxy group; or a saturated or partially unsaturated heterocycle having 1 to 3 separate or fused rings with one or more N, O or S atoms, or a heteroaryl having 1 to 3 separate or fused rings with one or more N, O or S atoms, e.g., coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such groups may be further substituted, e.g., with hydroxy, alkyl, alkoxy, halogen and amino. In certain embodiments “optionally substituted” includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH₂, alkyl including C₁-C₆alkyl, alkenyl including C₂-C₆alkenyl, alkynyl including C₂-C₆alkynyl, -C₁- C6alkoxy, alkanoyl including C₂-C₆alkanoyl, C₁-C₆alkylester, (mono- and di-C₁- C₆alkylamino)C₀-C₂alkyl, haloalkyl including C₁-C₆haloalkyl, hydoxyC₁-C₆alkyl, ester, carbamate, urea, sulfonamide,-C₁-C₆alkyl(heterocyclo), C₁-C₆alkyl(heteroaryl), -C₁-C₆alkyl(C₃- C₇cycloalkyl), O-C₁-C₆alkyl(C₃-C₇cycloalkyl), B(OH)₂, phosphate, phosphonate and haloalkoxy including C₁-C₆haloalkoxy. In some embodiments, the suitable group present on a “substituted” or “optionally substituted” is divalent including, but not limited to, oxo (=O), =S, =CH₂, etc. The suitable group on a “substituted” or “optional substituted” position may be monovalent, divalent, or trivalent such that it forms a stable molecule and meets the desired purpose of the invention. In one embodiment a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with one substituent. In one embodiment a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with two substituents. In one embodiment a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with three substituents. In one embodiment a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with four substituents. “Aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. "Aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In one embodiment, "aliphatic" is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis or trans configuration. In one embodiment, the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅ or C₁-C_6. The specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species. For example, the term C₁-C₆ aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C₁-C₄ aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. In one embodiment, the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety. The term "heteroaliphatic" refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. “Heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, "heteroaliphatic" is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms. In one embodiment, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc. A “dosage form” means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like. A “dosage form” can also include an implant, for example an optical implant. An “effective amount” as used herein, means an amount which provides a therapeutic or prophylactic benefit. By the term “modulating,” as used herein, is meant mediating a detectable increase or decrease in the level of a response in a patient compared with the level of a response in the patient in the absence of a treatment or compound, and/or compared with the level of a response in an otherwise identical but untreated patient. The term encompasses perturbing and/or affecting a native signal or response thereby mediating a beneficial therapeutic response in a patient, preferably, a human.

“Parenteral” administration of a pharmaceutical composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), intrasternal injection, or infusion techniques.

As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and the maximum number of amino acids present within the protein or peptide’s sequence is typically comparable to up to that found in nature. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof.

To “treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a patient (i.e., palliative treatment) or to decrease a cause or effect of the disease or disorder (i.e., disease-modifying treatment).

Throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as a limitation on the scope of the invention. The description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. As used herein, “pharmaceutical compositions” are compositions comprising at least one active agent, and at least one other substance, such as a carrier. “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein. As used herein, “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH₂)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p.1418 (1985). The term “carrier” applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided. A “pharmaceutically acceptable carrier” means a carrier or excipient that is usefill in preparing a pharmaceutical composition/combination that is generally safe, non-toxic and neither biologically nor otherwise inappropriate for administration to a patient, typically a human. In one embodiment, an excipient is used that is acceptable for veterinary use.

A “patient” or “subject" is a human or non-human animal in need of treatment or prevention of any of the disorders as specifically described herein, for example that is modulated by a natural (wild-type) or modified (non-wild type) protein that can be degraded according to the present invention, resulting in a therapeutic effect. As described further herein, the word patient or subject typically refers to a human patient or subject unless it is clear from the context or wording that the disclosure is meant to include a non-human animal. Typically, the patient is a human. In an alternative embodiment, the patient or subject is a non-human animal in need of such therapy and responsive thereto.

A “therapeutically effective amount” of a pharmaceutical composition/combination of this invention means an amount effective, when administered to a patient, typically a human patient, to provide a therapeutic benefit such as an amelioration of symptoms or reduction or diminution of the disease itself.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the specification, singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed application. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. II. NTRK Targeting Ligands

Non-limiting examples of NTRK Targeting Ligand for use in degraders of the present invention include:

In certain embodiments the NTRK Targeting Ligand or NTRK Targeting Ligand^B is selected from:



In certain embodiments the NTRK Targeting Ligand is selected from:

In certain embodiments the NTRK Targeting Ligand or the NTRK Targeting Ligand and a portion of the Linker is selected from:

.

In certain embodiments NTRK Targeting Ligand or NTRK Targeting Ligand^B is selected from

In certain embodiments NTRK Targeting Ligand^B is selected from

As used herein, a term that includes NTRK in the context of a protein refers independently to a protein encoded by the NTRK gene including for example independently TRKA, TRKB, or TRKC which are also known as NTRK1, NTRK2, and NTRK3 respectively. III. EMBODIMENTS OF THE PRESENT INVENTION Embodiments of R¹, R², R³, R⁴ and R⁵ In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ is alkyl. In certain embodiments, R¹ is alkenyl. In certain embodiments, R¹ is alkynyl. In certain embodiments, R¹ is halogen. In certain embodiments, R¹ is halogen, wherein the halogen is F. In certain embodiments, R¹ is halogen, wherein the halogen is Cl. In certain embodiments, R¹ is halogen, wherein the halogen is Br. In certain embodiments, R¹ is halogen, wherein the halogen is I. In certain embodiments, R² is hydrogen. In certain embodiments, R² is hydrogen, wherein the hydrogen is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments, R² is alkyl. In certain embodiments, R² is alkyl, wherein the alkyl is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments, R² is haloalkyl. In certain embodiments, R² is haloalkyl, wherein the haloalkyl is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments, R² is alkenyl. In certain embodiments, R² is alkenyl, wherein the alkenyl is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments, R² is alkynyl. In certain embodiments, R² is alkynyl, wherein the alkynyl is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments, R² is aryl. In certain embodiments, R² is aryl, wherein the aryl is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments, R² is heteroaryl. In certain embodiments, R² is heteroaryl, wherein the heteroaryl is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments, R² is heterocycle. In certain embodiments, R² is heterocycle, wherein the heterocycle is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments, R² is C(O)R⁹. In certain embodiments, R² is C(O)R⁹, wherein C(O)R⁹ is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments, R³ is hydrogen. In certain embodiments, R³ is alkyl. In certain embodiments, R³ is alkenyl. In certain embodiments, R³ is alkynyl. In certain embodiments, R³ is halogen. In certain embodiments, R³ is halogen, wherein the halogen is F. In certain embodiments, R³ is halogen, wherein the halogen is Cl. In certain embodiments, R³ is halogen, wherein the halogen is Br. In certain embodiments, R³ is halogen, wherein the halogen is I. In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is alkyl. In certain embodiments, R⁴ is alkenyl. In certain embodiments, R⁴ is alkynyl. In certain embodiments, R⁴ is halogen. In certain embodiments, R⁴ is halogen, wherein the halogen is F. In certain embodiments, R⁴ is halogen, wherein the halogen is Cl. In certain embodiments, R⁴ is halogen, wherein the halogen is Br. In certain embodiments, R⁴ is halogen, wherein the halogen is I. In certain embodiments, R³ and R⁴ together with the carbon to which they are bound form a 3-, 4-, 5-, or 6-membered spirocarbocycle. In certain embodiments, R³ and R⁴ together with the carbon to which they are bound form a 3-membered spirocarbocycle. In certain embodiments, R³ and R⁴ together with the carbon to which they are bound form a 4-membered spirocarbocycle. In certain embodiments, R³ and R⁴ together with the carbon to which they are bound form a 5- membered spirocarbocycle. In certain embodiments, R³ and R⁴ together with the carbon to which they are bound form a 6-membered spirocarbocycle. In certain embodiments, R³ and R⁴ together with the carbon to which they are bound form a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group. In certain embodiments, R³ and R⁴ together with the carbon to which they are bound form a 4-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group. In certain embodiments, R³ and R⁴ together with the carbon to which they are bound form a 5-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group. In certain embodiments, R³ and R⁴ together with the carbon to which they are bound form a 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group. In certain embodiments, R⁵ is alkyl. In certain embodiments, R⁵ is haloalkyl. In certain embodiments, R⁵ is alkenyl. In certain embodiments, R⁵ is alkynyl. In certain embodiments, R⁵ is halogen. In certain embodiments, R⁵ is halogen, wherein the halogen is F. In certain embodiments, R⁵ is halogen, wherein the halogen is Cl. In certain embodiments, R⁵ is halogen, wherein the halogen is Br. In certain embodiments, R⁵ is halogen, wherein the halogen is I. In certain embodiments, R⁵ is heteroaryl. In certain embodiments, R⁵ is aryl. In certain embodiments, R⁵ is heterocycle. In certain embodiments, R⁵ is cyano. In certain embodiments, R⁵ is -NR⁷R⁸. In certain embodiments, R⁵ is -NR⁷C(O)R⁹. In certain embodiments, R⁵ is -NR⁷C(S)R⁹. In certain embodiments, R⁵ is -NR⁷C(O)R⁹. In certain embodiments, R⁵ is -NR⁷S(O)₂R⁹. In certain embodiments, R⁵ is -OR^7-. In certain embodiments, R⁵ is -SR⁷. In certain embodiments, R⁵ is -S(O)₂R⁹. In certain embodiments, R⁵ is -C(O)R⁹.

Embodiments of R¹⁵ and R¹⁶ Non-limiting examples of R¹⁵ and R¹⁶ include:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments the compound of the present invention is selected from:

In certain embodiments the compound of the present invention is selected from:

In certain embodiments the compound of the present invention is selected from:

In certain embodiments the compound of the present invention is selected from:

In certain embodiments the compound of the present invention is selected from:

In the embodiments above and throughout the specification z is 0, 1, 2, 3, or 4.

In certain embodiments the compound of the present invention is selected from:

. Embodiments of R¹⁶, R¹⁷, R¹⁸, R²⁷, and R²⁸ In certain embodiments R¹⁶ is

which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁶ is

which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁶ is R¹². In certain embodiments R¹⁷ is

which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁷ is

which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁸ is

which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R²⁷ is

which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²⁹. In certain embodiments R²⁷ is

which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²⁹. In certain embodiments R²⁸ is

which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R³⁰. In certain embodiments R²⁸ is

which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R³⁰. In certain embodiments

is selected from

, wherein each Y is independently selected from N, CH, or CR⁵, wherein 0, 1, 2, 3, or 4 (as context allows) instances of Y are selected to be N and are selected to produce a stable ring as well known to those skilled in the art and that forms a pharmaceutically acceptable compound. In certain embodiments is selected from

, wherein each Y is independently selected from N, CH, or CR⁵, wherein 0, 1, 2, 3, or 4 (as context allows) instances of Y are selected to be N and are selected to produce a stable ring as well known to those skilled in the art and that forms a pharmaceutically acceptable compound. Examples of

when present in a compound of the present invention include the following:

Additional examples of

include the following: ,

. Additional examples of

include the following:

Additional examples of

include the following:

Additional examples of

include the following:

Additional examples of

include the following:

. Additional examples of

include the following:

In certain embodiments

is selected from

Examples of

when present in a compound of the present invention include:

Additional examples of

include:

Additional examples of

include:

Additional examples of

include:

, , , , Additional examples of

include:

Examples of

when present in a compound of a present invention include:

Additional examples of

include:

. Additional examples of

include:

Additional examples of

include:

Additional examples of

include:

Additional Embodiments:

In certain embodiments the compound of Formula I is a compound of Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of Formula I is a compound of Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of Formula I is a compound of Formula:

or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula I is a compound of Formula:

or a pharmaceutically acceptable salt thereof.

1. In certain aspects a compound of Formula A is provided:

or a pharmaceutically acceptable salt, A-oxide, isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; wherein: Heterocyclic Moiety is selected from:

Heterocyclic Moiety^B is selected from:

Q is CH₂, NR², O, or S; X³, X⁴, X⁵,and X⁶ are independently selected from N, CH, and CR⁵, wherein one of X³, X⁴, X⁵, and X⁶ is a carbon atom that is attached to Linker; R¹, R³, R⁴, and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R³ and R⁴ together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group; or R¹ and R⁶ are combined together to form a 1 or 2-carbon bridge; for example

and

and

and

includes

but does not include

NTRK Targeting Ligand^B is selected from:

X¹⁶ is selected from

and bond; each x is independently 0, 1, 2, 3, or 4; X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, and X¹⁵ are independently selected from N, CH, and CR³²; R²⁷ is selected from

, , , and

each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R³⁰; each R²⁹, R³⁰, R³¹, R³², and R³³ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)₂R⁹, -SC(O)R⁹, -OS(O)₂R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, -NR⁷P(O)(R⁹)₂, and -OP(O)(R⁹)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R³⁴ is selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -C(O)R⁹, and -C(S)R⁹, each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R³⁵ is selected from alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -P(O)(R⁹)₂, and -alkyl-O-alkyl; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. 2. The compound of embodiment 1 wherein Linker is selected from

wherein: X¹ and X² are independently at each occurrence selected from bond, heterocycle, NR², C(R²)₂, O, C(O), and S; R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO₂-, -S(O)-, -C(S)-, -C(O)NR²-, -NR²C(O)-, -O-, -S-, -NR²-, -C(R⁴⁰R⁴⁰)-, -P(O)(OR²⁶)O-, -P(O)(OR²⁶)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁰; R²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and R⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)₂, -NHSO₂(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO₂alkyl, -NHSO₂(aryl, heteroaryl or heterocycle), -N(alkyl)SO₂(aryl, heteroaryl or heterocycle), -NHSO₂alkenyl, -N(alkyl)SO₂alkenyl, -NHSO₂alkynyl, -N(alkyl)SO₂alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl. 3. The compound of embodiment 2, wherein Linker is selected from:

4. The compound of embodiment 2, wherein Linker is selected from:

. 5. The compound of embodiment 2, wherein Linker is selected from:

. 6. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety or Heterocyclic Moiety^B is

. 7. The compound of embodiment 6, wherein Q is NH. 8. The compound of embodiment 6, wherein Q is NCH₃. 9. The compound of embodiment 6, wherein Q is CH₂. 10. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety or Heterocyclic Moiety^B is

. 11. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety or Heterocyclic Moiety^B is

. 12. The compound of any one of embodiments 1-11, wherein R¹⁶ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. 13. The compound of any one of embodiments 1-11, wherein R¹⁶ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. 14. The compound of any one of embodiments 1-11, wherein R¹⁶ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. 15. The compound of any one of embodiments 1-11, wherein R¹⁶ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. 16. The compound of any one of embodiments 1-11, wherein R¹⁶ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. 17. The compound of any one of embodiments 1-11, wherein R¹⁶ is R¹². 18. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety or Heterocyclic Moiety^B is

19. The compound of embodiment 18, wherein R¹⁷ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. 20. The compound of embodiment 18, wherein R¹⁷ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. 21. The compound of embodiment 18, wherein R¹⁷ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. 22. The compound of embodiment 18, wherein R¹⁷ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. 23. The compound of embodiment 18, wherein R¹⁷ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. 24. The compound of embodiment 18, wherein R¹⁷ is R¹². 25. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety or Heterocyclic Moiety^B is

. 26. The compound of embodiment 25, wherein R¹⁸ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. 27. The compound of embodiment 25, wherein R¹⁸ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. 28. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety^B is

. 29. The compound of embodiment 28, wherein cycle is phenyl. 30. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety or Heterocyclic Moiety^B is

. 31. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety or Heterocyclic Moiety^B is

. 32. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety or Heterocyclic Moiety^B is

. 33. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety^B is

. 34. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety^B is

. 35. The compound of any one of embodiments 31-34, wherein X⁶ is CR¹². 36. The compound of any one of embodiments 31-34, wherein X⁵ is CR¹². 37. The compound of any one of embodiments 31-34, wherein X⁴ is CR¹². 38. The compound of any one of embodiments 31-34, wherein X³ is CR¹². 39. The compound of any one of embodiments 31-34 or 36-38, wherein X⁶ is CH. 40. The compound of any one of embodiments 31-34 or 36-38, wherein X⁶ is CR⁵. 41. The compound of any one of embodiments 31-34 or 36-38, wherein X⁶ is N. 42. The compound of any one of embodiments 31-35 or 37-41, wherein X⁵ is CH. 43. The compound of any one of embodiments 31-35 or 37-41, wherein X⁵ is CR⁵. 44. The compound of any one of embodiments 31-35 or 37-41, wherein X⁵ is N. 45. The compound of any one of embodiments 31-36 or 38-44, wherein X⁴ is CH. 46. The compound of any one of embodiments 31-36 or 38-44, wherein X⁴ is CR⁵. 47. The compound of any one of embodiments 31-36 or 38-44, wherein X⁴ is N. 48. The compound of any one of embodiments 31-37 or 39-47, wherein X³ is CH. 49. The compound of any one of embodiments 31-37 or 39-47, wherein X³ is CR⁵. 50. The compound of any one of embodiments 31-37 or 39-47, wherein X³ is N. 51. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety or Heterocyclic Moiety^B is

52. The compound of any one of embodiments 1-51, wherein R³ is hydrogen. 53. The compound of any one of embodiments 1-52, wherein R⁴ is hydrogen. 54. The compound of any one of embodiments 1-53, wherein R⁶ is hydrogen. 55. The compound of any one of embodiments 1-54, wherein Linker is of formula:

. 56. The compound of embodiment 55, wherein X¹ is bond. 57. The compound of embodiment 55, wherein X¹ is heterocycle. 58. The compound of embodiment 55, wherein X¹ is NR². 59. The compound of embodiment 55, wherein X¹ is C(O). 60. The compound of any one of embodiments 55-59, wherein X² is bond. 61. The compound of any one of embodiments 55-59, wherein X² is heterocycle. 62. The compound of any one of embodiments 55-59, wherein X² is NR². 63. The compound of any one of embodiments 55-59, wherein X² is C(O). 64. The compound of any one of embodiments 55-63, wherein R²⁰ is bond. 65. The compound of any one of embodiments 55-63, wherein R²⁰ is CH₂. 66. The compound of any one of embodiments 55-63, wherein R²⁰ is heterocycle. 67. The compound of any one of embodiments 55-63, wherein R²⁰ is aryl. 68. The compound of any one of embodiments 55-63, wherein R²⁰ is phenyl. 69. The compound of any one of embodiments 55-63, wherein R²⁰ is bicycle. 70. The compound of any one of embodiments 55-69, wherein R²¹ is bond. 71. The compound of any one of embodiments 55-69, wherein R²¹ is CH₂. 72. The compound of any one of embodiments 55-69, wherein R²¹ is heterocycle. 73. The compound of any one of embodiments 55-69, wherein R²¹ is aryl. 74. The compound of any one of embodiments 55-69, wherein R²¹ is phenyl. 75. The compound of any one of embodiments 55-69, wherein R²¹ is bicycle. 76. The compound of any one of embodiments 1-54, wherein Linker is of formula:

. 77. The compound of any one of embodiments 55-76, wherein R²² is bond. 78. The compound of any one of embodiments 55-76, wherein R²² is CH₂. 79. The compound of any one of embodiments 55-76, wherein R²² is heterocycle. 80. The compound of any one of embodiments 55-76, wherein R²² is aryl. 81. The compound of any one of embodiments 55-76, wherein R²² is phenyl. 82. The compound of any one of embodiments 55-76, wherein R²² is bicycle. 83. The compound of any one of embodiments 1-54, wherein Linker is of formula:

84. The compound of any one of embodiments 55-83, wherein R²³ is bond. 85. The compound of any one of embodiments 55-83, wherein R²³ is CH₂. 86. The compound of any one of embodiments 55-83, wherein R²³ is heterocycle. 87. The compound of any one of embodiments 55-83, wherein R²³ is aryl. 88. The compound of any one of embodiments 55-83, wherein R²³ is phenyl. 89. The compound of any one of embodiments 55-83, wherein R²³ is bicycle. 90. The compound of any one of embodiments 1-54, wherein Linker is of formula:

91. The compound of any one of embodiments 55-90, wherein R²⁴ is bond. 92. The compound of any one of embodiments 55-90, wherein R²⁴ is CH₂. 93. The compound of any one of embodiments 55-90, wherein R²⁴ is heterocycle. 94. The compound of any one of embodiments 55-90, wherein R²⁴ is aryl. 95. The compound of any one of embodiments 55-90, wherein R²⁴ is phenyl. 96. The compound of any one of embodiments 55-90, wherein R²⁴ is bicycle. 97. The compound of any one of embodiments 55-90, wherein R²⁴ is C(O). 98. The compound of any one of embodiments 1-97, wherein the NTRK Targeting Ligand is selected from:

. 99. The compound of any one of embodiments 1-97, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is selected from:

. 100. The compound of any one of embodiments 1-97, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is selected from:

. 101. The compound of any one of embodiments 1-97, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is selected from:

. 102. The compound of any one of embodiments 1-97, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is selected from:

. 103. The compound of any one of embodiments 1-97, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is selected from:

. 104. The compound of any one of embodiments 1-97, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is selected from:

105. The compound of any one of embodiments 1-104, wherein X¹⁶ is

106. The compound of any one of embodiments 1-104, wherein X¹⁶ is

107. The compound of any one of embodiments 1-104, wherein X¹⁶ is

. 108. The compound of any one of embodiments 1-104, wherein X¹⁶ is

109. The compound of any one of embodiments 1-104, wherein X¹⁶ is

110. The compound of any one of embodiments 1-109, wherein the compound is of Formula A. 111. The compound of any one of embodiments 1-109, wherein the compound is of Formula B. 112. In certain embodiments a compound from Table 1 is provided. 113. In certain embodiments a pharmaceutical composition comprising an effective amount of a compound of any one of embodiments 1-112 and a pharmaceutically acceptable excipient is provided. 114. In certain embodiments a method of treating a disorder mediated by NTRK comprising administering an effective amount of a compound of any one of embodiments 1-112 or a pharmaceutical composition of embodiment 113 is provided. 115. The method of embodiment 114, wherein the disorder is a cancer. 116. The method of embodiment 115, wherein the cancer is driven in part by an NTRK mutation. 117. The method of embodiment 115, wherein the mutant NTRK is mutant NTRK1. 118. The method of embodiment 116 or 117, wherein the NTRK mutation comprises a F589L mutation. 119. The method of any one of embodiments 116-118, wherein the NTRK mutation comprises a G595R mutation. 120. The method of any one of embodiments 116-119, wherein the NTRK mutation comprises a G667C mutation. 121. The method of embodiment 117, wherein the mutant NTRK is mutant NTRK3. 122. The method of embodiment 121, wherein the NTRK mutation comprises a F617L mutation. 123. The method of any one of embodiments 121-122, wherein the NTRK mutation comprises a G623R mutation. 124. The method of any one of embodiments 121-122, wherein the NTRK mutation comprises a G696A mutation. IV. EXEMPLARY COMPOUNDS OF THE PRESENT INVENTION In certain embodiments the Heterocyclic Moiety or Heterocyclic Moiety^B is selected from:

In certain embodiments the Heterocyclic Moiety or Heterocyclic Moiety^B is selected from:

In certain embodiments the Heterocyclic Moiety or Heterocyclic Moiety is selected from:

Non-limiting examples of Heterocyclic Moiety or Heterocyclic Moiety^B include:

Non-limiting examples of Heterocyclic Moiety or Heterocyclic Moiety^B include:

In certain embodiments Heterocyclic Moiety or Heterocyclic Moiety^B is selected from

. In certain embodiments Heterocyclic Moiety^B is selected from

. IV. LINKERS A Linker is included in the compounds of Formula A. Linker is a bond or a chemically stable bivalent group that covalently attaches the Heterocyclic Moiety to the selected NTRK Targeting Ligand. In certain embodiments, Linker can be any chemically stable group that attaches the Heterocyclic Moiety to the NTRK Targeting Ligand. In some embodiments, Linker has a chain of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more carbon atoms of which one or more carbon atoms can be replaced by a heteroatom such as O, N, S, or P, as long as the resulting molecule has a stable shelf life for at least two months, three months, six months, or one year as part of a pharmaceutically acceptable dosage form, and itself is pharmaceutically acceptable. In certain embodiments, the chain has 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 contiguous atoms in the chain. For example, the chain may include 1 or more ethylene glycol units, and in some embodiments, may have at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more contiguous, partially contiguous, or non-contiguous ethylene glycol the Linker. In certain embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 branches which can be independently alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl substituents, which in one embodiment, each branch has 10, 8, 6, 4, 3, 2, or 1 carbon. In other embodiments, the linker can include or be comprised of one or more of ethylene glycol, propylene glycol, lactic acid and/or glycolic acid. In general, propylene glycol adds hydrophobicity, while propylene glycol adds hydrophilicity. Lactic acid segments tend to have a longer half-life than glycolic acid segments. Block and random lactic acid-co-glycolic acid moieties, as well as ethylene glycol and propylene glycol, are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain the desired half-life and hydrophilicity. In certain aspects, these units can be flanked or interspersed with other moieties, such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc., as desired to achieve the appropriate drug properties. In certain embodiments the compound of the present invention has one or more exit vectors that appropriately orients the NTRK Targeting Ligand and/or E3 ligase ligand (heterocyclic moiety) to improve properties of the compound for example to increase binding potency or ternary complex formation. For example, in certain embodiments X¹⁶ is an exit vector for the NTRK Targeting Ligand. In certain embodiments X¹ or X² is an exit vector for the E3 ligase ligand. The exit vector may make interactions with the protein it exits and/or may direct the linker portion and targeting ligand portion of the molecule at appropriate angles to allow formation of the ternary complex comprising the NTRK Protein, compound of the present invention, and cereblon.

In certain aspects, Linker is selected from

wherein all variables are defined as above.

In certain embodiments the linker includes

In certain embodiments the linker includes

In certain embodiments the linker includes

In certain embodiments the linker includes

In certain embodiments the linker includes

In certain embodiments the linker includes

In certain embodiments the linker includes

In certain embodiments the linker includes

In certain embodiments the linker includes

In certain embodiments the linker includes

In certain embodiments the linker includes

In certain embodiments the linker includes

The following are non-limiting examples of Linkers that can be used in this invention.

Based on this elaboration, those of skill in the art will understand how to use the full breadth of

Linkers that will accomplish the goal of the invention.

As certain non -limiting examples, Linker includes:

, In an additional embodiment Linker is selected from:

. In one embodiment X¹ is attached to the NTRK Targeting Ligand. In another embodiment X² is attached to the NTRK Targeting Ligand. Non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, and R²⁴ include:

, ,

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, and R²⁴ include:

In additional embodiments, the Linker is an optionally substituted (poly)ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, ethylene glycol units, or optionally substituted alkyl groups interspersed with optionally substituted, O, N, S, P or Si atoms. In certain embodiments, Linker is flanked, substituted, or interspersed with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. In certain embodiments, Linker may be asymmetric or symmetrical. In some embodiments, Linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units. In any of the embodiments of the compounds described herein, Linker group may be any suitable moiety as described herein. In additional embodiments, Linker is selected from: -NR⁶¹(CH₂)_n1-(lower alkyl)-, -NR⁶¹(CH₂)_n1-(lower alkoxyl)-, -NR⁶¹(CH₂)_n1-(lower alkoxyl)-OCH₂-, -NR⁶¹(CH₂)_n1-(lower alkoxyl)-(lower alkyl)-OCH₂-, -NR⁶¹(CH₂)_n1-(cycloalkyl)-(lower alkyl)-OCH₂-, -NR⁶¹(CH₂)_n1-(heterocycloalkyl)-, -NR⁶¹(CH₂CH₂O)_n1-(lower alkyl)-O-CH₂-, -NR⁶¹(CH₂CH₂O)_n1-(heterocycloalkyl)-O-CH₂-, -NR⁶¹(CH₂CH₂O)_n1-Aryl-O-CH₂-, -NR⁶¹(CH₂CH₂O)_n1-(heteroaryl)-O-CH₂-, -NR⁶¹(CH₂CH₂O)_n1-(cycloalkyl)-O-(heteroaryl)-O-CH₂-, -NR⁶¹(CH₂CH₂O)_n1-(cycloalkyl)-O-Aryl-O-CH₂-, -NR⁶¹(CH₂CH₂O)_n1-(lower alkyl)-NH-Aryl-O- CH₂-, -NR⁶¹(CH₂CH₂O)_n1-(lower alkyl)-O-Aryl-CH₂, -NR⁶¹(CH₂CH₂O)_n1-cycloalkyl-O-Aryl-, - NR⁶¹(CH₂CH₂O)_n1-cycloalkyl-O-heteroaryl-, -NR⁶¹(CH₂CH₂)_n1-(cycloalkyl)-O-(heterocycle)-CH_2, -NR⁶¹(CH₂CH₂)_n1-(heterocycle)-(heterocycle)-CH₂, and -NR⁶¹-(heterocycle)-CH₂; wherein n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and R⁶¹ is H, methyl, or ethyl. In additional embodiments, Linker is selected from: -N(R⁶¹)-(CH₂)_m1-O(CH₂)_n2-O(CH₂)_o1-O(CH₂)_p1-O(CH₂)_q1-O(CH₂)_r1-OCH₂-, -O-(CH₂)_m1-O(CH₂)_n2-O(CH₂)_o1-O(CH₂)_p1-O(CH₂)_q1-O(CH₂)_r1-OCH₂-, -O-(CH₂)_m1-O(CH₂)_n2-O(CH₂)_o1-O(CH₂)_p1-O(CH₂)_q1-O(CH₂)_r1-O-; -N(R⁶¹)-(CH₂)_m1-O(CH₂)_n2-O(CH₂)_o1-O(CH₂)_p1-O(CH₂)_q1-O(CH₂)_r1-O-; -(CH₂)_m1-O(CH₂)_n2-O(CH₂)_o1-O(CH₂)_p1-O(CH₂)_q1-O(CH₂)_r1-O-; -(CH₂)_m1-O(CH₂)_n2-O(CH₂)_o1-O(CH₂)_p1-O(CH₂)_q1-O(CH₂)_r1-OCH₂-; -O(CH₂)_m1O(CH₂)_n2O(CH₂)_p1O(CH₂)_q1OCH₂-; -O(CH₂)_m1O(CH₂)_n2O(CH₂)_p1O(CH₂)_q1OCH₂-; wherein m1, n2, o1, p1, q1, and r1 are independently 1, 2, 3, 4, or 5; and R⁶¹ is H, methyl, or ethyl. In additional embodiments, Linker is selected from:

,

, m1, n2, o1, p1, q2, and r1 are independently 1, 2, 3, 4, or 5. In additional embodiments, Linker is selected from:

In additional embodiments, Linker is selected from:

In additional embodiments, Linker is selected from:

wherein R⁷¹ is -O-, -NH, Nalkyl, heteroaliphatic, aliphatic, or -NMe. In additional embodiments, Linker is selected from:

In additional embodiments, Linker is selected from:

In additional embodiments, Linker is selected from:

In additional embodiments, Linker is selected from:

, , In additional embodiments, Linker is selected from:

In additional embodiments, Linker is selected from:

In additional embodiments, Linker is selected from:

In certain embodiments, Linker is selected from:

In certain embodiments Linker is selected from:

In the above structures

represents

In certain embodiments, Linker can be a 4-24 carbon atom linear chains, wherein one or more the carbon atoms in the linear chain can be replaced or substituted with oxygen, nitrogen, amide, fluorinated carbon, etc., such as the following:

In certain embodiments, Linker can be a nonlinear chain, and can be, or include, aliphatic or aromatic or heteroaromatic cyclic moieties. In certain embodiments, Linker may include contiguous, partially contiguous or non- contiguous ethylene glycol unit groups ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units, for example, 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units. In certain embodiments, Linker may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 fluorine substituents. In another embodiment Linker is perfluorinated. In yet another embodiment Linker is a partially or fully fluorinated poly ether. Nonlimiting examples of fluorinated Linker moieties include:

Non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, and R²⁴ include:

, ,

In certain embodiments, the length can be adjusted as desired or as found necessary for the desired application. V. METHODS OF TREATMENT

A compound of the present invention be used in an effective amount to treat a host, including a human, in need thereof, optionally in a pharmaceutically acceptable carrier to treat a NTRK mediated disorder described herein. The control of protein level afforded by a compound of the present invention provides treatment of a disease state or condition, which is modulated through NTRK by lowering the level of that protein in the cell, e.g., cell of a patient. In certain embodiments, the method comprises administering an effective amount of the compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, i.e., a pharmaceutically acceptable composition, optionally in combination with another bioactive agent or combination of agents.

The term “disease state or condition” when used in connection with a compound of the present invention for example, refers to any therapeutic indication which can be treated by degrading the Target NTRK Protein.

In certain embodiments a compound of the present invention is used to treat a cancer that is caused or mediated by NTRK for example a cancer associated with an NTRK mutation. Nonlimiting examples of NTRK mutations include NTRK1 with one or more mutations selected form F589L, G595R, and G667C andNTRK3 with one or more mutations selected from F617L, G623R, and G696A. Additional examples of NTRK1 mutations include V573M and G667S.

Examples of disorders associated with an NTRK mutation or deletion include pulmonary neuroendocrine tumors, anhidrosis syndrome, obesity, congenital heart defects, and acute myeloid leukemia. Examples of disorders that are mediated by TRK amplifications include liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, pheochromocytoma, Wilms’ tumor, and prostate cancer.

In other embodiments a compound of the present invention is used to treat another disorder mediated by NTRK, for example a disorder related to pain, thermoregulation, movement, memory, mood, appetite, weight, sense of self-movement, and/or body position. In certain embodiments the disorder is related to pain and/or thermoregulation and the compound degrades NTRK1. In certain embodiments the disorder is related to movement, memory, mood, appetite, and/or weight and the compound degrades NTRK2. In certain embodiments the disorder is related to sense of selfmovement and/or body position and the compound degrades NTRK3.

In certain embodiments a compound of the present invention can be used to reduce pain in a subject in need thereof. In certain embodiments the compound used to reduce pain degrades wildtype NTRK. In certain embodiments a compound of the present invention reduces neuropathic pain, nociceptive pain, intense pain, acute pain, chronic pain, and/or inflammatory pain.

In certain embodiments a compound of the present invention is used to treat breast cancer.

In certain embodiments a compound of the present invention is used to treat cholangiocarcinoma.

In certain embodiments a compound of the present invention is used to treat colorectal cancer.

In certain embodiments a compound of the present invention is used to treat a gynecological cancer such as uterine or ovarian cancer.

In certain embodiments a compound of the present invention is used to treat a neuroendocrine cancer.

In certain embodiments a compound of the present invention is used to treat lung cancer for example non-small cell lung cancer.

In certain embodiments a compound of the present invention is used to treat salivary gland cancer.

In certain embodiments a compound of the present invention is used to treat pancreatic cancer.

In certain embodiments a compound of the present invention is used to treat a sarcoma.

In certain embodiments a compound of the present invention is used to treat a thyroid cancer.

In certain embodiments a compound of the present invention is used to treat a glioma.

In certain embodiments a compound of the present invention is used to treat a soft-tissue sarcoma.

In certain embodiments a compound of the present invention is used to treat an inflammatory myofibroblastic tumor.

In certain embodiments a compound of the present invention is used to treat congenital infantile fibrosarcoma. In certain embodiments a compound of the present invention is used to treat mesoblastic nephroma. Additional examples of disorders that can be mediated by NTRK include inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, including but not limited to neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric carcinoma, lung carcinoma, liver cancer, uterine cancer, adrenal cancer, biliary tree cancer, intestinal cancer, colorectal cancer, ovarian cancer, lung carcinoma, small cell lung cancer, non-small cell lung cancer, gastric carcinoma, breast cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secretory breast carcinoma, salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma, acute myeloid leukemia, large cell neuroendocrine tumors, pulmonary neuroendocrine tumors, sarcomas, pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, malignant fibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma, neoplasms of the central nervous systems, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, Spitzoid cancer, Wilms' tumor, lymphomas (e.g., including Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa- associated lymphoid tissue lymphoma, mantle cell lymphoma, B-Iineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma), inflammatory lung diseases (e.g., asthma), inflammatory bowel diseases, (e.g., ulcerative colitis, Crohn's disease), inflammatory skin diseases (e.g., atopic dermatitis, eczema and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, pain of osteoarthritis, chronic low back pain, low back pain of osteoporosis, pain of bone fracture, pain of rheumatoid arthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, pain of pulpitis, interstitial cystitis pain, painful bladder syndrome, central pain syndromes, postsurgical pain syndromes, bone and joint pain, repetitive motion pain, dental pain, myofascial pain, perioperative pain, dysmenorrhea, myofascial pain, angina pain, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain caused by central sensitization, systemic cutaneous pruritus, localized cutaneous pruritus, senile cutaneous pruritus, gestational pruritus, pruritus ani, vulvar pruritus, metastatic bone disease, treatment-induce bone loss, osteoporosis, rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelination and demyelination. In certain embodiments the compound of the present invention is used to treat a cancer. Non-limiting examples of cancer include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using compounds according to the present invention include, for example, T- lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B- cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML. Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor- positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltrating breast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma metastatic breast cancer, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis;; B-cell prolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma, T cell/histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric, Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

In certain embodiments, the condition treated with a compound of the present invention is a disorder related to abnormal cellular proliferation. Abnormal cellular proliferation, notably hyperproliferation, can occur as a result of a wide variety of factors, including genetic mutation, infection, exposure to toxins, autoimmune disorders, and benign or malignant tumor induction.

There are a number of skin disorders associated with cellular hyperproliferation. Psoriasis, for example, is a benign disease of human skin generally characterized by plaques covered by thickened scales. The disease is caused by increased proliferation of epidermal cells of unknown cause. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.

Other hyperproliferative cell disorders include blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancers.

Blood vessel proliferative disorders include angiogenic and vasculogenic disorders. Proliferation of smooth muscle cells in the course of development of plaques in vascular tissue cause, for example, restenosis, retinopathies and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

Fibrotic disorders are often due to the abnormal formation of an extracellular matrix. Examples of fibrotic disorders include hepatic cirrhosis and mesangial proliferative cell disorders. Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar. Hepatic cirrhosis can cause diseases such as cirrhosis of the liver. An increased extracellular matrix resulting in a hepatic scar can also be caused by viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis.

Mesangial disorders are brought about by abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell disorders include various human renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies.

Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease that is thought to be associated with activity of autoreactive T cells, and to be caused by autoantibodies produced against collagen and IgE.

Other disorders that can include an abnormal cellular proliferative component include Bechet’s syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post- dialysis syndrome, leukemia, acquired immune deficiency syndrome, vasculitis, lipid histiocytosis, septic shock and inflammation in general.

The term “neoplasia” or “cancer” is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors. Exemplary cancers which may be treated by the present compounds either alone or in combination with at least one additional anti -cancer agent include

The term “bioactive agent” is used to describe an agent, other than a compound according to the present invention, which is used in combination with the present compounds as an agent with biological activity to assist in effecting an intended therapy, inhibition and/or prevention/prophylaxis for which the present compounds are used.

Examples of pain include:

Nociceptive pain

Nociceptive pain can be induced by tissue injury or intense stimuli. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and sensitize the spinal cord at the level of their termination. The activation of nociceptors activates two types of afferent nerve fibers. Myelinated A-delta fibers transmit rapidly and are responsible for the sharp and stabbing pain sensations, whilst unmyelinated C fibers transmit at a slower rate and convey the dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to pain from strains/sprains, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, burns, myocardial infarction, acute pancreatitis, and renal colic. Nociceptive pain also includes cancer related acute pain syndromes commonly caused by therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormonal therapy and radiotherapy. Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to, cancer pain which may be tumor related pain, (e.g., bone pain, headache and facial pain, viscera pain) or associated with cancer therapy (e.g., postchemotherapy syndromes, chronic postsurgical pain syndromes, post radiation syndromes), back pain which may be due to herniated or ruptured intervertebral discs or abnormalities of the lumbar facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament.

Neuropathic pain

According to the invention a compound of the present invention can potentially be used to treat neuropathic pain and the symptoms of neuropathic pain including hyperalgesia, allodynia and ongoing pain. Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (IASP definition). Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologias. These include but are not limited to, Diabetic neuropathy, Post herpetic neuralgia, Back pain, Cancer neuropathy, HIV neuropathy, Phantom limb pain, Carpal Tunnel Syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia, or vitamin deficiencies. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patient’s quality of life (Woolf and Mannion 1999 Lancet 353: 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd 1999 Pain Supp. 6: S141-S147; Woolf and Mannion 1999 Lancet 353: 1959-1964). They include spontaneous pain, which can be continuous, or paroxysmal and abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).

Intense acute pain and chronic pain

Intense acute pain and chronic pain may involve the same pathways driven by pathophysiological processes and as such cease to provide a protective mechanism and instead contribute to debilitating symptoms associated with a wide range of disease states. Pain is a feature of many trauma and disease states. When a substantial injury, via disease or trauma, to body tissue occurs the characteristics of nociceptor activation are altered. There is sensitization in the periphery, locally around the injury and centrally where the nociceptors terminate. This leads to hypersensitivity at the site of damage and in nearby normal tissue. In acute pain these mechanisms can be useful and allow for the repair processes to take place and the hypersensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is normally due to nervous system injury. This injury often leads to maladaptation of the afferent fibers (Woolf & Salter 2000 Science 288: 1765-1768). Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. There are a number of typical pain subtypes: 1 ) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); 3) pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Although patients with back pain, arthritis pain, CNS trauma, or neuropathic pain may have similar symptoms, the underlying mechanisms are different and, therefore, may require different treatment strategies.

Chronic pain

Chronic pain comprises one or more of, chronic nociceptive pain, chronic neuropathic pain, chronic inflammatory pain, breakthrough pain, persistent pain hyperalgesia, allodynia, central sensitization, peripheral sensitization, disinhibition and augmented facilitation.

Chronic pain includes cancer pain, e.g., cancer pain arising from malignancy, adenocarcinoma in glandular tissue, blastoma in embryonic tissue of organs, carcinoma in epithelial tissue, leukemia in tissues that form blood cells, lymphoma in lymphatic tissue, myeloma in bone marrow, sarcoma in connective or supportive tissue, adrenal cancer, AIDS-related lymphoma, anemia, bladder cancer, bone cancer, brain cancer, breast cancer, carcinoid tumors, cervical cancer, chemotherapy, colon cancer, cytopenia, , endometrial cancer, esophageal cancer, gastric cancer, head cancer, neck cancer, hepatobiliary cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, Hodgkin's disease, lymphoma, non- Hodgkin's, nervous system tumors, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, urethral cancer, bone cancer, sarcomas cancer of the connective tissue, cancer of bone tissue, cancer of blood-forming cells, cancer of bone marrow, multiple myeloma, leukemia, primary or secondary bone cancer, tumors that metastasize to the bone, tumors infiltrating the nerve and hollow viscus, tumors near neural structures. Cancer pain also comprises visceral pain, e.g., visceral pain which arises from pancreatic cancer and/or metastases in the abdomen, somatic pain, e.g., somatic pain due to one or more of bone cancer, metastasis in the bone, postsurgical pain, sarcomas cancer of the connective tissue, cancer of bone tissue, cancer of blood-forming cells of the bone marrow, multiple myeloma, leukemia, primary or secondary bone cancer.

Inflammatory pain

Inflammatory pain includes acute inflammatory pain and/or chronic inflammatory pain wherein the chronic inflammatory pain can be pain involving both peripheral and central sensitization and/or mixed etiology pain involving both inflammatory pain and neuropathic pain or nociceptive pain components.

Inflammatory pain also comprises hyperalgesia, e.g., primary and/or secondary hyperalgesia. Additionally or alternatively the inflammatory pain can include allodynia. Inflammatory pain also comprises pain that persists beyond resolution of an underlying disorder or inflammatory condition or healing of an injury.

Inflammatory pain is pain resulting an inflammatory condition, e.g., in response to acute tissue injury due to trauma, disease e.g., an inflammatory disease, immune reaction, the presence of foreign substances, chemicals or infective particles for example micro-organisms. Inflammatory conditions can be either acute or chronic inflammation or both.

Inflammatory pain can result from an inflammatory condition due to an inflammatory disease such as inflammatory joint diseases, inflammatory connective tissue diseases, inflammatory autoimmune diseases, inflammatory myopathies, inflammatory digestive system diseases, inflammatory air way diseases, cellular immune inflammation diseases, hypersensitivities and allergies, vascular inflammation diseases, non-immune inflammatory disease, synovitis, arthralgias, ankylosing spondylitis, spondylarthritis, spondyloarthropathy, gout, Paget’s disease, periarticular disorders such as bursitis, rheumatoid disease, rheumatoid arthritis and osteoarthritis, rheumatoid arthritis or osteoarthritis. Rheumatoid arthritis in particular, represents ongoing inflammation associated with severe pain. Arthritic pain is a form of inflammatory pain and arises from inflammation in a joint which causes both peripheral sensitization and central sensitization. Under inflammatory conditions the nociceptive system is activated by normally innocuous and nonpainful mechanical stimuli. Additionally when the joint is at rest pain is present and appears as spontaneous pain and hyperalgesia (augmented pain response on noxious stimulation and pain on normally nonpainful stimulation). Inflammatory processes in peripheral tissues lead to central sensitization in the spinal cord, which contributes to hyperalgesia and allodynia typically associated with inflammatory pain. Other types of inflammatory pain include inflammatory bowel diseases (IBD).

Other types of pain

Additional examples of pain include: i) Musculoskeletal disorders including but not limited to myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, Glycogenolysis, polymyositis, and pyomyositis; ii) Central pain or 'thalamic pain' as defined by pain caused by lesion or dysfunction of the nervous system including but not limited to central post-stroke pain, multiple sclerosis, spinal cord injury, Parkinson's disease and epilepsy; iii) Heart and vascular pain including but not limited to angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma, scleredoma, and skeletal muscle ischemia; iv) Visceral pain, and gastrointestinal disorders. The viscera encompasses the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (GI) disorders include the functional bowel disorders (FBD) and the inflammatory bowel diseases (IBD). These GI disorders include a wide range of disease states that are currently only moderately controlled, including - for FBD, gastro-esophageal reflux, dyspepsia, the irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and - for IBD, Crohn's disease, ileitis, and ulcerative colitis, which all regularly produce visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis; Head pain including but not limited to migraine, migraine with aura, migraine without aura cluster headache, tension-type headache. Orofacial pain including but not limited to dental pain, temporomandibular myofascial pain, tinnitus, hot flushes, restless leg syndrome and blocking development of abuse potential. Further pain conditions may include, back pain (e.g., chronic lower back pain), cancer pain, complex regional syndrome, HIV- related neuropathic pain, post-operative induced neuropathic pain, post-stroke pain, spinal cord injury pain, traumatic nerve injury pain, diabetic peripheral neuropathy, moderate / severe interstitial cystitis pain, irritable bowel syndrome pain, moderate / severe endometriosis pain, moderate / severe pelvic pain, moderate / severe prostatitis pain, moderate / severe osteoarthritis pain, post-herpetic neuralgia, rheumatoid arthritis pain, dysmenorrhea pain, pre-emptive post-operative pain, trigeminal neuralgia, bursitis, dental pain, fibromyalgia or myofacial pain, menstrual pain, migraine, neuropathic pain (including painful diabetic neuropathy), pain associated with postherpetic neuralgia, post-operative pain, referred pain, trigeminal neuralgia, visceral pain (including interstitial cystitis and IBS) and pain associated with AIDS, allodynia, burns, cancer, hyperalgesia, hypersensitisation, spinal trauma and/or degeneration and stroke.

VI. PHARMACEUTICAL COMPOSITIONS

A selected compound of the present invention can be administered as the neat chemical, but is more typically administered as a pharmaceutical composition, that includes an effective amount for a host, typically a human, in need of such treatment for any of the disorders described herein. Accordingly, the disclosure provides pharmaceutical compositions comprising an effective amount of compound or pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition may contain a compound or salt as the only active agent, or, in an alternative embodiment, the compound and at least one additional active agent.

In certain embodiments the pharmaceutical composition is in a dosage form that contains from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 800 mg, from about 1 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms with at least about, or no more than, 0.001, 0.005, 0.010, 0.10, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt.

Compounds disclosed herein may be administered orally, topically, systemically, parenterally, by inhalation or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection, including intravenous, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, or rectal or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.

The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as a solid dosage form, liquid, an aerosol, a cream, a gel, a pill, an injection or infusion solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.

Carriers include excipients and diluents and should be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration in an effective amount to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.

Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidents, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.

The pharmaceutical compositions/combinations can be formulated for oral administration. These compositions can contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight % (wt.%) of the compound and usually at least about 5 wt.% of the compound. Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the compound.

In certain embodiments the LNP contains a cationic or ionizable limit. Examples include but are not limited to: U.S. Patent Publication Nos. 20060083780 and 20060240554; U.S. Pat. Nos. 5,208,036; 5,264,618; 5,279,833; 5,283,185; 5,753,613; and 5,785,992; and PCT Publication No. WO 96/10390, the disclosures of which are each herein incorporated by reference in their entirety for all purposes.

Formulations suitable for rectal administration are sometimes presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.

Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and sometimes take the form of an optionally buffered aqueous solution of the active compound. In one embodiment, microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue.

Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI). The devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung. VII. GENERAL SYNTHESIS

The compounds described herein can be prepared by methods known by those skilled in the art. In one non-limiting example, the disclosed compounds can be made using the schemes below.

Compounds of the present invention with stereocenters may be drawn without stereochemistry for convenience. One skilled in the art will recognize that pure enantiomers and diastereomers can be prepared by methods known in the art. Examples of methods to obtain optically active materials include at least the following: i) physical separation of crystals - a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the enantiomer is a conglomerate in the solid state; iii) enzymatic resolutions - a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step in the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis - a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved by chiral catalysts or chiral auxiliaries; vi) diastereomer separations - a technique whereby a racemic compound is reaction with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate quickly equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer of where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomers. The desired enantiomer is then released from the diastereomer; viii) kinetic resolutions - this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography - a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including vial chiral HPLC). The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography - a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique whereby a racemate is place in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through; xiv) simulated moving bed chromatography is used in one embodiment. A wide variety of chiral stationary phases are commercially available. SYNTHESIS OF REPRESENTATIVE COMPOUNDS OF THE PRESENT INVENTION SYNTHESIS OF CRBN BINDERS Example 1

Compound 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione hydrochloride was prepared according to the method described on page 102 of WO2021083949A1

Compound 1-(4-(piperidin-4-yl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate was prepared according to the method described on page 353 of WO2020132561A1.

Compound 3-[4-(4-piperidyl)phenoxy]piperidine-2,6-dione hydrochloride was prepared according to the method described on page 83 of WO2021083949A1

Compound 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride was prepared according to the method described on page 268 of WO2018237026A1.

Compound 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride was prepared according to the method described on page 265 of WO2018237026A1. Example 2 Synthesis of (3S)-3-[4-(4-piperidyl)anilino]piperidine-2,6-dione hydrochloride (4) and tert- butyl 4-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate (5)

Compound tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperidine-1-carboxylate was prepared according to the method described on page 347 of WO2021127561A1. Step-1: 1.3 g of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperidine-1-carboxylate (1) was separated by the following preparative SFC method to obtain 2, Early-Eluting Peak 1 and 3, Late-Eluting Peak 2 as single enantiomers. Column/dimensions: Chiralcel OJ-H (21×250) mm, 5μm % CO₂: 70% % Co solvent: 30%(ACN) Total Flow: 60 g/min Back Pressure: 100 bar Temperature: 30 °C UV: 243 nm Solubility: ACN No. of injections: 150 Total purification time: 12:00 hours Instrument details: Make/Model: SFC-200 2, Early-Eluting Peak 1 tert-butyl 4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate (2, 0.522 g, 1.32 mmol, 39% yield) (Stereochemistry arbitrarily assigned). LCMS (ES-): m/z 386.51 [M - H] -. 3, Late-Eluting Peak 2 tert-butyl 4-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate (3, 0.517 g, 1.31 mmol, 39% yield) (Stereochemistry arbitrarily assigned). LCMS (ES-): m/z 386.51 [M - H] -. Step-2: To a stirred solution of tert-butyl 4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1- carboxylate (2, 50 mg, 129.04 µmol) in DCM (1 mL),cooled to 0 °C, then 4 M hydrogen chloride in 1,4-dioxane, 99% (1 eq.) was added dropwise and the reaction mass was stirred at 25°C for 1 hour. The above reaction was monitored by UPLC. After consumption of the starting materials, the reaction mixture was concentrated under reduced pressure and the crude was triturated with Diethyl ether to afford crude product of (3S)-3-[4-(4-piperidyl)anilino]piperidine-2,6-dione hydrochloride (4, 42 mg, 123.32 µmol, 96% yield) as off white solid. LCMS (ES⁺): m/z 288.2 [M + H] ⁺. Step-3: To a stirred solution tert-butyl 4-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1- carboxylate (3, 75 mg, 193.56 µmol) in DCM (4 mL) cooled to 0°C, then 4 M hydrogen chloride in 1,4-dioxane, 99% (800.00 mg, 21.94 mmol, 1 mL) was added dropwise. The reaction mixture was stirred at 25°C for 1 hour and monitored by UPLC and TLC. After consumption of the starting material, the reaction mixture was concentrated under reduced pressure and triturated with diethyl ether to afford (3R)-3-[4-(4-piperidyl)anilino]piperidine-2,6-dione hydrochloride (5, 60 mg, 182.51 µmol, 94% yield) as an off white solid. LCMS (ES⁺): m/z 288.3 [M + H] ⁺. Example 3 Synthesis of tert-butyl 3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]azetidine-1-carboxylate

Step-1: A solution of N-(4-bromophenyl)-2,2,2-trifluoro-acetamide (1, 5 g, 18.65 mmol),tert-butyl 3- iodoazetidine-1-carboxylate (2, 5.28 g, 18.65 mmol), zinc (3.66 g, 55.96 mmol, 512.53 µL), nickel(II) chloride ethylene glycol dimethyl ether (819.76 mg, 3.73 mmol) and pyridine-2- carboxamidine hydrochloride (3, 587.99 mg, 3.73 mmol) in DMAC (80 mL) was stirred at 70 °C under nitrogen for 3 hours. The reaction was filtered, and filtrate was diluted with ethyl acetate (100 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by prep-TLC (PE:EA=2:1, Rf=0.6) to give tert-butyl 3-[4-[(2,2,2-trifluoroacetyl)amino]phenyl]azetidine-1-carboxylate (4, 1.53 g, 4.44 mmol, 24% yield) as white solid.¹H NMR (400 MHz, CHLOROFORM-d) δ = 8.49 (br s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 4.35 (t, J = 8.8 Hz, 2H), 3.95 (dd, J = 6.0, 8.8 Hz, 2H), 3.73 (tt, J = 6.0, 8.8 Hz, 1H), 1.49 (s, 9H). Step-2: To a solution of tert-butyl 3-(4-(2,2,2-trifluoroacetamido)phenyl)azetidine-1-carboxylate (4, 1.53 g, 4.44 mmol) in methanol (15 mL) were added cesium carbonate (1.45 g, 4.44 mmol) and potassium carbonate (614.11 mg, 4.44 mmol). The reaction mixture was then stirred at 60 °C for 12 hours. Upon completion of the reaction, the reaction mixture was concentrated under vacuum and the residue was poured into PE:EA=1:1 (30 mL) and stirred at 25°C for 30 minutes to give a suspension. Then the suspension was filtered, the filter cake was washed with PE:EA=1:1 (10×2 mL) and concentrated under vacuum to give tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate (5, 1 g, 3.13 mmol, 70% yield) as a brown solid. LCMS (ES⁺): m/z 193.2 [M-tBu+H]⁺. Step-3: To a solution of tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate (5, 1 g, 4.03 mmol), 3- bromopiperidine-2,6-dione (6, 1.16 g, 6.04 mmol), sodium bicarbonate (676.60 mg, 8.05 mmol, 313.24 µL), and tetra-n-butylammonium iodide (297.49 mg, 805.41 µmol) in MeCN (1 mL) was stirred at 90°C for 12 hours. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (silica gel, PE:EA=10:1 to PE:(EA:DCM=3:1)=1:1) to give tert-butyl 3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)azetidine-1-carboxylate (7, 695 mg, 1.91 mmol, 48% yield) as a blue oil. LCMS (ES⁺): m/z 304.1 [M-tBu+H]⁺. Step-4: To a solution of tert-butyl 3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)azetidine-1-carboxylate (7, 100 mg, 278.23 µmol) in DCM (1 mL) was added TFA (31.72 mg, 278.23 µmol, 21.44 µL). The mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was concentrated to give 3- ((4-(azetidin-3-yl)phenyl)amino)piperidine-2,6-dione (8, 102 mg, 191.25 µmol, 69% yield) as a green solid. LCMS (ES⁺): m/z 260.5 [M +H]⁺.¹H NMR (400 MHz, DMSO-d6) δ = 10.78 (s, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H), 4.32 (dd, J = 4.8, 11.2 Hz, 1H), 4.22 - 4.12 (m, 4H), 4.10 - 4.06 (m, 2H), 2.80 - 2.68 (m, 1H), 2.63 - 2.53 (m, 1H), 2.14 - 2.04 (m, 1H), 1.94 - 1.79 (m, 1H) Example 4 Synthesis of 3-[4-(piperazin-1-ylmethyl)anilino]piperidine-2,6-dione hydrochloride

Step-1: An oven dried round bottom flask was charged with tert-butyl 4-[(4- aminophenyl)methyl]piperazine-1-carboxylate (1, 2 g, 6.86 mmol) and 3-bromopiperidine-2,6- dione (2, 2.64 g, 13.73 mmol). Sodium bicarbonate (1.73 g, 20.59 mmol) was then added at room temperature and the resulting reaction mixture was stirred for 16 hours at 80 °C while monitored by TLC and UPLC. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered through a bed of celite. The filtrate was washed with water, brine solution, dried over Na₂SO₄, and concentrated in vacuo to yield the crude compound. The obtained crude compound was purified by column chromatography using 100-200 silica gel eluted with 7-9% MeOH in DCM to give the product as light green color solid. It was further purified by Prep-HPLC (0.1% HCOOH in H₂O:ACN as mobile phase) and lyophilized to afford tert-butyl 4-[[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]methyl]piperazine-1-carboxylate formate (3, 1.8 g, 3.97 mmol, 58% yield) as an off-white solid. LC-MS (ES⁺): m/z 403.2 [M + H] ⁺. Step-2: A solution of tert-butyl 4-[[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]piperazine-1- carboxylate (3, 200 mg, 496.91 µmol) in DCM (4 mL) was cooled to 0 °C before 4.0 M hydrogen chloride solution in dioxane (54.35 mg, 1.49 mmol, 67.94 µL) was added dropwise. The reaction mixture was stirred at 25 °C for 1 hour and the progress was monitored by UPLC. After consumption of the starting material, the reaction mixture was concentrated under reduced pressure and triturated with diethyl ether to afford 3-[4-(piperazin-1-ylmethyl)anilino]piperidine-2,6-dione hydrochloride (4, 190 mg, 496.82 µmol, 99% yield). LC-MS (ES⁺): m/z 303.3 [M + H] ⁺. Example 5 Synthesis of 3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione

Step-1: A solution of 1-bromo-2-fluoro-4-nitro-benzene (1, 6 g, 27.27 mmol) and tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2, 8.43 g, 27.27 mmol) in dioxane (60 mL) and water (15 mL) in a round bottom flask was purged with argon gas for 10 minutes, followed by the addition of potassium carbonate, granular (11.31 g, 81.82 mmol). The solution was purged with argon gas for another 20 minutes before palladium triphenylphosphane (1.58 g, 1.36 mmol) was added and the reaction was stirred at 90 °C for 16 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude product was diluted with water and extracted with ethyl acetate (2 × 150 ml). The combined organic layer was concentrated in vacuo and purified by normal phase column chromatography (Davisil silica, 5% ethyl acetate in pet ether) to obtain tert-butyl 4-(2-fluoro-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (3, 5.95 g, 18.27 mmol, 67% yield) as a light-yellow solid. LC-MS (ES⁺): m/z 267.15 [M-tBu+H]⁺. Step-2: To a stirred solution of tert-butyl 4-(2-fluoro-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1- carboxylate (3, 3 g, 9.31 mmol) in methanol (70 mL) was added palladium, 10% on carbon, type 487, dry (3 g, 28.19 mmol) at room temperature. The reaction mixture was stirred for 6 hours at this temperature under hydrogen atmosphere, and the reaction progress was monitored by LC-MS. After completion of reaction, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to afford compound tert-butyl 4-(4-amino-2-fluoro- phenyl)piperidine-1-carboxylate (4, 2.5 g, 5.95 mmol, 64% yield) as purple solid, which was taken to the next step without purification. LC-MS (ES⁺): m/z 239.30 [M-tBu +H]⁺. Step-3: In a sealed tube, a solution of tert-butyl 4-(4-amino-2-fluoro-phenyl)piperidine-1-carboxylate (4, 2.5 g, 8.49 mmol) and 3-bromopiperidine-2,6-dione (5, 4.08 g, 21.23 mmol) in DMF (40 mL) was stirred for 10 minutes before sodium bicarbonate (3.57 g, 42.46 mmol) was added and the reaction was heated at 60 °C for 16 hours. The progress of reaction was monitored by LC-MS and TLC. After completion of the reaction, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by column chromatography (Davisil silica, 0-30% ethyl acetate in pet ether) to furnish tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-1- carboxylate (6, 1.8 g, 3.64 mmol, 43% yield) as a brown solid. LC-MS (ES-): m/z 404.3 [M - H] -. Step-4: To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1- carboxylate (6, 100 mg, 246.63 μmol) in DCM (1 mL) was added HCl/dioxane (2 mL). The mixture was stirred at 25 °C for 0.5 hour. After completion of the reaction as confirmed by LC- MS, the solvent was removed and the residue was dissolved in MeCN (30 mL), adjusted to pH=7 with NaHCO₃, and filtered. The filtrate was concentrated in vacuo and used in the next step directly. Compound 3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione (7, 75 mg, 233.34 μmol, 95% yield) was obtained as a white solid. LC-MS (ES⁺): m/z 306.2 [M + H] ⁺. Example 6 Synthesis of 3-[4-(3,3-difluoro-4-piperidyl)anilino]piperidine-2,6-dione hydrochloride

Step-1: To a stirred a solution of 1-bromo-4-nitro-benzene (1, 5 g, 24.75 mmol, 2.56 mL) in DMF (40 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (6.91 g, 27.23 mmol) and potassium acetate (6.07 g, 61.88 mmol). The resulting mixture was purged with argon gas for 30 minutes before palladium acetate (166.71 mg, 742.55 µmol) was added and reaction was refluxed at 60 °C for 6 hours. After completion of the reaction as indicated by TLC, the mixture was poured into cold water (100 mL) and the resulting solid was filtered and dried under high vacuum to afford 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2- dioxaborolane (2, 3.5 g, 9.84 mmol, 40% yield) as a brown-black solid. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J= 8.8Hz, 2H), 7.96 (d, J=8.8Hz, 2H), 1.37 (s, 12H). Step-2: In a sealed tube, a solution of tert-butyl 3,3-difluoro-4-(trifluoromethylsulfonyloxy)-2,6- dihydropyridine-1-carboxylate (3, 8.0 g, 21.78 mmol) and 4,4,5,5-tetramethyl-2-(4-nitrophenyl)- 1,3,2-dioxaborolane (2, 7.05 g, 28.32 mmol) in 1,4-dioxane (80 mL) were added sodium carbonate (4.62 g, 43.56 mmol) and cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (1.59 g, 2.18 mmol) under argon atmosphere. The resulting mixture was stirred at 55 C for 3 hours, and progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, it was washed with water and extracted with ethyl acetate (3×250 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 230-400 mesh, EtOAc in pet ether) to afford tert-butyl 3,3-difluoro-4-(4-nitrophenyl)-2,6-dihydropyridine-1-carboxylate (4, 4.4 g, 11.64 mmol, 53% yield) as a gummy solid.¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J=8.8Hz, 2H), 7.74 (d, J=8.8Hz, 2H), 6.83 (bs, 1H), 4.22 (bs, 2H), 3.97 (t, J=6.8Hz, 2H), 1.44 (s, 9H). Step-3: To a stirred solution of tert-butyl 3,3-difluoro-4-(4-nitrophenyl)-2,6-dihydropyridine-1- carboxylate (4, 9.0 g, 26.45 mmol) in ethyl acetate (100 mL) were added platinum (IV) oxide (6.01 g, 26.45 mmol). The reaction flask was evacuated and back filled with hydrogen gas using a hydrogen bladder and the reaction was stirred under hydrogen atmosphere at room temperature for 16 hours. After completion of the reaction as shown by TLC, the reaction mixture was filtered through celite bed and the filtrate was concentrated and purified by column chromatography (silica gel, ethyl acetate/pet ether) to afford tert-butyl 4-(4-aminophenyl)-3,3-difluoro-piperidine-1- carboxylate (5, 5.4 g, 14.63 mmol, 55% yield) as a white solid. LC-MS (ES⁺): m/z 257.2 [M – tBu + H] ⁺. Step-4: To a stirred solution of tert-butyl 4-(4-aminophenyl)-3,3-difluoro-piperidine-1-carboxylate (5, 5.0 g, 16.01 mmol) and 3-bromopiperidine-2,6-dione (6, 9.22 g, 48.02 mmol) in DMF (50 mL) was added sodium bicarbonate (8.07 g, 96.04 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. Progress of the reaction was monitored by TLC and LC-MS. After completion, the reaction was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography (silica gel 100-200 mesh, 15% EtOAc in pet ether) to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-3,3-difluoro- piperidine-1-carboxylate (7, 5.17 g, 11.77 mmol, 74% yield). LC-MS (ES-): m/z 422.24 [M - H] -. Step-5: To a stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-3,3-difluoro- piperidine-1-carboxylate (7, 0.5 g, 1.18 mmol) in dioxane (2 mL) was added HCl (4 M, 5 mL) under nitrogen atmosphere. The reaction was stirred at 0-28 °C for 2 hours and monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was concentrated to dryness and washed with diethyl ether(10mL×2) to afford 3-[4-(3,3-difluoro-4- piperidyl)anilino]piperidine-2,6-dione hydrochloride (8, 0.4 g, 1.06 mmol, 89% yield) as a solid. LC-MS (ES⁺): m/z 324.09 [M + H] ⁺. Example 7 Synthesis of 1-[1-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine-2,4-dione trifluoroacetate

Step-1: To a stirred solution of 4-bromo-2-fluorobenzonitrile (1, 25 g, 125.00 mmol) in ethanol (500 mL) was added methyl hydrazine (2, 85% aqueous solution) (51.83 g, 1.12 mol) at room temperature. The reaction mixture was heated at 125 °C in autoclave for 7 hours. The reaction mixture was cooled to room temperature and poured into ice cold water (2000 ml) and stirred for 30 minutes. The solidified mass was filtered-off, washed with water, and dried well to afford 6- bromo-1-methyl-1H-indazol-3-amine (3, 25 g, 105.05 mmol, 84% yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d₆) δ 7.63 (s, 2H), 7.02 (d, J = 8.0 Hz,1H), 5.54 (s, 2H), 3.71 (s, 3H). LC-MS (ES⁺): m/z 226.0 [M + H] ⁺. Step-2: To the stirred solution of 6-bromo-1-methyl-indazol-3-amine (3, 50 g, 221.17 mmol) in hydrochloric acid (2 M, 500.00 mL, 1 mol) was added tetrabutylammonium bromide (7.13 g, 22.12 mmol) at room temperature. The reaction mixture was heated to 55 °C and acrylic acid (4, 23.91 g, 331.75 mmol, 22.77 mL) was added dropwise at this temperature. The reaction was heated to 100 °C for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with ice cold water (1000 ml). It was neutralized to pH 6.5 -7 with 2 M sodium bicarbonate solution (1000 ml) under fast stirring. The solid precipitate was filtered off, washed with excess ice cold water, and dried to afford 3-[(6-bromo-1-methyl-indazol- 3-yl)amino]propanoic acid (5, 54 g, 163.30 mmol, 74% yield) as an off-white solid. LC-MS (ES⁺): m/z 298.28 [M + H] ⁺. Step-3: To a stirred solution of 3-[(6-bromo-1-methyl-indazol-3-yl)amino]propanoic acid (5, 160 g, 536.67 mmol) in acetic acid (1.07 kg, 17.76 mol, 1.02 L) was added sodium cyanate (46.67 g, 717.88 mmol). The reaction mixture was heated at 100 °C for 12 hours. Upon completion, the reaction was cooled to room temperature, filtered through a Büchner funnel and the filter cake was washed with water (2 × 500 mL). The collected solid was dried to yield 1-(6-bromo-1-methyl- indazol-3-yl)hexahydropyrimidine-2,4-dione (6, 175 g, 527.69 mmol, 98% yield) as an off-white solid. LC-MS (ES⁺): m/z 323.27 [M + H] ⁺. Step-4: To a solution of 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (6, 15 g, 46.42 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (7, 18.66 g, 60.34 mmol) in 1,4-dioxane (150 mL) and water (30 mL) was added sodium acetate, anhydrous (11.42 g, 139.26 mmol) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes and 1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (3.40 g, 4.64 mmol) was added. The reaction mixture was degassed with argon for an additional 5 minutes before it was stirred at 90 °C for 16 hours. Subsequently, the reaction mixture was concentrated in vacuo to yield the crude product, which was purified by column chromatography (silica gel 230-400 mesh, 70% ethyl acetate in pet ether) to afford tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl- indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (8, 18 g, 34.69 mmol, 75% yield) as a brown solid. LC-MS (ES⁺): m/z 426.44 [M + H] ⁺. Step-5: A solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,6- dihydro-2H-pyridine-1-carboxylate(8, 3.6g,8.46 mmol) in ethanol(30 ml) and DCM (10 ml) and a catalytical amount of glacial acetic acid (508.09 mg,8.46 mmol, 3 ml) was added to a Parr Shaker hydrogenator. Palladium on carbon, 10 wt. % (3.08 g, 25.38 mmol) was added to this mixture under inert atmosphere, and the resulting reaction was stirred for 16 hours at room temperature. The reaction progress was monitored by TLC and LC-MS. Upon completion, the reaction was filtered through celite bed and washed with 10% MeOH/DCM. The filtrate was concentrated under reduced pressure to afford tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol- 6-yl]piperidine-1-carboxylate (9, 3.6 g, 8.17 mmol, 97% yield). LC-MS (ES⁺): m/z 428.45 [M + H] ⁺. Step-6: To a stirred solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6- yl]piperidine-1-carboxylate (9, 2.7 g, 6.32 mmol) in DCM (20 mL) was added TFA (22.20 g, 194.70 mmol, 15 mL) at 0 °C. The reaction was stirred for 3 hours, and the reaction progress was monitored by TLC and LC-MS. Upon completion, the reaction mixture was evaporated to obtain the crude product, which was triturated with diethyl ether and concentrated in vacuo to afford 1- [1-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine-2,4-dione trifluoroacetate (10, 2.5 g, 4.92 mmol, 78% yield) as a brown solid. LC-MS (ES⁺): m/z 328.48 [M + H] ⁺. Example 8 Synthesis of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione trifluoroacetate

Step-1: To sodium hydride (60% dispersion in mineral oil) (53.51 g, 2.33 mol) was added THF (2300 mL) and the suspension was cooled to 5-10 °C. A solution of 2,6-dibenzyloxypyridin-3-amine (1, 230 g, 750.76 mmol) in THF (1400 mL) was added at 5-10 °C over 20 minutes with exothermicity observed. The temperature was maintained for 30 minutes. To this solution was added 4-bromo- 1-fluoro-2-nitrobenzene, 98% (2, 247.75 g, 1.13 mol, 138.41 mL) in THF (1600 mL) at 5-10 °C over 20 minutes. The solution was warmed to room temperature and the temperature was maintained for 16 hours. TLC (20% EtOAc in pet ether) confirmed the formation of product. The reaction mass was quenched with 10% water in THF (5 V) at below 10 °C, with observed exothermicity. Saturated NaCl solution (10 V) was added at below 15 °C and warmed to room temperature. The layers were separated, and the organic layer was concentrated under vacuum. The aqueous layer was taken and extracted with DCM (15 V) and kept aside. The organic layer was combined with crude and washed with water (5 V) and concentrated completely under vacuum at 45 °C. The crude was charged into DCM (2.5 V) at 45 °C and maintained for 15 min until dissolution, then added pet ether (10 V) at 45 °C and maintained for 1 hour at 45 °C. Cooled to RT and maintained for 30 min. Filtered and washed with pet ether (2×3 V) to afford 2,6-dibenzyloxy- N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (3, 400 g, 686 mmol, 91% yield). LC-MS (ES⁺): m/z 506.32 [M + H] ⁺. Step-2: A solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (3, 50 g, 98.75 mmol) in ACN (450 mL) and water (50 mL) was cooled to 0-5 °C and sodium borohydride (7.47 g, 197.49 mmol, 6.98 mL) was added portion wise for 60 hours, during which room temperature was maintained for 4 hours. TLC was used to monitor the progress of the reaction. Sodium borohydride (7.47 g, 197.49 mmol, 6.98 mL) was added at 0-5 °C and temperature maintained for 2 hours. Then the reaction was quenched with 10% NH₄Cl solution (5 V), water added (5 V), followed by DCM (10 V), then stirred at RT for 15 min. The aqueous layer was extracted with DCM (10 V) and the combined organic layers were washed with water (10 V) and concentrated completely under vacuum at 40 °C. Pet ether was used to strip the residue (3 V), then charged into 10% EtOAc in pet ether (5 V) into a crude residue and heated to 45 °C. The temperature was maintained at 45 °C for 30 min, cooled to RT, and maintained for 30 min. The product was filtered and washed with pet ether (3 V) to give 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (4, 34 g, 69.73 mmol, 71% yield). LC-MS (ES⁺): m/z 476.33 [M + H] ⁺. Step-3: To the stirred solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (4, 200 g, 419.85 mmol) in DMF (800 mL) was added di(imidazol-1-yl)methanone (177.00 g, 1.09 mol) at 25-35°C with observed exothermicity. CDI was charged as a single lot. Initial temperature 25°C was monitored with the final temperature of 35°C noted at 15 minutes. The reaction was stirred for 14 hours at room temperature. TLC showed the consumption of starting material. The reaction was charged into water (420 mL) at room temperature. Precipitation was formed (Note: Slow addition required a minimum of 1 h for bulk scale) and the mixture was stirred for 3 hours. The solid was filtered and washed with water and pet ether (2×35ml). The product was dried under vacuum for 7 hours at 50 °C to afford 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol- 2-one (5, 200 g, 391.43 mmol, 93% yield). LC-MS (ES⁺): m/z 502.1 [M + H] ⁺. Step-4: To a stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (5, 108 g, 214.99 mmol) in DMF (1000 mL) was added sodium hydride (60% dispersion in mineral oil) (14.83 g, 644.96 mmol) portion wise at 0-28°C. The reaction mixture was stirred for 1 hour, followed by dropwise addition of methyl iodide (stored over copper) (31.16 g, 214.99 mmol, 13.37 mL) over half an hour. Progress of the reaction was monitored by TLC and LC-MS-. The reaction mixture was diluted with ice cold water, and the resulting solid was obtained, filtered, and dried over vacuum. The solid was extracted with ethyl acetate, then washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude compound was washed with pentane to afford the product 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (6, 95 g, 183.81 mmol, 86% yield) as a light brown solid. LC-MS (ES⁺): m/z 516.14 [M + H] ⁺. Step-5: To a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (6, 20 g, 38.73 mmol) in 1,4-dioxane (160 mL) and water (40 mL) was added sodium carbonate (12.32 g, 116.19 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (7, 15.57 g, 50.35 mmol). The reaction was purged with nitrogen for 20 minutes, then charged with palladium (0) tetrakis(triphenylphosphine) (2.24 g, 1.94 mmol) and heated to 90-100 °C for 5 hours. TLC confirmed the formation of product. The reaction was cooled to room temperature and filtered through a celite bed and washed with EtOAc. The filtrate was taken and distilled completely under vacuum at 45 °C. The crude product was dissolved in EtOAc (15 V) and separated with water (10 V). The organic layer was washed with water (5 V), brine (5 V), then dried over anhydrous Na₂SO₄. The organic layer was concentrated in vacuo at 45 °C then purified by column chromatography (100-200 mesh silica gel, 0-30% ethyl acetate in pet ether) to afford tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (8, 21 g, 33.06 mmol, 99% yield). LC-MS (ES⁺): m/z 619.41 [M + H] ⁺. Step-6: To a solution of tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]- 3,6-dihydro-2H-pyridine-1-carboxylate (8, 40 g, 64.65 mmol) in methanol (1600 mL) was added palladium, 10% on carbon, type 487, dry (12.00 g, 112.76 mmol) and nickel (12.00 g, 204.45 mmol). Hydrogen gas (10 kg) was applied and the reaction was maintained at 60-65 °C for 16 hours. The reaction mass was cooled to room temperature then filtered and washed with DCM and MeOH. The filtrate was taken and distilled completely under vacuum at 45 °C. To the crude residue was added IPA (3 V) and heated to 60 °C for 15 minutes. Pet ether (3 V) was added and the mixture cooled to room temperature, and stirred at this temperature for 1 hour. The solid was filtered and washed with pet ether to afford tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2- oxo-benzimidazol-5-yl]piperidine-1-carboxylate (9, 21 g, 44 mmol, 69% yield). LC-MS (ES-): m/z 441.18 [M - H] -. Step-7: To a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]piperidine-1-carboxylate (9, 7.5 g, 16.95 mmol) in DCM (75 mL) was added trifluoroacetic acid (55.87 g, 490.03 mmol, 37.75 mL) at 0-5 °C slowly and the temperature was maintained for 15 minutes. The reaction was warmed to room temperature and maintained for 3 hours. LCMS complied with the formation of product. DCM and TFA were removed under vacuum at 40 °C and the crude stripped off with toluene (2×5 V) and diethyl ether added with the formation of solid observed. The reaction was decanted after adding diethyl ether (3×5 V), then dried at 45 °C. The crude was dissolved in MeOH (10 V), stirred for 10 minutes, and filtered through a sintered funnel and washed with MeOH with slight undissolved particles observed. The distilled filtrate was completely evaporated under vacuum at 45 °C to afford 3-[3-methyl-2-oxo-5-(4- piperidyl)benzimidazol-1-yl]piperidine-2,6-dione trifluoroacetate (10, 7.72 g, 16.5 mmol, 97% yield). LC-MS (ES-): m/z 343.35 [M - H] -. Example 9 Synthesis of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

Step-1: Into a 250 mL single neck round bottom flask containing a well stirred solution of 4-bromo-2- fluoro-1-nitro-benzene (1, 10 g, 45.46 mmol) and DIPEA (29.37 g, 227.28 mmol, 39.59 mL) in THF (31.82 mL) was added DIPEA (29.37 g, 227.28 mmol, 39.59 mL) 33% methylamine solution in methanol (12.84 g, 136.37 mmol, 68.18 mL) at room temperature. The reaction mixture was stirred at 60 °C for 3 hours. The progress of the reaction was monitored by UPLC- MS/TLC. Upon completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 5-bromo-N-methyl-2-nitro-aniline (2, 10 g, 42.85 mmol, 94% yield) as an off white solid. LC-MS (ES⁺): m/z 233.2 [M + H] ⁺. Step-2: Into a 500 mL multi-neck round bottom flask containing a well stirred solution of 5-bromo-N- methyl-2-nitro-aniline (2, 10 g, 42.85 mmol) in water (25.04 mL) and methanol (30.05 mL) and THF (50.09 mL) were added zinc powder 325 mesh high grade material (28.02 g, 428.49 mmol) and ammonium chloride (22.92 g, 428.49 mmol) portion wise with a range of 10-15 min at 0 °C. The reaction mixture was stirred for 1-2 hours at room temperature and the reaction progress was monitored by UPLC and TLC. Upon completion of the reaction, the reaction mixture was filter through celite bed and the bed was washed with ethyl acetate. The filtrate was then evaporated to dryness under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by normal phase column chromatography (100 g SNAP) using 50% ethyl acetate in petroleum ether to afford 4-bromo-N2-methyl-benzene- 1,2-diamine (3, 7 g, 32.73 mmol, 76% yield) as a pale red solid. LC-MS (ES⁺): m/z 201.0 [M + H] ⁺. Step-3: Into a 1L three neck round bottom flask containing a well stirred solution of 4-bromo-N2-methyl- benzene-1,2-diamine (3, 6 g, 28.05 mmol) in anhydrous DCM (60 mL) was added triphosgene (16.65 g, 56.10 mmol) at 0 °C and stirred for 5 minutes. Then pyridine (11.09 g, 140.25 mmol, 11.34 mL) in DCM was added at 0 °C and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by UPLC-MS/TLC. Upon completion, the reaction was quenched with ice cubes and ice water (highly effervescent) and extracted with DCM (2×100). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 5-bromo-3-methyl-1H-benzimidazol-2-one (4, 3.5 g, 14.03 mmol, 50% yield) as brown colored solid. LC-MS (ES⁺): m/z 229.0 [M + H] ⁺. Step-4: In a 250 mL three-neck round bottom flask, a stirred solution of 5-bromo-3-methyl-1H- benzimidazol-2-one (4, 3 g, 12.02 mmol) in THF (130 mL) was added sodium hydride (60% dispersion in mineral oil) (36.86 mg, 96.19 mmol) portion wise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. Then 3-bromopiperidine-2,6- dione (5, 6.93 g, 36.07 mmol) in THF (60 mL) was added by dropwise at 0°C for 1 hour. The reaction mixture was then stirred at 60°C for 16 hours under nitrogen atmosphere. Progress of the reaction was monitored by TLC and UPLC. After completion, the reaction was cooled to 0°C and quenched with saturated ammonium chloride solution (50 mL) dropwise and extracted with ethyl acetate (3×50 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was washed with DCM (50 mL), filtered and dried under vacuum for 2 hours to afford 3-(5-bromo-3-methyl-2-oxo- benzimidazol-1-yl)piperidine-2,6-dione (6, 2.5 g, 5.69 mmol, 47% yield) as a light brown solid. LC-MS (ES⁺): m/z 340.0 [M + H] ⁺. Example 10 Synthesis of N-(2,6-dioxo-3-piperidyl)-4-(4-piperidyl)benzamide hydrochloride

Step-1: An oven dried round bottom flask was charged with 4-(1-tert-butoxycarbonyl-4-piperidyl)benzoic acid (1, 1 g, 3.27 mmol), 3-aminopiperidine-2,6-dione hydrochloride (2, 646.79 mg, 3.93 mmol) in DMF (10 mL). To this solution was added DIPEA (1.27 g, 9.82 mmol, 1.71 mL) at 0 °C and the resulting reaction mixture was stirred for 1 hour at room temperature and the reaction progress was monitored by TLC and UPLC. After completion of the reaction, the reaction mixture was quenched with ice cold water and the precipitate was filtered and dried under vacuum to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)carbamoyl]phenyl]piperidine-1-carboxylate (3, 1 g, 2.32 mmol, 71% yield) as an off-white solid. LC-MS (ES-): m/z 414.2 [M - H] -. Step-2: An oven dried Rb flask was charged with tert-butyl 4-[4-[(2,6-dioxo-3- piperidyl)carbamoyl]phenyl]piperidine-1-carboxylate (3, 200 mg, 481.37 µmol) in DCM (5 mL). To this solution was added 4.0 M hydrogen chloride solution in dioxane (1.60 g, 43.88 mmol, 2 mL) at 0 °C and the resulting reaction mixture was stirred for 2 hours at room temperature, while the reaction progress was monitored by TLC and UPLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the obtained residue was titrated with pet ether and diethyl ether to afford N-(2,6-dioxo-3-piperidyl)-4-(4-piperidyl)benzamide hydrochloride (4, 170 mg, 459.03 µmol, 95% yield) as an off-white solid. LC-MS (ES⁺): m/z 316.0 [M + H] ⁺. Example 11 Synthesis of 3-[2-[4-(4-piperidyl)phenyl]ethoxy]piperidine-2,6-dione hydrochloride

Step-1: To a stirred solution of (2,6-dimethoxy-3-pyridyl)boronic acid (1, 2 g, 10.93 mmol) in DCM (20 mL) was added 35% hydrogen peroxide (11.00 g, 323.43 mmol, 10 mL) and the reaction mixture was stirred at 25°C for 6 hours. Upon completion of the reaction, the reaction mixture was diluted with saturated sodium bicarbonate solution (75ml) and extract with DCM (2×200ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reducing pressure and give 2,6-dimethoxypyridin-3-ol (2, 1.7 g, 10.63 mmol, 97% yield) as a gummy liquid. LC-MS (ES⁺): m/z 156.2 [M + H] ⁺. Step-2: To a stirred solution of methyl 2-(4-bromophenyl)acetate (3, 5 g, 21.83 mmol) and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (4, 6.75 g, 21.83 mmol) in 1,4 dioxane (70 mL) was added potassium phosphate tribasic anhydrous (4.63 g, 21.83 mmol). The reaction mixture was purged with nitrogen gas for 5 minutes before Pd(dppf)Cl2 ·CH₂Cl₂ (1.78 g, 2.18 mmol) was added. The resulting mixture was stirred for 8 hours at 100 °C. Upon completion, the reaction was cooled to ambient temperature, diluted with ethyl acetate, and filtered through a pad of celite. The filter cake was washed with ethyl acetate. The combined organic layers were concentrated under reduced pressure and the resulting crude product was purified by flash column chromatography on silica gel eluted with 10 to 15% ethyl acetate in pet ether to yield tert-butyl 4-[4-(2-methoxy-2-oxo-ethyl)phenyl]-3,6-dihydro-2H-pyridine-1- carboxylate (5, 6 g, 13.58 mmol, 62% yield) as a colorless liquid. LC-MS (ES⁺): m/z 232.2 [M – Boc + H] ⁺. Step-3: To a stirred solution of tert-butyl 4-[4-(2-methoxy-2-oxo-ethyl)phenyl]-3,6-dihydro-2H-pyridine- 1-carboxylate (5, 6 g, 18.10 mmol) in ethyl acetate (60 mL) was added 10 wt.% palladium on carbon (2.5 g, 18.10 mmol) and the reaction mixture was stirred 25°C for 8 hours. After completion of the reaction, the resulting mixture was filtered through a pad of celite, the filter cake washed with ethyl acetate, and the filtrate was concentrated in vacuo to give the crude product. The crude was purified by flash column chromatography (50g silica gel, eluted with 15% to 25% ethyl acetate in pet ether) to afford tert-butyl 4-[4-(2-methoxy-2-oxo-ethyl)phenyl]piperidine-1-carboxylate (6, 5.2 g, 13.88 mmol, 77% yield) as a white color solid. LC-MS (ES⁺): m/z 234.2 [M – Boc + H] ⁺. Step-4: To a stirred solution of tert-butyl 4-[4-(2-methoxy-2-oxo-ethyl)phenyl]piperidine-1-carboxylate (6, 5.2 g, 15.60 mmol) in THF (15 mL) was added LiOH (1.87 g, 77.98 mmol) in methanol (15 mL) followed by water (15 mL). The reaction mixture was stirred 25°C for 2 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure and acidified with 1.5N HCl. The resulting precipitate was filtered and dried to afford 2-[4-(1-tert- butoxycarbonyl-4-piperidyl)phenyl]acetic acid (7, 4.5 g, 13.38 mmol, 86% yield) as a white solid. LC-MS (ES-): m/z 318.2 [M - H] -. Step-5: To a stirred solution of 2-[4-(1-tert-butoxycarbonyl-4-piperidyl)phenyl]acetic acid (7, 2 g, 6.26 mmol) in THF (35 mL) was added borane-tetrahydrofuran complex, 1M solution (6.26 mmol, 15 mL) in 0°C and stirred 80°C for 5 hours. Upon completion of the reaction, the reaction mixture was quench with saturated ammonium bicarbonate solution (2×50ML) and extracted with ethyl acetate(5×100mL). The organic layer was concentrated under reduced pressure and purified by flash column chromatography (100g silica gel, eluted with 40% to 60% ethyl acetate in pet ether) to afford tert-butyl 4-[4-(2-hydroxyethyl)phenyl]piperidine-1-carboxylate (8, 1.6 g, 5.19 mmol, 83% yield) as a white color solid. LC-MS (ES⁺): m/z 206.2 [M – Boc + H] ⁺. Step-6: To a stirred solution of tert-butyl 4-[4-(2-hydroxyethyl)phenyl]piperidine-1-carboxylate (8, 1 g, 3.27 mmol) and 2,6-dimethoxypyridin-3-ol (2, 609.61 mg, 3.93 mmol) in THF (15 mL) was added triphenylphosphine (1.03 g, 3.93 mmol). The reaction mixture was cooled to 0°C before diisopropyl azodicarboxylate (794.51 mg, 3.93 mmol, 771.37 µL) was added and the reaction mixture was stirred at 25°C for 16 hours. Upon completion of the reaction, the reaction mixture was diluted with water (50ml) and extracted with ethyl acetate (3×50ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (100-200 mesh silica gel, 5% to 10% ethyl acetate in pet ether) to afford tert-butyl 4-[4-[2-[(2,6-dimethoxy-3-pyridyl)oxy]ethyl]phenyl]piperidine- 1-carboxylate (9, 650 mg, 1.35 mmol, 41% yield) as a yellow color liquid. LC-MS (ES⁺): m/z 343.2 [M – Boc + H] ⁺. Step-7: To a stirred solution of tert-butyl 4-[4-[2-[(2,6-dimethoxy-3-pyridyl)oxy]ethyl]phenyl]piperidine- 1-carboxylate (9, 650 mg, 1.47 mmol) in acetic acid (3 mL) was added HCl (3 mL) and the reaction mixture was stirred at 80°C for 5 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo, triturated with diethyl ether and dried under reduced pressure and give 3-[2-[4-(4-piperidyl)phenyl]ethoxy]pyridine-2,6-diol hydrochloride (10, 500 mg, 1.01 mmol, 69% yield) as a black color solid. LC-MS (ES⁺): m/z 315.2 [M + H] ⁺. Step-8: To a stirred solution of 3-[2-[4-(4-piperidyl)phenyl]ethoxy]-3H-pyridine-2,6-dione (11, 500 mg, 1.59 mmol) in ethanol (15 mL) was added 5% palladium hydroxide on carbon (294.46 mg, 2.39 mmol) and the reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the reaction mixture was filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined organic layers were concentrated under reduced pressure and give 3-[2-[4- (4-piperidyl)phenyl]ethoxy]piperidine-2,6-dione hydrochloride (12, 400 mg, 725.51 µmol, 46% yield) as a black color gummy solid. LC-MS (ES⁺): m/z 317.2 [M + H] ⁺. Example 12 Synthesis of N-(2,6-dioxo-3-piperidyl)-2-[4-(4-piperidyl)phenyl]acetamide hydrochloride

Compound 2-[4-(1-tert-butoxycarbonyl-4-piperidyl)phenyl]acetic acid was prepared following the procedure in the synthesis of 3-[2-[4-(4-piperidyl)phenyl]ethoxy]piperidine-2,6-dione hydrochloride Step-1: To a stirred solution of 2-[4-(1-tert-butoxycarbonyl-4-piperidyl)phenyl]acetic acid (1, 1 g, 3.13 mmol) in DMF (10 mL) was added 3-aminopiperidine-2,6-dione (2, 772.98 mg, 4.70 mmol, 021) followed by DIPEA (1.21 g, 9.39 mmol, 1.64 mL) and HATU (1.79 g, 4.70 mmol) at 0°C. The reaction mixture was stirred 0°C-25°C for 1 hour and concentrated under reduced pressure. The crude product was purified by flash column chromatography (50g silica gel, 2% to 8% MeOH in DCM) to give tert-butyl 4-[4-[2-[(2,6-dioxo-3-piperidyl)amino]-2-oxo-ethyl]phenyl]piperidine- 1-carboxylate (3, 1.3 g, 1.27 mmol, 41% yield) as a semi solid. LC-MS (ES-): m/z 428.2 [M - H] -. Step-2: To a stirred solution of tert-butyl 4-[4-[2-[(2,6-dioxo-3-piperidyl)amino]-2-oxo- ethyl]phenyl]piperidine-1-carboxylate (3, 300 mg, 698.47 µmol) in DCM (3 mL) was added and 4.0 M hydrogen chloride solution in dioxane (400.00 mg, 10.97 mmol, 0.5 mL) at 0°C and the reaction mixture was stirred 25°C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure, triturated with diethyl ether, and dried under vacuum to give N-(2,6-dioxo-3-piperidyl)-2-[4-(4-piperidyl)phenyl]acetamide hydrochloride (4, 130 mg, 277.16 µmol, 40% yield) as a white solid. LC-MS (ES⁺): m/z 330.2 [M + H] ⁺. Example 13 Synthesis of 3-[4-(2-piperazin-1-ylethyl)anilino]piperidine-2,6-dione hydrochloride

Step-1: An oven dried round bottom flask (100mL) was charged with tert-butyl piperazine-1-carboxylate (1, 2 g, 10.74 mmol) in DMF (8 mL) before 1-(2-bromoethyl)-4-nitro-benzene (2, 2.96 g, 12.89 mmol) and N, N-diisopropylethylamine (4.16 g, 32.21 mmol, 5.61 mL) were added. The resulting reaction mixture was stirred at 80°C for 16 hours while the reaction progress was monitored by TLC and UPLC. Upon completion of the reaction, the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate(3×200mL). The combined organic layers were washed with brine solution, dried over anhydrous Na₂SO_4, filtered and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography using 100-200 silica gel eluted with 30-40% ethyl acetate in pet ether to afford tert-butyl 4-[2-(4-nitrophenyl)ethyl]piperazine-1-carboxylate (3, 2.5 g, 5.96 mmol, 56% yield) as off light yellow solid. LC-MS (ES⁺): m/z 336.2 [M + H] ⁺. Step-2: An oven dried round bottom flask (100mL) was charged with tert-butyl 4-[2-(4- nitrophenyl)ethyl]piperazine-1-carboxylate (3, 1 g, 2.98 mmol) in ethanol (10 mL). Iron powder (832.60 mg, 14.91 mmol) and ammonium chloride (797.41 mg, 14.91 mmol) were added and the resulting reaction mixture was stirred at 80°C for 2 hours. Progress of the reaction was monitored by TLC and UPLC. After completion of the reaction, the reaction mixture was filtered through a pad of celite, the filtrate was concentrated in vacuo and the residue was diluted with ice cold water and extracted with ethyl acetate(3×150ML) combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude compound was purified by column chromatography using 100-200 silica gel eluted with 50-60% ethyl acetate in pet ether to afford tert-butyl 4-[2-(4-aminophenyl)ethyl]piperazine-1-carboxylate (4, 700 mg, 1.90 mmol, 64% yield) as a light brown solid. LC-MS (ES⁺): m/z 306.2 [M + H] ⁺. Step-3: To a stirred solution of tert-butyl 4-[2-(4-aminophenyl)ethyl]piperazine-1-carboxylate (4, 700 mg, 2.29 mmol) and 3-bromopiperidine-2,6-dione (5, 880.16 mg, 4.58 mmol) in DMF (8 mL) was added sodium bicarbonate (577.65 mg, 6.88 mmol) and the mixture was stirred at 80°C for 16 hours while the progress was monitored by TLC and UPLC. Upon completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water, brine solution, dried over anhydrous sodium sulfate, filtered, and evaporated completely under reduced pressure. The resulting crude product was purified by column chromatography using silica eluted with 40-50 % ethyl acetate in pet ether to afford tert-butyl 4-[2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]ethyl]piperazine-1- carboxylate (6, 450 mg, 1.02 mmol, 44% yield)as purple color solid. LC-MS (ES⁺): m/z 417.2 [M + H] ⁺. Step-4: An oven dried round bottom flask was charged with tert-butyl 4-[2-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]ethyl]piperazine-1-carboxylate (6, 250 mg, 600.22 µmol) in DCM (5 mL) before 4M HCl in dioxane (200 mg, 3.00 mmol, 2 mL) added the resulting reaction mixture was stirred for hours under N2 atmosphere at room temperature. Progress of the reaction was monitored by TLC and UPLC. Upon completion of the reaction, the reaction mixture was evaporated under reduced pressure and the obtained crude residue was triturated with pet ether and diethyl ether to afford the compound 3-[4-(2-piperazin-1-ylethyl)anilino]piperidine-2,6-dione hydrochloride (7, 240 mg, 564.40 µmol, 94% yield) as a light grey solid. LC-MS (ES⁺): m/z 317.0 [M + H] ⁺. Example 14 Synthesis of 3-[4-(3-piperazin-1-ylpropyl)anilino]piperidine-2,6-dione hydrochloride

Step-1: To a stirred solution of 3-(4-nitrophenyl)propanoic acid (1, 5.0 g, 25.62 mmol) and tert-butyl piperazine-1-carboxylate (2, 4.77 g, 25.62 mmol) in DMF (50 mL) were added 3- (ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine;hydrochloride (9.82 g, 51.24 mmol), TEA (7.78 g, 76.86 mmol, 10.71 mL) and HOBt (1.73 g, 12.81 mmol). The reaction mixture was stirred at room temperature for 16 hours while the progress was monitored by UPLC. Upon completion, the reaction was quenched with ice cold water (400 mL) and the resulting precipitate was filtered, washed with water(100 mL) and dried under vacuum to give tert-butyl 4-[3-(4- nitrophenyl)propanoyl]piperazine-1-carboxylate (3, 5.3 g, 14.55 mmol, 57% yield) as white solid. LC-MS (ES⁺): m/z 308.1[M-56+H]⁺. Step-2: To a stirred solution of tert-butyl 4-[3-(4-nitrophenyl)propanoyl]piperazine-1-carboxylate (3, 500 mg, 1.38 mmol) in THF (5 mL) was added borane in THF (2 M, 2.06 mL) and the reaction mixture was heated at 85°C for 8 hours. The reaction was then cooled to 0°C followed by the dropwise addition of methanol (2 mL). The reaction mixture was stirred at room temperature for another 3 hours while monitoring by LCMS. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford tert-butyl 4-[3-(4-nitrophenyl)propyl]piperazine-1- carboxylate (4, 500 mg, 1.35 mmol, 98% yield) as a thick yellow liquid. LC-MS (ES⁺): m/z 350.3 [M + H] ⁺. Step-3: To a stirred solution of tert-butyl 4-[3-(4-nitrophenyl)propyl]piperazine-1-carboxylate (4, 500 mg, 1.43 mmol) in ethanol (5 mL) was added iron powder (399.59 mg, 7.15 mmol) and ammonium chloride (382.70 mg, 7.15 mmol) in water (3 mL). The reaction mixture was refluxed for 2 hours and monitored by TLC. After consumption of the reactant, the reaction mixture was cooled and filtered through a celite bed and washed with ethyl acetate (5mL). The filtrate was concentrated under reduced pressure. The crude was dissolved again in ethyl acetate (50mL) and washed with water (10mL). The organic layer was separated and washed with brine, dried over with anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (Biotage^® Isolera, silica gel, 0-60% ethyl acetate in pet ether) to afford tert-butyl 4-[3-(4-aminophenyl)propyl]piperazine-1-carboxylate (5, 300 mg, 892.00 µmol, 62% yield) as a thick yellow liquid. LC-MS (ES⁺): m/z 320.3 [M + H] ⁺. Step-4: To a stirred solution of tert-butyl 4-[3-(4-aminophenyl)propyl]piperazine-1-carboxylate (5, 600 mg, 1.88 mmol) and 3-bromopiperidine-2,6-dione (6, 432.78 mg, 2.25 mmol) in DMF (6 mL) was added sodium bicarbonate (315.59 mg, 3.76 mmol) and the reaction mixture was heated at 60°C for 16 hours. Progress of the reaction was monitored by UPLC and upon completion, the reaction was quenched with ice cold water and extracted with ethyl acetate (2×30mL). The combined organics were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (Biotage^® Isolera, 25g silica gel, 0-10% of methanol in dichloromethane) to afford tert-butyl 4-[3-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]propyl]piperazine-1-carboxylate (7, 630 mg, 1.25 mmol, 67% yield) as a thick brown liquid. LC-MS (ES⁺): m/z 431.2 [M + H] ⁺. Step-5: To a stirred solution of tert-butyl 4-[3-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]propyl]piperazine-1-carboxylate (7, 200.00 mg, 464.53 µmol) in DCM (2 mL) was added HCl in dioxane (4 M, 1 mL) at 0 °C and the mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by UPLC and TLC. After consumption of the reactant, the reaction mixture was concentrated under reduced pressure, co- distilled with DCM twice, and triturated with diethyl ether to afford 3-[4-(3-piperazin-1- ylpropyl)anilino]piperidine-2,6-dione hydrochloride (8, 200 mg, 425.20 µmol, 92% yield) as a thick brown liquid. LC-MS (ES⁺): m/z 331.3 [M + H] ⁺. Example 15 Synthesis of 5-[4-(4-piperidyl)anilino]-3-azabicyclo[3.1.1]heptane-2,4-dione hydrochloride

Step-1: 4-Iodoaniline (13.2 g, 60.1 mmol) followed by trimethylsilyl cyanide (1, 10.8 g, 109 mmol, 13.7 mL) were added to a stirred solution of methyl 3-oxocyclobutanecarboxylate (2, 7 g, 54.6 mmol) in methanol (270 mL). The resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (5-10% ethyl acetate-hexane) to afford methyl 3-cyano-3-(4- iodoanilino)cyclobutanecarboxylate (3, 15.2 g, 42.7 mmol, 78% yield) as an off-white solid. LC- MS (ES⁺): m/z 357 [M + H] ⁺. Step-2: Acetaldehyde oxime (4.98 g, 84.2 mmol), followed by indium chloride (62.1 mg, 281 µmol) were added to a stirred solution of methyl 3-cyano-3-(4-iodoanilino) cyclobutanecarboxylate (3, 10 g, 28.1 mmol) in toluene (120 mL) at ambient temperature. The resulting mixture was heated to reflux for 1 h. After completion, the reaction mixture was cooled to ambient temperature and the precipitate thus formed was filtered, washed with toluene:ether (1:1) and dried to yield methyl 3- carbamoyl-3-(4-iodoanilino) cyclobutanecarboxylate (4, 8.4 g, 22.5 mmol, 80% yield). It was used in the next step without further purification. LC-MS (ES⁺): m/z 375 [M + H] ⁺. Step-3: Potassium tert-butoxide (4.62 g, 41.2 mmol) was added at 0 °C to a stirred solution of methyl 3- [2-amino-1-(4-iodoanilino)-2-oxo-ethyl]cyclobutanecarboxylate (4, 8 g, 20.6 mmol) in THF (150 mL), and the reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was neutralized with 1M citric acid solution and adjusted to pH~6 and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue mass was purified by column chromatography (40% ethyl acetate/hexane) to afford 5- (4-iodoanilino)-3-azabicyclo[3.1.1]heptane-2,4-dione (5, 2.9 g, 8.48 mmol, 41% yield). LC-MS (ES⁺): m/z 343 [M + H] ⁺. Step-4: Sodium carbonate (1.98 g, 18.7 mmol) was added to a stirred solution of 5-(4-iodoanilino)-3- azabicyclo[3.1.1]heptane-2,4-dione (5, 2.9 g, 8.48 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (6, 5.24 g, 17.0 mmol) in DMF (32 mL) and water (8 mL) and the reaction was degassed with argon. Pd(dppf)Cl₂ (692 mg, 848 µmol) was added under inert atmosphere. The resulting mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate and filtered through a short pad of celite. The filtrate was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (5-10% ethyl acetate-hexane) to yield tert-butyl 4-[4-[(2,4-dioxo-3-azabicyclo[3.1.1]heptan-5- yl)amino]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (7, 1.91 g, 4.81 mmol, 57% yield). LC- MS (ES⁺): m/z 398 [M + H] ⁺. Step-5: 10% Pd-C (50% wet, 1 g) was added to a degassed solution of tert-butyl 4-[4-[(2,4-dioxo-3- azabicyclo[3.1.1]heptan-5-yl)amino]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (7, 1.91 g, 4.81 mmol) in ethanol (20 mL). The resulting mixture was stirred at ambient temperature under a hydrogen balloon atmosphere for 3 h. After completion, the reaction mixture was filtered through a short pad of celite, washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (60-70% ethyl acetate-hexane) to yield tert- butyl 4-[4-[(2,4-dioxo-3-azabicyclo[3.1.1]heptan-5-yl)amino]phenyl]piperidine-1-carboxylate (8, 1.4 g, 3.50 mmol, 73% yield). LC-MS (ES⁺): m/z 400 [M + H] ⁺. Step 6: Dioxane HCl (4M, 15 mL, 60 mmol) was added to tert-butyl 4-[4-[(2,4-dioxo-3- azabicyclo[3.1.1]heptan-5-yl)amino]phenyl]piperidine-1-carboxylate (8, 1.4 g, 3.50 mmol) at 10 °C. The resulting mixture was warmed to ambient temperature and stirred for 5 h. The reaction mixture was concentrated under reduced pressure, triturated with ether and lyophilized to yield 5- [4-(4-piperidyl)anilino]-3-azabicyclo[3.1.1]heptane-2,4-dione hydrochloride (9, 1.08 g, 3.34 mmol, 95% yield) as an off white solid. LC-MS (ES⁺): m/z 300 [M + H] ⁺. ¹H-NMR (400 MHz, DMSO-D6) d 10.72 (s, 1H), 8.95 (br s, 1H), 8.81-8.79 (m, 1H), 6.90 (d, J = 8.2 Hz, 2H), 6.44 (d, J = 8.16 Hz, 2H), 3.32-3.29 (m, 2H), 2.95-2.91 (m, 3H), 2.73-2.62 (m, 3H), 2.49 (br m, 2H), 1.85-1.72 (m, 4H). Example 16 Synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1-yl]anilino]piperidine-2,6-dione hydrochloride

Step-1: An oven dried round bottom flask was charged with 3-(4-piperazin-1-ylanilino)piperidine-2,6- dione hydrochloride (1, 400 mg, 1.23 mmol) in DMF (2 mL). DIPEA (692.08 mg, 5.35 mmol, 932.72 µL) and tert-butyl N-(2-bromoethyl)carbamate (2, 400 mg, 1.78 mmol) were added at room temperature and the resulted mixture was stirred at 60 °C for 24 hours. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 10- 15% methanol in DCM) to give the crude compound. The crude was further purified by reverse phase column [Mobile-phase A: H₂O_, Mobile-phase B: ACN, Column: ISCO 150g}, lyophilized the fraction to yield tert-butyl N-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1- yl]ethyl]carbamate (3, 100 mg, 226.17 µmol, 13% yield) as a brown solid. LC-MS (ES⁺): m/z 432.3 [M + H] ⁺. Step-2: An oven dried round bottom flask was charged with tert-butyl N-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]ethyl]carbamate (3, 180 mg, 417.12 µmol) in DCM (2 mL). To this solution was added 4 M HCl in 1,4 dioxane (417.12 µmol, 7 mL) at 0 °C and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride (4, 160 mg, 407.49 µmol, 98% yield) as a grey color solid. LC-MS (ES⁺): m/z 332.3 [M + H] ⁺. Example 17 3-[4-[4-(4-aminobutyl)piperazin-1-yl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 360.3[M + H] ⁺. 3-[4-[4-(6-aminohexyl)piperazin-1-yl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 388.2 [M + H] ⁺. 3-[4-[4-(8-aminooctyl)piperazin-1-yl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 416.4 [M + H] ⁺. 3-[4-[[4-(5-aminopentyl)piperazin-1-yl]methyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 388.3 [M + H] ⁺. 3-[4-[[4-(6-aminohexyl)piperazin-1-yl]methyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 402.3 [M + H] ⁺. 3-[4-[[4-(7-aminoheptyl)piperazin-1-yl]methyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 416.4 [M + H] ⁺. 3-[4-[[4-(8-aminooctyl)piperazin-1-yl]methyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 430.1 [M + H] ⁺. 3-[4-[1-(5-aminopentyl)-4-piperidyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 373.2 [M + H] ⁺. 3-[4-[1-(6-aminohexyl)-4-piperidyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 387.3 [M + H] ⁺. 3-[4-[1-(7-aminoheptyl)-4-piperidyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 401.2 [M + H] ⁺. 3-[4-[1-(9-aminononyl)-4-piperidyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 429.5 [M + H] ⁺. 3-[4-[1-(10-aminodecyl)-4-piperidyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 443.0 [M + H] ⁺. 3-[4-[1-(12-aminododecyl)-4-piperidyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 471.3 [M + H] ⁺. 3-[4-[2-[4-(8-aminooctyl)piperazin-1-yl]ethyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoethyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 444.0 [M + H] ⁺. Example 18 Synthesis of 3-[4-[4-(2-aminoacetyl)piperazin-1-yl]anilino]piperidine-2,6-dione hydrochloride

Step-1: An oven dried 100mL round bottom flask was charged with 3-(4-piperazin-1- ylanilino)piperidine-2,6-dione hydrochloride (1, 1.5 g, 4.62 mmol) and 2-(tert- butoxycarbonylamino)acetic acid (2, 809.02 mg, 4.62 mmol) in DMF (10 mL). DIPEA (2.98 g, 23.09 mmol, 4.02 mL) and PyBOP (2.88 g, 5.54 mmol) were added at 0 °C and the reaction mixture was stirred for 4 hours at room temperature. Progress of the reaction was monitored by UPLC. Upon completion of the reaction, the mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (50mL×3). The combined organic layers were washed with brine solution and dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography (230-400 mesh silica gel, 90-100% ethyl acetate in pet ether). The compound was further purified by reverse-phase chromatography [Mobile-phase A: 0.1% Ammonium acetate in H2O, Mobile-phase B: ACN, Column: ISCO 100g column.] and lyophilized to afford tert-butyl N-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1- yl]-2-oxo-ethyl]carbamate (3, 900 mg, 1.65 mmol, 36% yield) as a light brown colored solid. LC- MS (ES⁺): m/z 446.3 [M + H] ⁺. Step-2: A solution of tert-butyl N-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-2-oxo- ethyl]carbamate (3, 120 mg, 269.35 µmol) in DCM (2 mL) was cooled to 0 °C with stirring before 4 M HCl in dioxane (1 mL) was added dropwise at the same temperature. The reaction mixture was stirred at 25 °C for 1 hour and the reaction progress was monitored by UPLC. After consumption of the starting materials, the reaction mixture was concentrated under reduced pressure and the crude product was triturated with diethyl ether to afford 3-[4-[4-(2- aminoacetyl)piperazin-1-yl]anilino]piperidine-2,6-dione hydrochloride (4, 100 mg, 250.70 µmol, 93% yield) as a white solid. LC-MS (ES⁺): m/z 346.0 [M + H] ⁺. Example 19 3-[4-[4-(4-aminobutanoyl)piperazin-1-yl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoacetyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 374.1 [M + H] ⁺. 3-[4-[4-(6-aminohexanoyl)piperazin-1-yl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoacetyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 402.0[M + H] ⁺. 3-[4-[4-(8-aminooctanoyl)piperazin-1-yl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoacetyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 430.3 [M + H] ⁺. 3-[4-[[4-(8-aminooctanoyl)piperazin-1-yl]methyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoacetyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 443.9 [M + H] ⁺. 3-[4-[2-[4-(8-aminooctanoyl)piperazin-1-yl]ethyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoacetyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 458.0 [M + H] ⁺. 3-[4-[3-[4-(8-aminooctanoyl)piperazin-1-yl]propyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoacetyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 472.0 [M + H] ⁺. 3-[4-[1-(8-aminooctanoyl)-4-piperidyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoacetyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 429.3 [M + H] ⁺. 3-[4-[1-(10-aminodecanoyl)-4-piperidyl]anilino]piperidine-2,6-dione hydrochloride

Prepared substantially following the synthesis of 3-[4-[4-(2-aminoacetyl)piperazin-1- yl]anilino]piperidine-2,6-dione hydrochloride. LC-MS (ES⁺): m/z 457.0 [M + H] ⁺.

Example 20 Synthesis of 3-[4-[1-(2,2-dimethoxyethyl)-4-piperidyl]anilino]piperidine-2,6-dione

Step-1: In a 50 mL sealed tube containing a well-stirred solution of 3-[4-(4-piperidyl)anilino]piperidine- 2,6-dione (1, 500 mg, 1.54 mmol) in DMF (10 mL) was added bromo acetaldehyde dimethyl acetal (2, 391.46 mg, 2.32 mmol, 273.75 µL) and DIPEA (598.69 mg, 4.63 mmol, 806.85 µL) under nitrogen atmosphere at room temperature and the resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated and purified by reverse phase chromatography (mobile phase 0.1% NH4OAc in water and CAN) to give3-[4-[1-(2,2-dimethoxyethyl)-4- piperidyl]anilino]piperidine-2,6-dione (3, 300 mg, 759.07 µmol, 49% yield) as a brown gum. LC- MS (ES⁺): m/z 376.2 [M + H] ⁺. Step-2: In a 25 mL sealed tube containing a well-stirred solution of 3-[4-[1-(2,2-dimethoxyethyl)-4- piperidyl]anilino]piperidine-2,6-dione (3, 300 mg, 799.02 µmol) in THF (5 mL) was added 3N HCl (799.02 µmol, 5 mL) at room temperature and the resulting mixture was stirred at 50 °C for 16 h. Excess organic solvent was concentrated under reduced pressure at room temperature and the aqueous layer was lyophilized to afford 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]acetaldehyde hydrochloride (4, 200 mg, 431.87 µmol, 54% yield) as a brown solid. LC- MS (ES⁺): m/z 330.1 [M + H] ⁺. 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetaldehyde

Prepared substantially following the synthesis of 3-[4-[1-(2,2-dimethoxyethyl)-4- piperidyl]anilino]piperidine-2,6-dione. LC-MS (ES⁺): m/z 347.1 [M + H] ⁺. 2-[4-[4-[(2,4-dioxo-3-azabicyclo[3.1.1]heptan-5-yl)amino]phenyl]-1-piperidyl]acetaldehyde

Prepared substantially following the synthesis of 3-[4-[1-(2,2-dimethoxyethyl)-4- piperidyl]anilino]piperidine-2,6-dione. LC-MS (ES⁺): m/z 342.3 [M + H] ⁺. 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetaldehyde

Prepared substantially following the synthesis of 3-[4-[1-(2,2-dimethoxyethyl)-4- piperidyl]anilino]piperidine-2,6-dione. LC-MS (ES⁺): m/z 333.2 [M + H] ⁺. Example 21 Synthesis of 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetic acid

Step-1: A solution of 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione trifluoroacetate (1, 0.150 g, 388.23 µmol) in acetonitrile (3 mL) was stirred in a sealed tube at room temperature under nitrogen atmosphere. To the reaction mixture was added N,N-diisopropylethylamine (150.53 mg, 1.16 mmol, 202.87 µL), followed by tert-butyl 2-bromoacetate (2, 75.73 mg, 388.23 µmol, 56.94 µL) at the same temperature. The reaction mixture was then stirred at 70 °C for 1 hour. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the solvent was removed under reduced pressure. The crude product was quenched with water, extracted with ethyl acetate, and washed with brine solution. The combined organic layers were concentrated under reduced pressure to afford tert-butyl 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetate (3, 0.150 g, 319.69 µmol, 82% yield) as a light yellow color solid. LC-MS (ES⁺): m/z 387.50 [M + H] ⁺. Step-2: To a stirred solution of tert-butyl 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetate (3, 0.2 g, 517.49 µmol) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (885.08 mg, 7.76 mmol, 598.03 µL) at 0 °C under N2 atmosphere. The reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was concentrated in vacuo and the residue was washed with diethyl ether (5 mL) to afford 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetic acid trifluoroacetate (4, 0.14 g, 226.29 µmol, 43.73% yield) a black gummy. LC-MS (ES⁺): m/z 331.46 [M + H] ⁺. Example 22 Synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetic acid hydrochloride

Step-1: To a stirred solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione hydrochloride (1, 5 g, 14.98 mmol) in DMF (30 mL) were added triethylamine (6.06 g, 59.91 mmol, 8.35 mL) and tert-butyl 2-bromoacetate (2, 2.92 g, 14.98 mmol, 2.20 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 14 hours. The reaction progress was monitored by TLC/LCMS. Upon completion, the reaction was diluted with water (15 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine solution (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 2-[4- [4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (3, 3.2 g, 7.83 mmol, 52% yield) as a light blue colored solid. Step-2: To a solution of tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (3, 3.2 g, 7.81 mmol) in DCM (10 mL) was added 4.0 M hydrogen chloride solution in dioxane (19.53 mL) at 0°C under nitrogen atmosphere. The resulting solution was stirred at room temperature under nitrogen atmosphere for 2 hours, while the reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and washed with petroleum ether to give 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]acetic acid hydrochloride (4, 3 g, 7.58 mmol, 97% yield) as a light green colored solid. LC-MS (ES⁺): m/z 346.2 [M + H] ⁺. 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetic acid hydrochloride

Prepared substantially following the synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]- 1-piperidyl]acetic acid hydrochloride. LC-MS (ES⁺): m/z 331.2 [M + H] ⁺. 2-[4-[4-[(2,4-dioxohexahydropyrimidin-1-yl)methyl]phenyl]-1-piperidyl]acetic acid hydrochloride

Prepared substantially following the synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]- 1-piperidyl]acetic acid hydrochloride. LC-MS (ES⁺): m/z 346.1 [M + H] ⁺. 2-[4-[4-[(2,4-dioxo-3-azabicyclo[3.1.1]heptan-5-yl)amino]phenyl]-1-piperidyl]acetic acid hydrochloride

Prepared substantially following the synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]- 1-piperidyl]acetic acid hydrochloride. LC-MS (ES⁺): m/z 358.1 [M + H] ⁺. 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetic acid

Prepared substantially following the synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]- 1-piperidyl]acetic acid hydrochloride. LC-MS (ES⁺): m/z 364.1 [M + H] ⁺. 2-[4-[2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]ethyl]piperazin-1-yl]acetic acid hydrochloride

Prepared substantially following the synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]- 1-piperidyl]acetic acid hydrochloride. LC-MS (ES⁺): m/z 375.2 [M + H] ⁺. 2-[4-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]propyl]piperazin-1-yl]acetic acid hydrochloride

Prepared substantially following the synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]- 1-piperidyl]acetic acid hydrochloride. LC-MS (ES⁺): m/z 389.1 [M + H] ⁺. 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]butanoic acid hydrochloride

Prepared substantially following the synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]- 1-piperidyl]acetic acid hydrochloride. LC-MS (ES⁺): m/z 374.3 [M + H] ⁺. 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]butanoic acid hydrochloride

Prepared substantially following the synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]- 1-piperidyl]acetic acid hydrochloride. LC-MS (ES-): m/z 373.0 [M - H] -. Example 23 Synthesis of 2-[4-[[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]piperazin-1-yl]acetic acid

An oven dried round bottom flask (25 mL) was charged with 3-[4-(piperazin-1- ylmethyl)anilino]piperidine-2,6-dione hydrochloride (1, 130 mg, 383.67 µmol) and oxaldehydic acid (2, 28.41 mg, 383.67 µmol, 21.20 µL) were added methanol (1.50 mL) and MP- cyanoborohydride (250 mg, 767.34 µmol), acetic acid (2.30 mg, 38.37 µmol, 2.19 µL) at room temperature and the resulting mixture was stirred at room temperature for 1 hour. After reaction was complete, the reaction mixture was filtered and the filtrate was dried under reduced pressure to give 2-[4-[[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]piperazin-1-yl]acetic acid (3, 95 mg, 97.53 µmol, 25% yield) as an off-white solid. LC-MS (ES⁺): m/z 361.1 [M + H] ⁺. Example 24 Synthesis of 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate)

Step-1: An oven dried round bottom flask (25 mL) was charged with 3-(4-piperazin-1- ylanilino)piperidine-2,6-dione dihydrochloride (1, 4.00 g, 11.07 mmol) and 4-tert-butoxy-4-oxo- butanoic acid (2, 1.93 g, 11.07 mmol) were added DMF (35 mL), DIPEA (4.29 g, 33.22 mmol, 5.79 mL) and HATU (5.05 g, 13.29 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 15 mL of water and extracted with ethyl acetate (3×20mL) and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel (25g) column chromatography eluted with 0-100% ethyl acetate in pet ether. The product was further purified by reverse phase column chromatography [Mobile-phase A: 0.1% NH4OAc in H₂O, Mobile-phase B: ACN, Column: ISCO (50g)] and lyophilized to afford tert-butyl 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoate (3, 650 mg, 1.30 mmol, 11.73% yield) as brown solid. LC-MS (ES⁺): m/z 445.2 [M + H] ⁺. Step-2: An oven dried round bottom flask (25 mL) was charged with tert-butyl 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoate (3, 200 mg, 449.92 µmol) were added DCM (5 mL) and TFA (51.30 mg, 449.92 µmol, 34.66 µL) at 0°C and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and co distilled with toluene to give 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate) (4, 250 mg, 322.81 µmol, 72% yield) as a green gummy liquid. LC-MS (ES⁺): m/z 389.0 [M + H] ⁺. Example 25 7-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo-heptanoic acid trifluoroacetate

Prepared substantially following the synthesis of 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate). LC-MS (ES⁺): m/z 431.4 [M + H] ⁺. 10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-10-oxo-decanoic acid hydrochloride

Prepared substantially following the synthesis of 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate), except 4 M HCl in dioxane (1 eq.) was used instead of trifluoroacetic acid for Step-2. LC-MS (ES⁺): m/z 473.3 [M + H] ⁺. 12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-12-oxo-dodecanoic acid trifluoroacetate

Prepared substantially following the synthesis of 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate). LC-MS (ES⁺): m/z 501.32 [M + H] ⁺. 14-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-14-oxo-tetradecanoic acid trifluoroacetate

Prepared substantially following the synthesis of 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate). LC-MS (ES⁺): m/z 529.33 [M + H] ⁺. 3-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]propanoic acid trifluoroacetate

Prepared substantially following the synthesis of 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate). LC-MS (ES⁺): m/z 433.1 [M + H] ⁺. 3-[2-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]propanoic acid trifluoroacetate

Prepared substantially following the synthesis of 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate). LC-MS (ES⁺): m/z 477.53 [M + H] ⁺. 3-[2-[2-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]propanoic acid trifluoroacetate

Prepared substantially following the synthesis of 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate). LC-MS (ES⁺): m/z 521.68 [M + H] ⁺. 3-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]ethoxy]propanoic acid trifluoroacetate

Prepared substantially following the synthesis of 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate). LC-MS (ES⁺): m/z 565.51 [M + H] ⁺. 3-[2-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid trifluoroacetate

Prepared substantially following the synthesis of 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate). LC-MS (ES⁺): m/z 609.59 [M + H] ⁺. 3-[2-[2-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid trifluoroacetate

Prepared substantially following the synthesis of 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate). LC-MS (ES⁺): m/z 653.67 [M + H] ⁺. 10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-10-oxo-decanoic acid hydrochloride

Prepared substantially following the synthesis of 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate), except 4 M HCl in dioxane (13 eq.) was used instead of trifluoroacetic acid for Step-2. LC-MS (ES⁺): m/z 472.2 [M + H] ⁺. 12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-12-oxo-dodecanoic acid hydrochloride

Prepared substantially following the synthesis of 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate), except 4 M HCl in dioxane (10 eq.) was used instead of trifluoroacetic acid for Step-2. LC-MS (ES⁺): m/z 500.2 [M + H] ⁺. 12-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]dodecanoic acid

Compound 12-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]dodecanoic acid was prepared according to the method described on page 70 of WO2021083949A1.

3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]propanoic acid

Prepared substantially following the synthesis of 12-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]amino]methyl]triazol-1-yl]dodecanoic acid. LC-MS (ES⁺): m/z 427.28 [M + H] ⁺. 6-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]hexanoic acid

Prepared substantially following the synthesis of 12-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]amino]methyl]triazol-1-yl]dodecanoic acid. LC-MS (ES⁺): m/z 469.45 [M + H] ⁺.

9-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]nonanoic acid

Prepared substantially following the synthesis of 12-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]amino]methyl]triazol-1-yl]dodecanoic acid. LC-MS (ES⁺): m/z 511.26 [M + H] ⁺. 15-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]pentadecanoic acid

Prepared substantially following the synthesis of 12-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]amino]methyl]triazol-1-yl]dodecanoic acid. LC-MS (ES⁺): m/z 595.51 [M + H] ⁺.

Example 26 Synthesis of 3-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]amino]methyl]triazol-1-yl]ethoxy]propanoic acid trifluoroacetate

Step-1: To a stirred solution of 2-(2,6-dioxo-3-piperidyl)-4-(prop-2-ynylamino)isoindoline-1,3-dione (1, 200 mg, 642.48 µmol) in THF (4 mL) and water (1 mL) was added tert-butyl 3-(2- azidoethoxy)propanoate (2, 138.29 mg, 642.48 µmol) and copper sulfate pentahydrate (160.42 mg, 642.48 µmol) and L-ascorbic acid sodium salt (127.28 mg, 642.48 µmol). The reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction was quenched with water (20ml) and extracted twice with ethyl acetate (150ml×2). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (Davisil silica gel, 90% ethyl acetate in pet ether) to afford tert-butyl 3-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]amino]methyl]triazol-1-yl]ethoxy]propanoate (3, 150 mg, 277.76 µmol, 43% yield) as a yellow color solid. LC-MS (ES⁺): m/z 527.1 [M + H] ⁺. Step-2: A stirred solution of tert-butyl 3-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]amino]methyl]triazol-1-yl]ethoxy]propanoate (3, 0.5 g, 949.59 µmol) in DCM (10 mL) was cooled to 0°C. Trifluoroacetic acid (108.28 mg, 949.59 µmol, 73.16 µL) was added and the reaction mixture was warmed up to room temperature and stirred for another 16 hours. The reaction progress was monitored by LCMS. Upon completion of the reaction, the reaction mixture was concentrated in vacuo to afford 3-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]amino]methyl]triazol-1-yl]ethoxy]propanoic acid trifluoroacetate (4, 0.5 g, 829.83 µmol, 87% yield). LC-MS (ES⁺): m/z 471.4 [M + H] ⁺. Example 27 3-[2-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]ethoxy]ethoxy]propanoic acid trifluoroacetate

Prepared substantially following the synthesis of 3-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]amino]methyl]triazol-1-yl]ethoxy]propanoic acid trifluoroacetate. LC-MS (ES⁺): m/z 515.45 [M + H] ⁺. 3-[2-[2-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]ethoxy]ethoxy]ethoxy]propanoic acid trifluoroacetate

Prepared substantially following the synthesis of 3-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]amino]methyl]triazol-1-yl]ethoxy]propanoic acid trifluoroacetate. LC-MS (ES⁺): m/z 559.42 [M + H] ⁺. 3-[2-[2-[2-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol- 1-yl]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid trifluoroacetate

Prepared substantially following the synthesis of 3-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]amino]methyl]triazol-1-yl]ethoxy]propanoic acid trifluoroacetate. LC-MS (ES⁺): m/z 603.48 [M + H] ⁺. 3-[2-[2-[2-[2-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]amino]methyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid trifluoroacetate

Prepared substantially following the synthesis of 3-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]amino]methyl]triazol-1-yl]ethoxy]propanoic acid trifluoroacetate. LC-MS (ES⁺): m/z 647.52 [M + H] ⁺. 3-[2-[2-[2-[2-[2-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]amino]methyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid trifluoroacetate

Prepared substantially following the synthesis of 3-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]amino]methyl]triazol-1-yl]ethoxy]propanoic acid trifluoroacetate. LC-MS (ES⁺): m/z 691.69 [M + H] ⁺. SYNTHESIS OF DEGRADERS Example 28 Synthesis of 2,4-dichloro-5-(pyridin-2-yl)benzoic acid

Step-1: Methyl 2,4-dichlorobenzoate (1, 20.0 g, 97.54 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2, 18.58 g, 73.16 mmol) and 4,4'-di-tert-butyl-2,2'- bipyridine (1.05 g, 3.90 mmol) were dissolved in tetrahydrofuran (200 mL) and the resulting contents were purged with nitrogen for 15 min. To this, bis(1,5-cyclooctadiene)di-μ- methoxydiiridium(I) (1.29 g, 1.95 mmol) was added and purged with nitrogen for additional 5 min. The reaction mixture was heated 75 °C for 3 h. The reaction mixture was cooled to room temperature and the in-situ generated boronic ester was taken to next step. The boronic ester was taken in 1,4-dioxane (140 mL) and water (60 mL), were added 2- bromopyridine (3, 18.49 g, 117.05 mmol, 11.35 mL), potassium carbonate (26.96 g, 195.09 mmol) and palladium triphenylphosphane (11.27 g, 9.75 mmol) and the resulting mixture was purged with nitrogen for 10 min and heated the contents at 110 °C for 16 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water (150 mL), extracted with ethyl acetate (2 x 300 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluting with 10-40% ethyl acetate in petroleum ether followed by trituration with methyl tert-butyl ether to get methyl 2,4-dichloro-5-(2- pyridyl)benzoate (4, 10.2 g, 31.62 mmol, 32% yield) as a brown gum. LC-MS (ES⁺): m/z 284.0 [M + H] ⁺. Step-2: To a solution of methyl 2,4-dichloro-5-(2-pyridyl)benzoate (4, 10.50 g, 37.22 mmol) in methanol (100 mL), was added lithium hydroxide monohydrate (7.81 g, 186.09 mmol) and the resulting mixture was stirred at room temperature for 3 h. The solvent was removed partially under reduced pressure, and the reaction mixture was acidified with 2M aqueous HCl and solid product was precipitated out. The solid was filtered and washed with water (100 mL) and dried under vacuum to get 2,4-dichloro-5-(2-pyridyl)benzoic acid (5, 9.2 g, 32.65 mmol, 88% yield) as an off-white solid. LC-MS (ES⁺): m/z 268.0 [M + H] ⁺.

Example 29 Synthesis of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid

Step-1: To a solution of potassium tert-butoxide (7.68 g, 68.43 mmol) in acetonitrile at 0 °C, was added diethyl oxalate (1, 10 g, 68.43 mmol, 9.26 mL) and the resulting mixture was stirred at room temperature for 3 h. The precipitated solid was filtered and dried under vacuum to get [(Z)-2- cyano-1-ethoxycarbonyl-vinyloxy]potassium (2, 11 g, 49.10 mmol, 72% yield). ¹H NMR (300 MHz, CDCl₃): δ 5.89 (s, 1H), 4.24 (q, J = 9.2 Hz, 2H), 1.27 (t, J = 9.6 Hz, 3H) ppm. Step-2: To a solution of [(Z)-2-cyano-1-ethoxycarbonyl-vinyloxy]potassium (2, 10.1 g, 56.36 mmol) and phenylhydrazine hydrochloride (3, 6.09 g, 56.36 mmol) in ethanol (70 mL) was acidified to pH 3 by the addition of aqueous HCl solution. The resulting mixture was heated at 80 °C for 16 h. The mixture was cooled to room temperature, basified to pH 8 by the addition of aqueous potassium carbonate solution, and then concentrated. The residue was partitioned between ethyl acetate (300 mL) water (100 mL), the organic layer was separated, and the aqueous layer was extracted using ethyl acetate (2 x 50 mL). The combined organics were washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to get the crude product which was purified by flash chromatography (silica gel, 230-400 mesh) eluting with 40-50% ethyl acetate in petroleum ether to get ethyl 5-amino-1-phenyl- pyrazole-3-carboxylate (4, 3.8 g, 9.86 mmol, 17% yield) as a pale-yellow solid. LC-MS (ES⁺): m/z 232.1 [M + H] ⁺. Step-3: To a solution of 2,4-dichloro-5-(2-pyridyl)benzoic acid (5, 4.0 g, 14.92 mmol) and ethyl 5-amino- 1-phenyl-pyrazole-3-carboxylate (4, 4.14 g, 17.90 mmol) in 2-methyltetrahydrofuran (100 mL) was added N,N-diisopropylethylamine (5.78 g, 44.76 mmol, 7.80 mL) and the resulting mixture was heated at 95 °C, was added T3P (50% solution in ethyl acetate) (9.49 g, 29.84 mmol) and the resulting mixture was heated at 95 °C for 18 h. The mixture was cooled to room temperature and partitioned between saturated aqueous sodium carbonate solution (100 mL) and ethyl acetate (150 mL). The organic phase was collected, washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to get the crude product which was recrystallized using diethyl ether, filtered and dried under vacuum to get ethyl 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxylate (6, 4.3 g, 6.93 mmol, 46% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 481.1 [M + H] ⁺. Step-4: To a solution of ethyl 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3- carboxylate (6, 3.70 g, 7.69 mmol) in methanol (120 mL) was added lithium hydroxide monohydrate (1M solution in water, 40 mL) and the resulting mixture was stirred at room temperature for 3 h. The solvent was removed partially under reduced pressure, and the reaction mixture was acidified with 2M aqueous HCl and solid product was precipitated out. The solid was filtered and washed with water (100 mL) and dried under vacuum to get 5-[[2,4-dichloro-5-(2- pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxylic acid (7, 3.5 g, 6.13 mmol, 80% yield) as an off-white solid. LC-MS (ES⁺): m/z 453.0 [M + H] ⁺.

Example 30 Synthesis of N-(2-(2-aminoethoxy)ethyl)-5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1- phenyl-1H-pyrazole-3-carboxamide

Step-1: To a solution of 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxylic acid (1, 1.0 g, 2.21 mmol) and tert-butyl N-[2-(2-aminoethoxy)ethyl]carbamate (2, 540.77 mg, 2.65 mmol) in dimethylformamide (10 mL), were added HATU (1.26 g, 3.31 mmol) and N,N- diisopropylethylamine (570.26 mg, 4.41 mmol, 768.55 µL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL), the combined organics were washed with brine solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to get the crude product which was purified by flash chromatography (silica gel, 230-400 mesh) eluting with 40-90% ethyl acetate in petroleum ether to get tert-butyl N-[2-[2-[[5-[[2,4- dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3- carbonyl]amino]ethoxy]ethyl]carbamate (3, 1.3 g, 1.40 mmol, 64% yield) as a yellow gum. LC- MS (ES⁺): m/z 639.2 [M + H] ⁺. Step-2: To a solution of tert-butyl N-[2-[2-[[5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl- pyrazole-3-carbonyl]amino]ethoxy]ethyl]carbamate (3, 600 mg, 938.19 µmol) in dichloromethane (5 mL) at 0 °C, was added 4 M HCl in 1,4-dioxane (2 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and, the residue was triturated with diethyl ether to get a solid which was filtered and dried under vacuum to get N-[2-(2-aminoethoxy)ethyl]-5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3- carboxamide hydrochloride (4, 530 mg, 899.54 µmol, 96% yield) as an white solid. LC-MS (ES⁺): m/z 539.1 [M + H] ⁺. Example 31 2,4-Dichloro-N-(1-phenyl-3-(piperazine-1-carbonyl)-1H-pyrazol-5-yl)-5-(pyridin-2- yl)benzamide

Prepared substantially following the synthesis of N-[2-(2-aminoethoxy)ethyl]-5-[[2,4-dichloro-5- (2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxamide. LC-MS (ES-): m/z 519.0 [M - H] -. ¹H NMR (400 MHz, DMSO-d₆): δ 10.96 (s, 1H), 9.43 (br s, 2H), 8.78 (d, J = 4.8 Hz, 1H), 8.06 (t, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.79 (d, J = 5.2 Hz, 2H), 7.64-7.45 (m, 6H), 6.91 (s, 1H), 4.28 (br s, 2H), 3.88 (br s, 2H), 3.18-3.11 (m, 2H), 2.89 (d, J = 2.8 Hz, 2H) ppm. 5-(2,4-Dichloro-5-(pyridin-2-yl)benzamido)-N-((4-hydroxypiperidin-4-yl)methyl)-1-phenyl- 1H-pyrazole-3-carboxamide

Prepared substantially following the synthesis of N-[2-(2-aminoethoxy)ethyl]-5-[[2,4-dichloro-5- (2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxamide. LC-MS (ES⁺): m/z 565.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 1H), 8.93 (br s, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.51 (br s, 1H), 8.24 (t, J = 6.4 Hz, 1H), 8.06 (t, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.63-7.55 (m, 2H), 7.53-7.41 (m, 6H), 6.90 (s, 1H), 3.41-3.35 (m, 2H), 3.14-3.10 (m, 2H), 3.05-2.99 (m, 2H), 1.78-1.71 (m, 2H), 1.63-1.60 (m, 2H) ppm. Example 32 Synthesis of 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[2-[[10-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-10-oxo-decanoyl]amino]ethoxy]ethyl]-1-phenyl- pyrazole-3-carboxamide (Compound 1)

Step-1: To a solution of N-[2-(2-aminoethoxy)ethyl]-5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1- phenyl-pyrazole-3-carboxamide (1, 30 mg, 55.62 µmol) and 10-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-10-oxo-decanoic acid trifluoroacetate (2, 38.97 mg, 55.62 µmol) in dimethylformamide (1 mL), were added PyBOP (43.41 mg, 83.42 µmol) and N,N- diisopropylethylamine (35.94 mg, 278.08 µmol) and the resulting mixture was stirred at room temperature for 1 h. The crude mixture was evaporated under Genevac at 50 °C to get the crude product which was purified by mass-directed preparative HPLC [Column: Sunfire C18 OBD, 19 x 100 mm, 5 micron; Mobile phase: A, 0.1% ammonium acetate in water; B: Acetonitrile, Wavelength: 215 nm] and the fractions containing the compound were combined and lyophilized to afford 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[2-[[10-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-10-oxo-decanoyl]amino]ethoxy]ethyl]-1-phenyl- pyrazole-3-carboxamide (Compound 1, 18.0 mg, 17.90 µmol, 32% yield) as a yellow solid. LC- MS (ES⁺): m/z 993.2 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.84 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.25 (t, J = 5.6 Hz, 1H), 7.99-7.94 (m, 1H), 7.89 (s, 1H), 7.81-7.71 (m, 1H), 7.62-7.54 (m, 2H), 7.52-7.49 (m, 2H), 7.48-7.45 (m, 4H), 6.93 (s, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.45 (d, J = 7.6 Hz, 1H), 4.23-4.18 (m, 1H), 3.55-3.51 (m, 6H), 3.44- 3.41 (m, 4H), 3.21-3.15 (m, 2H), 2.90 (br s, 2H), 2.85 (br s, 2H), 2.71-2.65 (m, 1H), 2.34-2.28 (m, 2H), 2.06-2.02 (m, 3H), 1.45-1.48 (m, 4H), 1.24 (br s, 11H) ppm. Example 33 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[2-[3-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]propanoylamino]ethoxy]ethyl]-1-phenyl-pyrazole-3-carboxamide (Compound 2)

Compound 2 was prepared substantially following the synthesis of Compound 1. LC-MS (ES-): m/z 995.0 [M - H] -. ¹H NMR (400 MHz, DMSO-d₆): δ 10.83 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.25 (t, J = 6.0 Hz, 1H), 7.99-7.94 (m, 1H), 7.91-7.88 (m, 2H), 7.75 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.56-7.45 (m, 4H), 6.93 (s, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 5.44 (d, J = 7.2 Hz, 1H), 4.33-4.22 (m, 1H), 3.60-3.51 (m, 11H), 3.48-3.42 (m, 9H), 3.23- 3.18 (m, 2H), 2.91 (br s, 2H), 2.86 (br s, 2H), 2.59-2.53 (m, 4H), 2.34-2.28 (m, 1H), 1.82-1.73 (m, 1H) ppm.

5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[2-[3-[2-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]ethoxy]ethyl]-1-phenyl-pyrazole-3- carboxamide (Compound 3)

Compound 3 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1129.1 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.83 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.25 (t, J = 5.6 Hz, 1H), 7.99-7.89 (m, 1H), 7.90 (d, J = 6.4 Hz, 2H), 7.75 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.56-7.46 (m, 4H), 6.93 (s, 1H), 6.77 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 5.44 (d, J = 7.2 Hz, 1H), 4.19-4.14 (m, 2H), 3.63 (t, J = 6.8 Hz, 2H), 3.58-3.51 (m, 7H), 3.49-3.43 (m, 21H), 3.23-3.20 (m, 2H), 2.92 (br s, 2H), 2.87 (br s, 2H), 2.85-2.76 (m, 1H), 2.60 (t, J = 6.40 Hz, 2H), 2.55-2.50 (m, 2H), 2.34-2.29 (m, 1H), 1.87-1.75 (m, 1H) ppm.

5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[2-[3-[2-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]propanoylamino]ethoxy]ethyl]-1-phenyl-pyrazole-3-carboxamide (Compound 4)

Compound 4 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1041.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.83 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.25 (t, J = 5.2 Hz, 1H), 7.97 (td, J = 7.6, 1.6 Hz, 1H), 7.89 (s, 2H), 7.75 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.60 Hz, 2H), 7.55 (d, J = 7.2 Hz, 1H), 7.52-7.45 (m, 3H), 6.93 (s, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.40 (s, 1H), 4.23-4.15 (m, 1H), 3.63 (t, J = 6.4 Hz, 2H), 3.59-3.51 (m, 8H), 3.48-3.38 (m, 13H), 3.22-3.18 (m, 2H), 2.91 (br s, 2H), 2.85 (br s, 2H), 2.57 (t, J = 10.8 Hz, 2H), 2.50-2.30 (m, 2H), 2.12-2.08 (m, 1H), 1.83-1.71 (m, 1H) ppm.

5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[2-[[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]amino]ethoxy]ethyl]-1-phenyl- pyrazole-3-carboxamide (Compound 5)

Compound 5 was prepared substantially following the synthesis of Compound 1. LC-MS (ES-): m/z 907.2 [M - H] -. ¹H NMR (400 MHz, DMSO-d₆): δ 10.83 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.26 (t, J = 6.0 Hz, 1H), 7.97 (td, J = 7.6, 1.6 Hz, 1H), 7.90 (s, 2H), 7.89 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 7.6 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.52-7.47 (m, 3H), 6.93 (s, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 5.45 (d, J = 7.2 Hz, 1H), 4.23-4.15 (m, 1H), 3.56-3.51 (m, 6H), 3.43 (t, J = 5.6 Hz, 4H), 3.24-3.18 (m, 2H), 2.91 (br s, 2H), 2.84 (br s, 2H), 2.68-2.55 (m, 1H), 2.54-2.50 (m, 1H), 2.34-2.33 (m, 3H), 2.13-2.05 (m, 1H), 1.83-1.74 (m, 1H) ppm.

5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[2-[3-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]ethoxy]propanoylamino]ethoxy]ethyl]-1-phenyl-pyrazole-3- carboxamide (Compound 6)

Compound 6 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1085.1 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.83 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 8.25 (t, J = 5.6 Hz, 1H), 7.97 (td, J = 7.8, 2.0 Hz, 1H), 7.91 (s, 2H), 7.89 (s, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.52-7.47 (m, 2H), 6.93 (s, 1H), 6.77 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 4.95-4.89 (m, 1H), 4.23-4.16 (m, 1H), 3.63-3.58 (m, 3H), 3.56- 3.42 (m, 7H), 3.35-3.31 (m, 16H), 3.24-3.20 (m, 2H), 2.89 (br s, 2H), 2.82 (br s, 2H), 2.60 (t, J = 6.80 Hz, 3H), 2.33-2.29 (m, 2H), 2.14-2.08 (m, 1H), 1.82-1.76 (m, 1H) ppm. 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[2-[3-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]propanoylamino]ethoxy]ethyl]-1- phenyl-pyrazole-3-carboxamide (Compound 7)

Compound 7 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 953.0 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.84 (s, 1H), 10.77 (s, 1H), 8.74 (s, 1H), 8.25 (t, J = 5.6 Hz, 1H), 7.97 (td, J = 7.8, 1.6 Hz, 1H), 7.89 (s, 1H), 7.88 (d, J = 5.6 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.52-7.45 (m, 2H), 6.93 (s, 1H), 6.77 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.44 (d, J = 7.2 Hz, 1H), 4.22-4.15 (m, 1H), 3.60-3.51 (m, 10H), 3.44-3.42 (m, 4H), 3.22-3.18 (m, 2H), 2.90 (br s, 2H), 2.86 (br s, 2H), 2.70- 2.51 (m, 3H), 2.34-2.28 (m, 2H), 2.12-2.06 (m, 1H), 1.82-1.76 (m, 1H) ppm. 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[2-[[7-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo-heptanoyl]amino]ethoxy]ethyl]-1-phenyl- pyrazole-3-carboxamide (Compound 8)

Compound 8 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 951.0 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.84 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.25 (t, J = 5.6 Hz, 1H), 7.96 (td, J = 7.8, 2.0 Hz, 1H), 7.89 (s, 1H), 7.81 (t, J = 5.2 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.55-7.49 (m, 2H), 7.49-7.45 (m, 2H), 6.93 (s, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.44 (d, J = 7.2 Hz, 1H), 4.21-4.16 (m, 1H), 3.56-3.49 (m, 7H), 3.46-3.38 (m, 5H), 3.21-3.17 (m, 2H), 2.89 (br s, 2H), 2.84 (br s, 2H), 2.34-2.28 (m, 2H), 2.09-2.03 (m, 3H), 1.51-1.43 (m, 4H), 1.26-1.21 (m, 3H) ppm. 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[2-[[14-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-14-oxo-tetradecanoyl]amino]ethoxy]ethyl]-1- phenyl-pyrazole-3-carboxamide (Compound 9)

Compound 9 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1049.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.84 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.24 (t, J = 6.0 Hz, 1H), 7.97 (td, J = 7.8, 2.0 Hz, 1H), 7.89 (s, 1H), 7.80 (t, J = 5.6 Hz, 1H), 7.74 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.52-7.47 (m, 4H), 7.89 (s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 7.6 Hz, 2H), 5.45 (d, J = 7.6 Hz, 1H), 4.21-4.15 (m, 1H), 3.56-3.50 (m, 6H), 3.44-3.41 (m, 4H), 3.20-3.17 (m, 2H), 2.90 (br s, 2H), 2.86 (br s, 2H), 2.69-2.60 (m, 1H), 2.53-2.50 (m, 2H), 2.34-2.29 (m, 1H), 2.09-2.02 (m, 2H), 1.50-1.43 (m, 4H), 1.25-1.17 (m, 18H) ppm.

5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[2-[[12-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-12-oxo-dodecanoyl]amino]ethoxy]ethyl]-1-phenyl- pyrazole-3-carboxamide (Compound 10)

Compound 10 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1022.0 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.84 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.24 (t, J = 6.0 Hz, 1H), 7.97 (td, J = 7.8, 2.0 Hz, 1H), 7.89 (s, 1H), 7.80 (t, J = 5.6 Hz, 1H), 7.74 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.6 Hz, 2H), 7.51-7.45 (m, 2H), 6.93 (s, 1H), 6.77 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.45 (d, J = 7.6 Hz, 1H), 4.24-4.18 (m, 1H), 3.55-3.50 (m, 6H), 3.44-3.41 (m, 4H), 3.21-3.16 (m, 2H), 2.90 (br s, 2H), 2.85 (br s, 2H), 2.69-2.67 (m, 1H), 2.34-2.29 (m, 2H), 2.09-2.00 (m, 4H), 1.50-1.45 (m, 4H), 1.26-1.20 (m, 12H) ppm. 2,4-dichloro-N-[5-[4-[3-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-3- oxo-propoxy]propanoyl]piperazine-1-carbonyl]-2-phenyl-pyrazol-3-yl]-5-(2- pyridyl)benzamide (Compound 11)

Compound 11 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 935.1 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.76 (s, 1H), 8.75 (d, J = 4.4 Hz, 1H), 7.99-7.95 (m, 1H), 7.90 (s, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.20 Hz, 2H), 7.51-7.46 (m, 4H), 6.87 (s, 1H), 6.76 (br s, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.44 (d, J = 7.6 Hz, 1H), 4.21-4.17 (m, 1H), 4.02-3.95 (m, 2H), 3.63-3.55 (m, 16H), 2.91 (br s, 2H), 2.85 (br s, 2H), 2.12- 2.08 (m, 1H), 1.85-1.81 (m, 1H), 1.24 (s, 3H) ppm. 2,4-dichloro-N-[5-[4-[3-[2-[2-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]- 3-oxo-propoxy]ethoxy]ethoxy]propanoyl]piperazine-1-carbonyl]-2-phenyl-pyrazol-3-yl]-5- (2-pyridyl)benzamide (Compound 12)

Compound 12 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1023.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.63-7.59 (m, 2H), 7.53-7.48 (m, 4H), 6.88 (s, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.44 (d, J = 7.6 Hz, 1H), 4.22-4.10 (m, 1H), 4.03-3.95 (m, 2H), 3.63 (br s, 6H), 3.56 (br s, 7H), 3.49 (br s, 9H), 2.91 (br s, 2H), 2.85 (br s, 2H), 2.70-2.67 (m, 5H), 2.34-2.29 (m, 1H), 1.86-1.82 (m, 1H) ppm.

2,4-dichloro-N-[5-[4-[3-[2-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin- 1-yl]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoyl]piperazine-1-carbonyl]-2- phenyl-pyrazol-3-yl]-5-(2-pyridyl)benzamide (Compound 13)

Compound 13 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1111.1 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.75 (d, J = 4.0 Hz, 1H), 7.97 (td, J = 7.6, 1.6 Hz, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.51-7.46 (m, 4H), 6.88 (s, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 5.44 (d, J = 7.2 Hz, 1H), 4.23-4.15 (m, 1H), 4.05-3.93 (m, 2H), 3.63 (br s, 6H), 3.56 (br s, 6H), 3.49 (br s, 17H), 2.91 (br s, 2H), 2.85 (br s, 2H), 2.68-2.58 (m, 6H), 2.12-2.05 (m, 1H), 1.86-1.81 (m, 1H) ppm.

2,4-dichloro-N-[5-[4-[3-[2-[2-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3- oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoyl]piperazine-1-carbonyl]-2- phenyl-pyrazol-3-yl]-5-(2-pyridyl)benzamide (Compound 14)

Compound 14 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1155.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 7.97 (td, J = 7.8, 2.0 Hz, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 7.6 Hz, 2H), 7.51-7.44 (m, 2H), 6.88 (s, 1H), 6.77 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.44 (d, J = 7.6 Hz, 1H), 4.25-4.18 (m, 1H), 4.05-3.93 (m, 1H), 3.63 (t, J = 6.4 Hz, 6H), 3.56 (d, J = 4.8 Hz, 8H), 3.49-3.44 (m, 22H), 2.91 (br s, 2H), 2.86 (br s, 2H), 2.60 (t, J = 6.0 Hz, 5H), 2.11-2.04 (m, 1H), 1.86-1.78 (m, 1H) ppm. 2,4-dichloro-N-[5-[4-[7-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo- heptanoyl]piperazine-1-carbonyl]-2-phenyl-pyrazol-3-yl]-5-(2-pyridyl)benzamide (Compound 15)

Compound 15 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 933.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.75 (d, J = 4.4 Hz, 1H), 7.97 (td, J = 7.8, 1.6 Hz, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.2 Hz, 2H), 7.52-7.45 (m, 4H), 6.87 (s, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.45 (d, J = 7.2 Hz, 1H), 4.22-4.17 (m, 1H), 4.03 (br s, 1H), 3.92 (br s, 1H), 3.64-3.58 (m, 2H), 3.55 (br s, 8H), 2.91 (br s, 2H), 2.86 (br s, 2H), 2.34-2.30 (m, 5H), 2.12-2.01 (m, 1H), 1.84-1.79 (m, 1H), 1.52 (br s, 4H), 1.32 (br s, 2H) ppm. 2,4-dichloro-N-[5-[4-[3-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1- yl]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]propanoyl]piperazine-1-carbonyl]-2-phenyl- pyrazol-3-yl]-5-(2-pyridyl)benzamide (Compound 16)

Compound 16 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1069.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 7.97 (td, J = 7.6, 2.0 Hz, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 7.2 Hz, 2H), 7.51-7.46 (m, 2H), 6.88 (s, 1H), 6.77 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.44 (d, J = 7.2 Hz, 1H), 4.21-4.16 (m, 1H), 4.02-3.95 (m, 2H), 3.62 (br s, 6H), 3.56 (br s, 9H), 3.49 (br s, 13H), 2.91 (br s, 2H), 2.85 (br s, 2H), 2.68-2.53 (m, 5H), 2.13-2.07 (m, 1H), 1.85-1.79 (m, 1H) ppm. 2,4-dichloro-N-[5-[4-[14-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-14-oxo- tetradecanoyl]piperazine-1-carbonyl]-2-phenyl-pyrazol-3-yl]-5-(2-pyridyl)benzamide (Compound 17)

Compound 17 was prepared substantially following the synthesis of Compound 1. LC-MS (ES-): m/z 1029.2 [M - H] -. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.75 (d, J = 4.4 Hz, 1H), 7.97-7.95 (m, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.52-7.46 (m, 4H), 6.87 (s, 1H), 6.78 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 5.45 (d, J = 7.2 Hz, 1H), 4.23-4.19 (m, 1H), 4.03-3.94 (m, 2H), 3.67-3.61 (m, 2H), 3.55 (br s, 8H), 2.91 (br s, 2H), 2.85 (br s, 2H), 2.34-2.29 (m, 4H), 2.13-2.08 (m, 1H), 1.88-1.79 (m, 1H), 1.49 (s, 4H), 1.25 (s, 18H) ppm. 2,4-dichloro-N-[5-[4-[10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-10-oxo- decanoyl]piperazine-1-carbonyl]-2-phenyl-pyrazol-3-yl]-5-(2-pyridyl)benzamide (Compound 18)

Compound 18 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 975.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.75 (d, J = 4.4 Hz, 1H), 7.97 (td, J = 7.8, 1.6 Hz, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 0.8 Hz, 2H), 7.50-7.45 (m, 2H), 6.87 (s, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.45 (d, J = 7.2 Hz, 1H), 4.22-4.15 (m, 1H), 4.06-3.92 (m, 2H), 3.55 (br s, 8H), 2.91 (br s, 2H), 2.85 (br s, 2H), 2.34-2.29 (m, 6H), 2.08-2.03 (m, 1H), 1.81-1.76 (m, 1H), 1.50 (br s, 5H), 1.27 (br s, 9H) ppm. 2,4-dichloro-N-[5-[4-[12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-12-oxo- dodecanoyl]piperazine-1-carbonyl]-2-phenyl-pyrazol-3-yl]-5-(2-pyridyl)benzamide (Compound 19)

Compound 19 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1003.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.99-7.95 (m, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.52-7.47 (m, 2H), 6.87 (s, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.45 (d, J = 7.6 Hz, 1H), 4.21-4.18 (m, 1H), 4.05-3.92 (m, 2H), 3.67-3.55 (m, 11H), 2.91 (br s, 2H), 2.85 (br s, 2H), 2.33-2.27 (m, 5H), 2.13-2.08 (m, 1H), 1.86-1.82 (m, 1H), 1.49 (br s, 4H), 1.26 (br s, 12H) ppm. 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[3-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]propanoyl]-4-hydroxy-4- piperidyl]methyl]-1-phenyl-pyrazole-3-carboxamide (Compound 20)

Compound 20 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 978.8 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.01-7.94 (m, 2H), 7.88 (s, 1H), 7.75 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.55-7.45 (m, 4H), 6.95 (s, 1H), 6.77 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.44 (d, J = 7.2 Hz, 1H), 4.80 (s, 1H), 4.22-4.19 (m, 1H), 4.06-3.97 (m, 2H), 3.62-3.56 (m, 12H), 2.91 (br s, 2H), 2.86 (br s, 2H), 2.73-2.67 (m, 2H), 2.59-2.50 (m, 4H), 2.12-2.06 (m, 1H), 1.84-1.78 (m, 1H), 1.48-1.36 (m, 4H) ppm. Example 34 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[3-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]propanoyl]- 4-hydroxy-4-piperidyl]methyl]-1-phenyl-pyrazole-3-carboxamide (Compound 21)

Compound 21 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1112.7 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.00 Hz, 1H), 8.01- 7.94 (m, 2H), 7.88 (s, 1H), 7.75 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.56- 7.45 (m, 4H), 6.95 (s, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 5.03-4.94 (m, 1H), 4.80 (s, 1H), 4.18-4.12 (m, 1H), 4.03-3.96 (m, 1H), 3.63-3.55 (m, 12H), 3.48 (t, J = 4.00 Hz, 18H), 2.92 (br s, 2H), 2.86 (br s, 2H), 2.14-2.08 (m, 1H), 1.82-1.76 (m, 1H), 1.48-1.32 (m, 4H) ppm. Example 35 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]-4-hydroxy-4-piperidyl]methyl]-1- phenyl-pyrazole-3-carboxamide (Compound 22)

Compound 22 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 934.7 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.86 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.03-7.94 (m, 3H), 7.89 (s, 1H), 7.75 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.52-7.46 (m, 2H), 6.95 (s, 1H), 6.78 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.45 (d, J = 6.8 Hz, 1H), 4.81 (s, 1H), 4.23-4.16 (m, 1H), 4.04-3.94 (m, 1H), 3.68-3.55 (m, 6H), 2.93 (br s, 2H), 2.85 (br s, 2H), 2.55-2.50 (m, 6H), 2.13-2.04 (m, 1H), 1.85-1.77 (m, 1H), 1.51 (br s, 2H), 1.47-1.36 (m, 4H) ppm. 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[10-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-10-oxo-decanoyl]-4-hydroxy-4-piperidyl]methyl]-1- phenyl-pyrazole-3-carboxamide (Compound 23)

Compound 23 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1018.4 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.78 (s, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.02-7.95 (m, 2H), 7.89 (s, 1H), 7.75 (s, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.52-7.46 (m, 4H), 6.95 (d, J = 3.6 Hz, 3H), 6.94 (t, J = 5.20 Hz, 2H), 5.67 (d, J = 7.6 Hz, 1H), 4.79 (s, 1H), 4.54-4.48 (m, 1H), 4.28-4.26 (m, 1H), 4.01-3.92 (m, 2H), 3.62-3.54 (m, 1H), 3.58-3.50 (m, 2H), 3.04-2.95 (m, 1H), 2.74-2.73 (m, 1H), 2.70-2.61 (m, 2H), 2.32-2.25 (m, 5H), 2.11-2.08 (m, 1H), 1.92-1.87 (m, 1H), 1.73-1.65 (m, 2H), 1.48 (br s, 8H), 1.40-1.31 (m, 2H), 1.26 (s, 8H) ppm. 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[7-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo-heptanoyl]-4-hydroxy-4-piperidyl]methyl]-1- phenyl-pyrazole-3-carboxamide (Compound 24)

Compound 24 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 978.8 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.00-7.95 (m, 2H), 7.89 (s, 1H), 7.75 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.52-7.47 (m, 2H), 6.95 (s, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.45 (d, J = 7.2 Hz, 1H), 4.80 (s, 1H), 4.22-4.16 (m, 1H), 4.03-3.97 (m, 1H), 3.58-3.52 (m, 6H), 2.91 (br s, 2H), 2.85 (br s, 2H), 2.68-2.60 (m, 1H), 2.34-2.26 (m, 5H), 2.12-2.08 (m, 1H), 1.81- 1.76 (m, 1H), 1.52-1.43 (m, 8H), 1.30-1.24 (m, 5H) ppm. 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[12-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-12-oxo-dodecanoyl]-4-hydroxy-4- piperidyl]methyl]-1-phenyl-pyrazole-3-carboxamide (Compound 25)

Compound 25 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1047.8 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.01-7.94 (m, 2H), 7.89 (s, 1H), 7.75 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.52-7.45 (m, 2H), 6.95 (s, 1H), 6.78 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 5.45 (d, J = 7.2 Hz, 1H), 4.80 (s, 1H), 4.25-4.16 (m, 1H), 4.06-3.98 (m, 1H), 3.56 (br s, 5H), 2.91 (br s, 2H), 2.86 (br s, 2H), 2.69-2.59 (m, 1H), 2.33-2.25 (m, 6H), 2.12-2.08 (m, 1H), 1.84-1.79 (m, 1H), 1.49 (br s, 7H), 1.24 (s, 14H) ppm. 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[10-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-10-oxo-decanoyl]-4-hydroxy-4-piperidyl]methyl]-1- phenyl-pyrazole-3-carboxamide (Compound 26)

Compound 26 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1020.8 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.02-7.95 (m, 2H), 7.89 (s, 1H), 7.73 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.52-7.46 (m, 2H), 6.95 (s, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.45 (d, J = 7.6 Hz, 1H), 4.80 (s, 1H), 4.23-4.18 (m, 1H), 4.05-3.98 (m, 1H), 3.55 (s, 5H), 2.90 (s, 2H), 2.85 (s, 2H), 2.33-2.25 (m, 6H), 2.13-2.08 (m, 1H), 1.87-1.81 (m, 1H), 1.48 (s, 8H), 1.25 (s, 11H) ppm. 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[14-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-14-oxo-tetradecanoyl]-4-hydroxy-4- piperidyl]methyl]-1-phenyl-pyrazole-3-carboxamide (Compound 27)

Compound 27 was prepared substantially following the synthesis of Compound 1. LC-MS (ES⁺): m/z 1074.8 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.02-7.95 (m, 2H), 7.89 (s, 1H), 7.74 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.52-7.46 (m, 2H), 6.94 (s, 1H), 6.78 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.45 (d, J = 7.2 Hz, 1H), 4.80 (s, 1H), 4.21-4.15 (m, 1H), 4.03-3.97 (m, 1H), 3.55 (s, 5H), 2.91 (s, 2H), 2.86 (s, 2H), 2.69-2.63 (m, 1H), 2.33-2.25 (m, 5H), 2.12-2.05 (m, 1H), 1.83-1.78 (m, 1H), 1.48 (br s, 8H), 1.24 (s, 20H) ppm. Example 36 Synthesis of 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]octyl]-4-hydroxy-4-piperidyl]methyl]-1-phenyl- pyrazole-3-carboxamide (Compound 28)

Step-1: To a stirred solution of 8-bromooctan-1-ol (1, 1 g, 4.78 mmol) in dichloromethane (10 mL), was added pyridinium chlorochromate (1.24 g, 5.74 mmol) and the resulting mixture was stirred at room temperature for 2 h. After completion of the reaction, silica gel (2 g) was added to the mixture, filtered through a pad of celite, washed repeatedly with diethyl ether. The filtrate was concentrated under reduced pressure to get 8-bromooctanal (2, 800 mg, 3.86 mmol, 81% yield) as a colorless oil.¹H NMR (400 MHz, CDCl₃): δ 9.79 (s, 1H), 3.43 (t, J = 6.8 Hz, 2H), 2.48-2.44 (m, 2H), 1.91-1.84 (m, 2H), 1.70-1.63 (m, 2H), 1.50-1.41 (m, 2H), 1.38-1.35 (m, 4H) ppm. Step-2: To a solution of 3-(4-piperazin-1-ylanilino)piperidine-2,6-dione (3, 100 mg, 346.81 µmol) and 8- bromooctanal (2, 71.83 mg, 346.81 µmol) in dichloromethane (6 mL) was added tetramethylammonium triacetoxyborohydride (118.62 mg, 450.85 µmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was treated with ice-cold water and extracted with dichloromethane (2 x 20 mL). The combined organics were washed with brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to get N-[[1-(8-bromooctyl)-4-hydroxy-4-piperidyl]methyl]- 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxamide (4, 120 mg, 65% yield) as a pale brown oil. The crude product was taken to next step without further purification. LC-MS (ES⁺): m/z 479.2 [M + H] ⁺. Step-3: To a solution of 3-[4-[4-(8-bromooctyl)piperazin-1-yl]anilino]piperidine-2,6-dione (5, 84.79 mg, 176.85 µmol) and 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[(4-hydroxy-4- piperidyl)methyl]-1-phenyl-pyrazole-3-carboxamide (4, 100 mg, 176.85 µmol) in acetonitrile (5 mL), was added N,N-diisopropylethylamine (114.28 mg, 884.25 µmol, 154.02 µL). The resulting mixture was heated at 90 °C for 8 h. The mixture was concentrated under reduced pressure to get the crude product which was purified by mass-directed preparative HPLC [Column: Sunfire C18 (19 x 100) mm; 5 micron, Mobile phase: A, 0.1% TFA in water; B, Acetonitrile, Wavelength: 215 nm] and the fractions containing the compound were combined and lyophilized to get 5-[[2,4- dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]octyl]-4-hydroxy-4-piperidyl]methyl]-1-phenyl-pyrazole- 3-carboxamide trifluoroacetate (Compound 28, 12 mg, 10.39 µmol, 6% yield) as an off-white solid. LC-MS (ES-): m/z 961.3 [M - H] -.¹H NMR (400 MHz, DMSO-d₆): δ 10.86 (s, 1H), 10.77 (s, 1H), 9.36 (br s, 1H), 8.84 (br s, 1H), 8.75 (d, J = 4.4 Hz, 1H), 8.34 (t, J = 6.4 Hz, 1H), 7.97 (td, J = 7.8, 2.0 Hz, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.62-7.48 (m, 6H), 6.96 (d, J = 3.6 Hz, 1H), 6.82 (d, J = 9.2 Hz, 2H), 6.65 (d, J = 9.2 Hz, 2H), 5.08 (s, 1H), 4.25-4.21 (m, 1H), 3.56-3.50 (m, 5H), 3.17-3.12 (m, 9H), 2.83 (t, J = 11.2 Hz, 2H), 2.69-2.60 (m, 3H), 2.09-2.04 (m, 1H), 1.88-1.79 (m, 4H), 1.68-1.61 (m, 6H), 1.30 (s, 9H) ppm. Example 37 Synthesis of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-N-((1-(2-(4-(4-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piperidin-1-yl)ethyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1H- pyrazole-3-carboxamide (Compound 29)

Step-1: To a solution of 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[(4-hydroxy-4- piperidyl)methyl]-1-phenyl-pyrazole-3-carboxamide hydrochloride (1, 250 mg, 415.34 µmol) in methanol (5 mL), were added 2,2-dimethoxyacetaldehyde, 60% solution in water (2, 144.13 mg, 830.69 µmol), MP-cyanoborohydride (Biotage^®, 500 mg) and acetic acid (2.49 mg, 41.53 µmol, 2.38 µL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude product was triturated using diethyl ether, filtered and dried to get 5-[[2,4-dichloro-5-(2- pyridyl)benzoyl]amino]-N-[[1-(2,2-dimethoxyethyl)-4-hydroxy-4-piperidyl]methyl]-1-phenyl- pyrazole-3-carboxamide (3, 240 mg, 321.43 µmol, 77% yield) as an off-white solid. LC-MS (ES⁺): m/z 653.1 [M + H] ⁺. Step-2: To a solution of 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-(2,2-dimethoxyethyl)-4- hydroxy-4-piperidyl]methyl]-1-phenyl-pyrazole-3-carboxamide (3, 240 mg, 367.22 µmol) in tetrahydrofuran (4 mL), was added 3N aqueous hydrochloric acid (4 mL) and the resulting mixture was stirred at 65 °C for 10 h. The reaction mixture was cooled to room temperature, purged with an inert atmosphere of nitrogen to remove HCl. The resulting solvent was concentrated under reduced pressure at 20 °C. The residue was triturated with diethyl ether to get 5-[[2,4-dichloro-5- (2-pyridyl)benzoyl]amino]-N-[[4-hydroxy-1-(2-oxoethyl)-4-piperidyl]methyl]-1-phenyl- pyrazole-3-carboxamide hydrochloride (4, 240 mg, 167.49 µmol, 46% yield) as an off-white solid. LC-MS (ES-): m/z 606.9 [M - H] -. The crude product was taken to next step without purification. Step-3: To a solution of 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[4-hydroxy-1-(2-oxoethyl)-4- piperidyl]methyl]-1-phenyl-pyrazole-3-carboxamide hydrochloride (4, 240 mg, 167.72 µmol) and 3-(4-piperazin-1-ylanilino)piperidine-2,6-dione dihydrochloride (5, 60.59 mg, 167.72 µmol) in methanol (6 mL), were added MP-cyanoborohydride (Biotage^®, 500 mg) and acetic acid (catalytic) and the resulting mixture was stirred at 65 °C for 10 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to get the crude product which was purified by mass- directed preparative HPLC [Column: X-bridge C18, 19 x 100 mm; 5 micron, Mobile phase: A, 0.1% ammonium acetate in water; B, Acetonitrile, Wavelength: 215 nm] and the fractions containing the compound were combined and lyophilized to get 5-[[2,4-dichloro-5-(2- pyridyl)benzoyl]amino]-N-[[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1- yl]ethyl]-4-hydroxy-4-piperidyl]methyl]-1-phenyl-pyrazole-3-carboxamide (Compound 29, 2.5 mg, 2.78 µmol, 2% yield) as an off-white solid. LC-MS (ES⁺): m/z 879.0 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.45 (s, 1H), 7.96-7.93 (m, 1H), 7.77- 7.69 (m, 5H), 7.48-7.36 (m, 5H), 6.97 (s, 1H), 6.74 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 5.37 (d, J = 7.2 Hz, 1H), 4.57 (s, 1H), 4.21-4.16 (m, 1H), 3.26-3.21 (m, 2H), 2.91 (s, 4H), 2.68- 2.67 (m, 1H), 2.52-2.50 (m, 6H), 2.34-2.33 (m, 6H), 2.11-2.08 (m, 1H), 1.89-1.82 (m, 1H), 1.47 (br s, 4H) ppm.

Example 38 Synthesis of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-N-(prop-2-yn-1-yl)-1H- pyrazole-3-carboxamide

To a solution of 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxylic acid (1, 500 mg, 1.10 mmol) and prop-2-yn-1-amine (2, 72.91 mg, 1.32 mmol, 84.78 µL) in dimethylformamide (3 mL), were added HATU (629.14 mg, 1.65 mmol) and N,N- diisopropylethylamine (285.13 mg, 2.21 mmol, 384.27 µL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organics were washed with brine solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to get the crude product which was purified by flash chromatography (silica gel) using 40-70% ethyl acetate in petroleum ether to get 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1- phenyl-N-prop-2-ynyl-pyrazole-3-carboxamide (3, 550 mg, 937.04 µmol, 85% yield) as a yellow gum. LC-MS (ES⁺): m/z 489.9 [M + H] ⁺.

Example 39 Synthesis of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-N-((1-(5-(4-(4-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piperazin-1-yl)-5-oxopentyl)-1H-1,2,3-triazol-4-yl)methyl)-1-phenyl-1H- pyrazole-3-carboxamide (Compound 30)

Step-1: To a solution of 3-(4-piperazin-1-ylanilino)piperidine-2,6-dione (1, 500 mg, 1.73 mmol) and 5- azidopentanoic acid (2, 248.22 mg, 1.73 mmol) in dimethylformamide (5 mL), were added PyBOP (1.35 g, 2.60 mmol) and N,N-diisopropylethylamine (672.34 mg, 5.20 mmol, 906.11 µL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organics were washed with brine solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to get the crude product which was purified by flash chromatography (silica gel, 230-400 mesh) eluting with 0-95% ethyl acetate in petroleum ether to get 3-[4-[4-(5-azidopentanoyl)piperazin-1-yl]anilino]piperidine-2,6-dione (3, 480 mg, 641.51 µmol, 37% yield) as a dark blue gum. LC-MS (ES⁺): m/z 414.1 [M + H] ⁺. Step-2: To a solution of 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-N-prop-2-ynyl-pyrazole- 3-carboxamide (4, 40 mg, 81.58 µmol) and 3-[4-[4-(5-azidopentanoyl)piperazin-1- yl]anilino]piperidine-2,6-dione (3, 67.46 mg, 89.73 µmol) in tetrahydrofuran (2 mL), were added copper(II) sulfate pentahydrate (2.04 mg, 8.16 µmol) and sodium ascorbate (3.23 mg, 16.32 µmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (20 mL), filtered through a pad of celite, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase [Column: RediSep Rf Gold^® reversed-phase C18, 30 g snap, Mobile phase: A, 0.1% ammonium acetate in water; B: Acetonitrile, Wavelength: 215 nm] to get 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[5- [4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-5-oxo-pentyl]triazol-4-yl]methyl]-1- phenyl-pyrazole-3-carboxamide (Compound 30, 8.0 mg, 8.47 µmol, 10% yield) as an off-white solid. LC-MS (ES⁺): m/z 903.8 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 1H), 8.73 (s, 2H), 7.97-7.92 (m, 2H), 7.81-7.69 (m, 4H), 7.49-7.39 (m, 4H), 6.97 (s, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 5.44 (d, J = 7.6 Hz, 1H), 4.49 (d, J = 6.0 Hz, 2H), 4.35 (t, J = 6.8 Hz, 2H), 4.24-4.20 (m, 1H), 3.54 (br s, 5H), 2.90 (s, 2H), 2.85 (s, 2H), 2.38-2.34 (m, 3H), 2.13- 2.08 (m, 2H), 1.90-1.81 (m, 4H), 1.51-1.45 (m, 2H) ppm. Example 40 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[7-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo-heptyl]triazol-4-yl]methyl]-1-phenyl- pyrazole-3-carboxamide (Compound 31)

Compound 31was prepared substantially following the synthesis of Compound 30. LC-MS (ES⁺): m/z 930.7 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.91 (s, 1H), 10.76 (s, 1H), 8.79 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 7.99-7.95 (m, 2H), 7.88 (s, 1H), 7.75 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 7.6 Hz, 2H), 7.51-7.46 (m, 2H), 6.95 (s, 1H), 6.77 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.44 (d, J = 6.8 Hz, 1H), 4.49 (d, J = 5.6 Hz, 2H), 4.31 (t, J = 7.20 Hz, 2H), 4.14- 4.08 (m, 1H), 4.09 (d, J = 5.20 Hz, 1H), 3.56 (s, 4H), 3.17 (d, J = 5.20 Hz, 3H), 2.90 (s, 2H), 2.86 (s, 2H), 2.69-2.67 (m, 2H), 2.52-2.50 (m, 2H), 2.34-2.29 (m, 1H), 1.91-1.81 (m, 1H), 1.80-1.77 (m, 3H), 1.49-1.42 (m, 2H), 1.30-1.24 (m, 4H) ppm. 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[[1-[9-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-9-oxo-nonyl]triazol-4-yl]methyl]-1-phenyl- pyrazole-3-carboxamide (Compound 32)

Compound 32 was prepared substantially following the synthesis of Compound 30. LC-MS (ES⁺): m/z 959.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 1H), 8.74 (d, J = 4.4 Hz, 2H), 7.98-7.94 (m, 2H), 7.84 (s, 1H), 7.77-7.70 (m, 3H), 7.50-7.47 (m, 4H), 6.97 (s, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 5.44 (d, J = 7.2 Hz, 1H), 4.49 (d, J = 6.0 Hz, 2H), 4.31 (t, J = 7.2 Hz, 2H), 4.23-4.17 (m, 1H), 3.55 (d, J = 4.0 Hz, 4H), 2.90 (s, 2H), 2.90 (s, 2H), 2.73-2.70 (m, 1H), 2.69-2.59 (m, 2H), 2.34-2.29 (m, 2H), 2.12-2.05 (m, 1H), 1.85-1.77 (m, 1H), 1.48 (br s, 2H), 1.25 (s, 8H) ppm. Example 41 Synthesis of 5-(2,4-Dichloro-5-(pyridin-2-yl)benzamido)-N-(8-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperazin-1-yl)-8-oxooctyl)-1-phenyl-1H-pyrazole-3-carboxamide (Compound 33)

To a solution of 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxylic acid (1, 30 mg, 66.18 µmol) and 3-[4-[4-(8-aminooctanoyl)piperazin-1-yl]anilino]piperidine-2,6- dione (2, 30.84 mg, 66.18 µmol) in dimethylformamide (1 mL), were added HATU (30.20 mg, 79.42 µmol) and N,N-diisopropylethylamine (42.77 mg, 330.92 µmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated using Genevac at 50 °C for 1 h to get the crude product which was purified by mass-directed preparative HPLC [Column: Sunfire C18 OBD, 19 x 100 mm; 5 micron, Mobile phase: A, 0.1% ammonium acetate in water; B, Acetonitrile, Wavelength: 215 nm] and the prep fractions containing the compound were lyophilized to get 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-8-oxo-octyl]-1-phenyl-pyrazole-3-carboxamide (Compound 33, 15.24 mg, 24% yield) as a yellow solid. LC-MS (ES⁺): m/z 866.1 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.82 (s, 1H), 10.77 (s, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.27 (t, J = 6.0 Hz, 1H), 7.97 (td, J = 7.6, 1.6 Hz, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 7.2 Hz, 2H), 7.51-7.44 (m, 2H), 6.91 (s, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 5.45 (d, J = 7.2 Hz, 1H), 4.23-4.18 (m, 1H), 3.56 (s, 4H), 3.34-3.21 (m, 2H), 2.91 (s, 2H), 2.85 (s, 2H), 2.73-2.68 (m, 1H), 2.60 (t, J = 4.40 Hz, 1H), 2.33 (q, J = 7.6 Hz, 2H), 2.13-2.08 (m, 1H), 1.86-1.82 (m, 1H), 1.51 (s, 4H), 1.30 (s, 6H) ppm. Example 42 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[6-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]hexyl]-1-phenyl-pyrazole-3-carboxamide (Compound 34)

Compound 34 was prepared substantially following the synthesis of Compound 33. LC-MS (ES⁺): m/z 822.1 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 2H), 8.74 (d, J = 4.4 Hz, 1H), 8.27 (br s, 1H), 7.96 (td, J = 7.8, 1.6 Hz, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.54-7.43 (m, 4H), 6.91 (s, 1H), 6.74 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 9.2 Hz, 2H), 5.37 (d, J = 7.2 Hz, 1H), 4.21-4.17 (m, 1H), 3.29-3.22 (m, 2H), 2.92 (s, 4H), 2.73-2.61 (m, 2H), 2.60-2.55 (m, 1H), 2.46 (s, 4H), 2.34-2.27 (m, 2H), 2.13-2.09 (m, 1H), 1.91-1.82 (m, 1H), 1.52-1.45 (m, 4H), 1.31 (s, 4H) ppm.

5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]octyl]-1-phenyl-pyrazole-3-carboxamide (Compound 35)

Compound 35 was prepared substantially following the synthesis of Compound 33. LC-MS (ES⁺): m/z 850.2 [M + H] ⁺.1H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 1H), 10.76 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.26 (br s, 1H), 7.96 (td, J = 7.8, 2.0 Hz, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.55-7.44 (m, 4H), 6.91 (s, 1H), 6.74 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 5.37 (d, J = 7.2 Hz, 1H), 4.22-4.16 (m, 1H), 3.27-3.21 (m, 2H), 2.92 (s, 4H), 2.73-2.65 (m, 2H), 2.46 (s, 4H), 2.12 (t, J = 4.0 Hz, 2H), 2.13-2.06 (m, 1H), 1.91-1.81 (m, 1H), 1.51 (br s, 2H), 1.44 (br s, 2H), 1.29 (s, 9H) ppm.

Example 43 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[8-[4-[4-[2-[(2,6-dioxo-3- piperidyl)oxy]ethyl]phenyl]-1-piperidyl]-8-oxo-octyl]-1-phenyl-pyrazole-3-carboxamide (Compound 36)

Step-1: To a stirred solution of methyl 8-aminooctanoate (2, 114.67 mg, 661.85 µmol) in DMF (5 mL) was added 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxylic acid (1, 200 mg, 441.23 µmol) followed by DIPEA (171.07 mg, 1.32 mmol, 230.56 µL) and HATU (251.65 mg, 661.85 µmol) at 0°C. The reaction mixture was stirred 0°C-25°C for 1 hour, after which the reaction mixture was directly concentrated under reduced pressure and purified by flash column chromatography (50g silica gel, 5% to 8% MeOH in DCM) to afford methyl 8-[[5-[[2,4- dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carbonyl]amino]octanoate (3, 340 mg, 435.82 µmol, 99% yield) as a gummy compound. LC-MS (ES⁺): m/z 608.2 [M + H] ⁺. Step-2: To a stirred solution of methyl 8-[[5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl- pyrazole-3-carbonyl]amino]octanoate (3, 340 mg, 558.74 µmol) in methanol (3 mL) was added lithium hydroxide monohydrate, 98% (117.23 mg, 2.79 mmol, 77.64 µL) in water (3 mL) and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was directly concentrated under reduced pressure and acidified with 1.5N HCl. The solid precipitation was filtered and dried under vacuum to give 8-[[5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1- phenyl-pyrazole-3-carbonyl]amino]octanoic acid (4, 300 mg, 454.17 µmol, 81% yield) as a white solid. LC-MS (ES⁺): m/z 594.2 [M + H] ⁺. Step-3: To a stirred solution of 3-[2-[4-(4-piperidyl)phenyl]ethoxy]piperidine-2,6-dione hydrochloride (5, 44.52 mg, 126.16 µmol) in DMF (1 mL) was added 8-[[5-[[2,4-dichloro-5-(2- pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carbonyl]amino]octanoic acid (4, 50 mg, 84.11 µmol) followed by DIPEA (10.87 mg, 84.11 µmol, 14.65 µL) and PyBOP (43.77 mg, 84.11 µmol) at 0°C and the reaction mixture was stirred 25°C for 30 minutes. Then the reaction mixture was directly concentrated under reduced pressure and purified by prep-HPLC (formic acid condition) to give 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[8-[4-[4-[2-[(2,6-dioxo-3- piperidyl)oxy]ethyl]phenyl]-1-piperidyl]-8-oxo-octyl]-1-phenyl-pyrazole-3-carboxamide formate (Compound 36, 7 mg, 7.42 µmol, 9% yield) as a white color solid. LC-MS (ES⁺): m/z 894.3 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.83 (s, 1H), 10.74 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.30 (t, J = 5.6 Hz, 1H), 7.98 (td, J = 7.6, 1.6 Hz, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.52-7.47 (m, 2H), 7.18-7.13 (m, 4H), 6.91 (s, 1H), 4.58-4.52 (m, 1H), 4.10-4.07 (m, 1H), 3.93-3.89 (m, 2H), 3.72-3.69 (m, 1H), 3.27-3.21 (m, 2H), 3.08-2.98 (m, 2H), 2.82-2.78 (m, 2H), 2.68-2.61 (m, 1H), 2.34-2.30 (m, 1H), 2.04-1.99 (m, 2H), 1.93-1.88 (m, 1H), 1.78-1.71 (m, 2H), 1.50 (s, 6H), 1.37-1.26 (m, 8H) ppm. Example 44 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[8-[4-[4-[(2,6-dioxo-3- piperidyl)carbamoyl]phenyl]-1-piperidyl]-8-oxo-octyl]-1-phenyl-pyrazole-3-carboxamide (Compound 37)

Compound 37 was prepared substantially following the synthesis of Compound 36. LC-MS (ES⁺): m/z 891.4 [M + H] ⁺. Example 45 Synthesis of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-N-((2-((8-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)-8-oxooctyl)amino)pyridin-4-yl)methyl)- 1-phenyl-1H-pyrazole-3-carboxamide (Compound 38)

Step-1: To a solution of 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxylic acid (1, 400 mg, 882.46 µmol) and (2-fluoro-4-pyridyl)methanamine (2, 133.57 mg, 1.06 mmol) in dimethylformamide (3 mL), were added HATU (503.31 mg, 1.32 mmol) and N,N- diisopropylethylamine (342.15 mg, 2.65 mmol, 461.12 µL). The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 75 mL), the combined organics were washed with brine solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to get the crude product which was purified by flash chromatography (silica gel, 230-400 mesh) eluting with 50-90% ethyl acetate in petroleum ether to get 5-[[2,4-dichloro-5-(2- pyridyl)benzoyl]amino]-N-[(2-fluoro-4-pyridyl)methyl]-1-phenyl-pyrazole-3-carboxamide (3, 500 mg, 754.20 µmol, 85% yield) as a yellow gum. LC-MS (ES⁺): m/z 562.2 [M + H] ⁺. Step-2: To a stirred solution of 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[(2-fluoro-4- pyridyl)methyl]-1-phenyl-pyrazole-3-carboxamide (3, 200 mg, 356.26 µmol) and 8- aminooctanoic acid (4, 283.63 mg, 1.78 mmol) in dimethyl sulfoxide (4 mL), was added cesium carbonate (580.38 mg, 1.78 mmol). The resulting mixture was irradiated in a microwave at 150 °C for 5 h. The mixture was quenched with water (15 mL) and washed with ethyl acetate (2 x 10 mL) to remove organic impurities. The aqueous layer was acidified with potassium bisulfate solution to pH 4.0 and extracted using ethyl acetate (2 x 20 mL). The combined organics were washed with brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to get 8-[[4-[[[5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]- 1-phenyl-pyrazole-3-carbonyl]amino]methyl]-2-pyridyl]amino]octanoic acid (5, 100 mg, 97.63 µmol, 27% yield) as a colorless gum. LC-MS (ES⁺): m/z 700.2 [M + H] ⁺. Step-3: To a solution of 8-[[4-[[[5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3- carbonyl]amino]methyl]-2-pyridyl]amino]octanoic acid (5, 50 mg, 71.37 µmol) and 3-(4- piperazin-1-ylanilino)piperidine-2,6-dione (6, 20.58 mg, 71.37 µmol) in dimethylformamide (1 mL), were added HATU (40.70 mg, 107.05 µmol) and N,N-diisopropylethylamine (27.67 mg, 214.10 µmol, 37.29 µL) and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated using Genevac at 50 °C for 1 h. The crude product was purified by mass-directed preparative HPLC [Column: Sunfire C18 OBD, 19 x 100 mm; 5 micron, Mobile phase: A, 0.1% TFA in water; B, Acetonitrile, Wavelength: 215 nm] to get 5-[[2,4-dichloro-5-(2- pyridyl)benzoyl]amino]-N-[[2-[[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-8- oxo-octyl]amino]-4-pyridyl]methyl]-1-phenyl-pyrazole-3-carboxamide trifluoroacetic acid salt (Compound 38, 9.0 mg, 7.79 µmol, 11% yield) as a grey solid. LC-MS (ES⁺): m/z 969.7 [M + H] ⁺.

Example 46 Synthesis of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-N-(3-(4-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)phenyl)propyl)-1-phenyl-1H- pyrazole-3-carboxamide (Compound 39)

Step-1: To a solution of methyl 2-[4-(3-aminopropyl)phenyl]acetate (2, 150.90 mg, 728.03 µmol) and 5- [[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxylic acid (1, 300 mg, 661.85 µmol) in dimethylformamide (5 mL), were added PyBOP (413.30 mg, 794.22 µmol) and N,N-diisopropylethylamine (427.70 mg, 3.31 mmol, 576.41 µL). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 x 30 mL). The combined organics were washed with brine solution (20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to get the crude product which was purified by flash chromatography (silica gel, 230-400 mesh) eluting with 5-10% methanol in ethyl acetate to get methyl 2-[4-[3-[[5-[[2,4-dichloro-5-(2- pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carbonyl]amino]propyl]phenyl]acetate (3, 420 mg, 606.99 µmol, 92% yield) as an off-white solid. LC-MS (ES⁺): m/z 643.7 [M + H] ⁺. Step-2: To a solution of methyl 2-[4-[3-[[5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl- pyrazole-3-carbonyl]amino]propyl]phenyl]acetate (3, 70 mg, 108.94 µmol) in methanol (3 mL) and water (3 mL), was added lithium hydroxide monohydrate (22.86 mg, 544.72 µmol, 15.14 µL). The resulting mixture was stirred at room temperature for 3 h. The solvent was partially removed under reduced pressure and the reaction mixture was acidified with 1.5N aqueous HCl solution until the solution became pH 4.0. The resulting solid was filtered and washed with water (10 mL) and dried under vacuum to get 2-[4-[3-[[5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl- pyrazole-3-carbonyl]amino]propyl]phenyl]acetic acid (4, 60 mg, 88.20 µmol, 81% yield) as an white solid. LC-MS (ES⁺): m/z 628.2 [M + H] ⁺. Step-3: To a solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (5, 25 mg, 87.00 µmol) and 2-[4- [3-[[5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3- carbonyl]amino]propyl]phenyl]acetic acid (4, 54.68 mg, 87.00 µmol) in dimethylformamide (3 mL) at 0 °C, were added N,N-diisopropylethylamine (33.73 mg, 261.00 µmol, 45.46 µL) and PyBOP (54.33 mg, 104.40 µmol). The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was treated with cold water (20 mL) and stirred for 10 min. The resulting solid was filtered and dried to get the crude product which was purified by reverse phase purification [Column: RediSep Rf Gold^® reversed-phase C18, 30 g snap, Mobile phase: A, 0.1% HCOOH in water; B, Acetonitrile] to get 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[3-[4-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]phenyl]propyl]-1-phenyl-pyrazole-3- carboxamide formate (Compound 39, 20 mg, 20.92 µmol, 24% yield). LC-MS (ES⁺): m/z 896.8 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 2H), 8.74 (d, J = 4.4 Hz, 1H), 8.35 (br s, 2H), 7.97 (td, J = 7.6, 1.6 Hz, 2H), 7.88 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.55-7.46 (m, 4H), 7.20-7.15 (m, 4H), 6.92-6.88 (m, 3H), 6.60 (d, J = 8.8 Hz, 2H), 5.66 (d, J = 7.6 Hz, 1H), 4.54-4.51 (m, 1H), 4.28-4.25 (m, 1H), 4.04-4.01 (m, 1H), 3.69 (d, J = 3.2 Hz, 2H), 3.05- 2.94 (m, 2H), 2.74-2.67 (m, 2H), 2.59-2.52 (m, 4H), 2.12-2.04 (m, 1H), 1.87-1.80 (m, 3H), 1.71- 1.62 (m, 3H), 1.34-1.24 (m, 2H) ppm. Example 47 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[4-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-3-oxo-propyl]phenyl]ethyl]-1-phenyl-pyrazole-3- carboxamide (Compound 40)

Compound 40 was prepared substantially following the synthesis of Compound 39. LC-MS (ES⁺): m/z 898.7 [M + H] ⁺. Example 48 Synthesis of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-N-(3-(4-(2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)ethyl)phenyl)propyl)-1-phenyl-1H- pyrazole-3-carboxamide (Compound 41)

Step-1: To a solution of methyl 2-[4-[3-[[5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl- pyrazole-3-carbonyl]amino]propyl]phenyl]acetate (1, 250 mg, 389.09 µmol) in toluene (5 mL) and tetrahydrofuran (5 mL) at -78 °C, was added diisobutylaluminium hydride (1 M solution in toluene, 1.95 mL, 1.95 mmol). The resulting mixture was stirred at -78 °C for 25 min and allowed to stir at room temperature for 2 h. The reaction mixture was treated with wet silica gel at -20 °C and filtered, washed with ethyl acetate (20 mL). The filtrate was washed with brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to get 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[3-[4-(2- hydroxyethyl)phenyl]propyl]-1-phenyl-pyrazole-3-carboxamide (2, 0.2 g, 313.38 µmol, 81% yield) as a yellow gum. The crude product was taken to next step without further purification. LC- MS (ES⁺): m/z 613.8 [M + H] ⁺. Step-2: To a solution of 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[3-[4-(2- hydroxyethyl)phenyl]propyl]-1-phenyl-pyrazole-3-carboxamide (2, 100 mg, 162.73 µmol) in dichloromethane (5 mL) at 0 °C, was added phosphorous tribromide (66.07 mg, 244.09 µmol, 22.94 µL) and the resulting mixture was stirred at 50 °C for 16 h. The crude mixture was concentrated under reduced pressure, the obtained residue was treated with ice water. The solid was filtered and dried under vacuum to get N-[3-[4-(2-bromoethyl)phenyl]propyl]-5-[[2,4- dichloro-5-(2-pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxamide (3, 80 mg, 103.96 µmol, 64% yield) as an off-white solid. LC-MS (ES⁺): m/z 678.0 [M + H] ⁺. Step-3: To a solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (30 mg, 92.64 µmol, 021) in acetonitrile (3 mL), were added N-[3-[4-(2-bromoethyl)phenyl]propyl]-5-[[2,4-dichloro-5-(2- pyridyl)benzoyl]amino]-1-phenyl-pyrazole-3-carboxamide (3, 62.76 mg, 92.64 µmol) N,N- diisopropylethylamine (59.87 mg, 463.22 µmol, 80.69 µL). The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to get the crude product which was purified by reverse phase [Column: RediSep Rf Gold^® reversed-phase C18, 30 g snap, Mobile phase: A, 0.1% HCOOH in water, B, Acetonitrile] and the fractions containing the compound was lyophilized to get 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[3-[4-[2-[4-[4- [(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]ethyl]phenyl]propyl]-1-phenyl-pyrazole-3- carboxamide formate (Compound 41, 30 mg, 32.02 µmol, 35% yield) as an off-white solid. LC- MS (ES-): m/z 883.3 [M - H]. ¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 2H), 8.74 (d, J = 4.4 Hz, 1H), 8.36 (t, J = 6.0 Hz, 1H), 8.16 (s, 1H), 7.97 (td, J = 7.6, 1.6 Hz, 2H), 7.89 (s, 1H), 7.74 (d, J = 6.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.55-7.45 (m, 5H), 7.15 (s, 4H), 6.96 (d, J = 8.4 Hz, 2H), 6.92 (s, 1H), 6.61 (d, J = 8.4 Hz, 1H), 5.66 (d, J = 7.2 Hz, 1H), 4.29-4.24 (m, 1H), 3.11-3.06 (m, 3H), 2.77-2.67 (m, 2H), 2.59-2.52 (m, 4H), 2.40-2.33 (m, 3H), 2.17-2.08 (m, 4H), 1.88-1.81 (m, 3H), 1.80-1.71 (m, 2H), 1.65-1.60 (m, 2H) ppm.

Example 49 5-[[2,4-dichloro-5-(2-pyridyl)benzoyl]amino]-N-[2-[4-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]propyl]phenyl]ethyl]-1-phenyl-pyrazole-3- carboxamide (Compound 42)

Compound 42 was prepared substantially following the synthesis of Compound 41. LC-MS (ES⁺): m/z 884.7 [M + H] ⁺. Example 50 Synthesis of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride

Step-1: To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1, 10.0 g, 64.45 mmol) and ethyl (E)- 3-ethoxyprop-2-enoate (2, 13.94 g, 96.68 mmol, 14.06 mL) in N,N-dimethylformamide (130 mL), was added cesium carbonate (42.00 g, 128.90 mmol). The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water (100 mL) and acidified to pH 5 using acetic acid. The precipitated solid was filtered, washed with water (100 mL) and dried under vacuum to give ethyl 5-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate (3, 13.0 g, 55.22 mmol, 86% yield) as a beige solid. LC-MS (ES⁺): m/z 208.1 [M + H] ⁺. Step-2: To a solution of ethyl 5-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate (3, 13.0 g, 62.75 mmol) in THF (150 mL) and ethanol (75 mL) was added sodium hydroxide (2M aqueous solution, 125.5 mL). The resulting mixture was heated at 50 °C for 16 h. The reaction mixture was evaporated under reduced pressure and neutralized using 2M aqueous HCl until pH 4. The precipitated solid was filtered, washed with water (100 mL) and dried under vacuum to give 5-oxo-4H-pyrazolo[1,5- a]pyrimidine-3-carboxylic acid (4, 9.5 g, 49.61 mmol, 79% yield) as a beige solid. LC-MS (ES⁺): m/z 179.9 [M + H] ⁺. Step-3: Phosphorus oxychloride (92.44 g, 602.90 mmol, 56.4 mL) was charged in a round bottomed flask and cooled to 0 °C, were added 5-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4, 4.0 g, 22.33 mmol) and N,N-diisopropylethylamine (9.52 g, 73.69 mmol, 12.84 mL). The resulting mixture was heated at 130 °C for 4 h. The reaction mixture concentrated under reduced pressure, the residue was partitioned with toluene (50 mL) and water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was washed with brine solution (50 ml) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The precipitated solid was filtered to give the crude product which was triturated with n- heptane, filtered, washed with n-heptane and dried under vacuum to give 5-chloropyrazolo[1,5- a]pyrimidine-3-carbonyl chloride (5, 3.6 g, 16.66 mmol, 75% yield) as a beige solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.30 (d, J = 7.2 Hz, 1H), 8.60 (s, 1H), 7.37 (d, J = 7.2 Hz, 1H) ppm.

Example 51 Synthesis of (63E,64E)-14-fluoro-5-oxo-2-oxa-4,7-diaza-6(3,5)-pyrazolo[1,5-a]pyrimidina- 1,3(1,2)-dibenzenacyclooctaphane-34-carboxylic acid

Step-1: To a solution of 5-fluoro-2-hydroxy-benzaldehyde (1, 10 g, 71.37 mmol) in THF (30 mL), were added 2-methylpropane-2-sulfinamide (2, 12.98 g, 107.06 mmol) and titanium(IV) ethoxide (24.42 g, 107.06 mmol). The resulting mixture was heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature, were added methanol (20 mL). The contents were cooled to 0 °C, was added sodium borohydride (8.10 g, 214.12 mmol) portion wise and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned with ethyl acetate (500 mL) and water (200 mL). The precipitated yellow solid was filtered through a pad of celite, washed with ethyl acetate (50 mL). The filtrate was extracted with ethyl acetate (2 x 300 mL). The combined organic phase was washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give N-[(5- fluoro-2-hydroxy-phenyl)methyl]-2-methyl-propane-2-sulfinamide (3, 15 g, 51.97 mmol, 73% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 245.9 [M + H] ⁺. Step-2: To a solution of tert-butyl 4-fluoro-3-nitro-benzoate (4, 2.50 g, 10.36 mmol) and N-[(5-fluoro-2- hydroxy-phenyl)methyl]-2-methyl-propane-2-sulfinamide (3, 2.54 g, 10.36 mmol) in N,N- dimethylformamide (20 mL), was added potassium carbonate (2.86 g, 20.73 mmol). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was treated with water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with brine solution (40 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product which was purified flash chromatography (silica gel, 230-400 mesh) eluted with 0-20% ethyl acetate in petroleum ether to give tert-butyl 4-[2-[(tert-butylsulfinylamino)methyl]-4-fluoro-phenoxy]-3-nitro-benzoate (5, 3.5 g, 6.08 mmol, 59% yield) as a yellow gum. LC-MS (ES⁺): m/z 466.8 [M + H] ⁺. Step-3: To a solution of tert-butyl 4-[2-[(tert-butylsulfinylamino)methyl]-4-fluoro-phenoxy]-3-nitro- benzoate (5, 2.0 g, 4.29 mmol) in ethanol (20 mL), were added iron powder (1.20 g, 21.44 mmol) and ammonium chloride (1.15 g, 21.44 mmol) in water (10 mL). The resulting mixture was heated at 80 °C for 2 h. The reaction mixture was cooled and filtered through a pad of celite and washed with ethyl acetate (25 mL). The filtrate was concentrated under reduced pressure to give the residue which was partitioned between ethyl acetate (50 mL) and water (25 mL). The organic phase was separated, and the aqueous phase was further extracted with ethyl acetate (2 × 30 mL). The combined organics were washed with brine solution (40 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give tert-butyl 3- amino-4-[2-[(tert-butylsulfinylamino)methyl]-4-fluoro-phenoxy]benzoate (6, 1.8 g, 3.09 mmol, 72% yield) as a brown gum. LC-MS (ES⁺): m/z 437.1 [M + H] ⁺. Step-4: To a solution of tert-butyl 3-amino-4-[2-[(tert-butylsulfinylamino)methyl]-4-fluoro- phenoxy]benzoate (6, 1.00 g, 2.29 mmol) in acetonitrile (10 mL), was added N,N- diisopropylethylamine (1.48 g, 11.45 mmol, 2.00 mL). The contents were cooled to 0 °C, was added 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (7, 494.86 mg, 2.29 mmol) in acetonitrile (10 mL) dropwise. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was purified flash chromatography (silica gel, 230-400 mesh) eluted with 0-100% ethyl acetate in petroleum ether and the required product was eluted with 80% ethyl acetate in petroleum ether to give tert-butyl 4-[2-[(tert-butylsulfinylamino)methyl]-4-fluoro-phenoxy]-3-[(5- chloropyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]benzoate (8, 900 mg, 1.13 mmol, 49% yield) as an off-white solid. LC-MS (ES⁺): m/z 616.2 [M + H] ⁺. Step-5: To a solution of tert-butyl 4-[2-[(tert-butylsulfinylamino)methyl]-4-fluoro-phenoxy]-3-[(5- chloropyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]benzoate (8, 1 g, 1.62 mmol) in dichloromethane (20 mL), cooled to 0 °C, was added HCl/Dioxane (4M solution, 5 mL) dropwise. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure to give 4-[2-(aminomethyl)-4-fluoro-phenoxy]-3-[(5- chloropyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]benzoic acid hydrochloride (9, 800 mg, 1.42 mmol, 88% yield) as an off-white solid. LC-MS (ES⁺): m/z 456.0 [M + H] ⁺. Step-6: To a solution of 4-[2-(aminomethyl)-4-fluoro-phenoxy]-3-[(5-chloropyrazolo[1,5-a]pyrimidine- 3-carbonyl)amino]benzoic acid hydrochloride (9, 1.00 g, 2.19 mmol) in dimethyl sulfoxide (20 mL), was added N,N-diisopropylethylamine (1.42 g, 10.97 mmol, 1.91 mL). The resulting mixture was heated at 100 °C for 2 h. The reaction mixture was cooled to room temperature, treated with cold water (150 mL). The precipitated solid was filtered and dried under vacuum to give 11-fluoro- 19-oxo-29-oxa-21,22,23,24,25-pentazapentacyclohexacosa- (2),1(11),3(12),4,6(10),7(15),8(21),13(16),14(22),17-decaene-10-carboxylic acid (10, 630 mg, 1.25 mmol, 57% yield) as a yellow solid. LC-MS (ES⁺): m/z 420.1 [M + H] ⁺. Example 52 Synthesis of (63E,64E)-14-fluoro-5-oxo-2-oxa-4,7-diaza-6(3,5)-pyrazolo[1,5-a]pyrimidina- 1,3(1,2)-dibenzenacyclooctaphane-35-carboxylic acid

Step-1: To a solution of 3-fluoro-4-nitro-benzoic acid (1, 10 g, 54.02 mmol) in toluene (100 mL) and tert- butyl alcohol (20 mL), were added 4-dimethylaminopyridine (659.99 mg, 5.40 mmol), di-tert- butyl dicarbonate (23.58 g, 108.04 mmol, 24.80 mL). The resulting mixture was heated at 100 °C, for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-10% ethyl acetate in petroleum ether to give tert-butyl 3-fluoro-4-nitro-benzoate (2, 11 g, 45.60 mmol, 87% yield) as an off-white solid. LC-MS (ES-): m/z 183.9 [M - H] -.¹H NMR (400 MHz, DMSO-d₆): δ 8.27 (t, J = 7.6 Hz, 1H), 7.96 (dd, J = 11.6, 1.6 Hz, 1H), 7.90 (dd, J = 5.0, 0.8 Hz, 1H), 1.57 (s, 9H) ppm. Step-2: To a solution of tert-butyl 3-fluoro-4-nitro-benzoate (2, 7 g, 29.02 mmol) and N-[(5-fluoro-2- hydroxy-phenyl)methyl]-2-methyl-propane-2-sulfinamide (3, 7.12 g, 29.02 mmol) in N,N- dimethylformamide (20 mL), was added potassium carbonate (16.04 g, 116.08 mmol). The resulting mixture was stirred at room temperature for 6 h. The reaction mixture was treated with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organics were washed with brine solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 50-60% ethyl acetate in petroleum ether to give tert-butyl 3-[2-[(tert-butylsulfinylamino)methyl]-4-fluoro-phenoxy]-4-nitro- benzoate (4, 9 g, 19.10 mmol, 66% yield). LC-MS (ES⁺): m/z 466.9 [M + H] ⁺. Step-3: To a solution of tert-butyl 3-[2-[(tert-butylsulfinylamino)methyl]-4-fluoro-phenoxy]-4-nitro- benzoate (4, 9 g, 19.29 mmol) in ethanol (50 mL), were added iron powder (5.38 g, 96.38 mmol) and ammonium chloride (5.16 g, 96.46 mmol) in water (50 mL). The resulting mixture was heated at 80 °C for 6 h. The reaction mixture was cooled and filtered through a pad of celite and washed with ethyl acetate (500 mL). The filtrate was concentrated under reduced pressure to give the residue which was partitioned between ethyl acetate (500 mL) and water (500 mL). The organic phase was separated, washed with brine solution and dried over with anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-60% of ethyl acetate in petroleum ether to give tert-butyl 4-amino-3-[2-[(tert-butylsulfinylamino)methyl]-4- fluoro-phenoxy]benzoate (5, 8.5 g, 17.13 mmol, 89% yield) as a red oil. LC-MS (ES⁺): m/z 459.2 [M + Na] ⁺. Step-4: To a solution of tert-butyl 4-amino-3-[2-[(tert-butylsulfinylamino)methyl]-4-fluoro- phenoxy]benzoate (5, 1.0 g, 2.29 mmol) in acetonitrile (20 mL), was added 5-chloropyrazolo[1,5- a]pyrimidine-3-carbonyl chloride (6, 494.86 mg, 2.29 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at room temperature for 16 h. Acetonitrile (20 mL) was added to reaction mixture and stirred for 10 min. The precipitated solid was filtered and dried to give tert-butyl 3- [2-[(tert-butylsulfinylamino)methyl]-4-fluoro-phenoxy]-4-[(5-chloropyrazolo[1,5-a]pyrimidine- 3-carbonyl)amino]benzoate (7, 600 mg, 827.78 µmol, 36% yield) as a yellow solid. LC-MS (ES⁺): m/z 616.2 [M + H] ⁺. Step-5: To a solution of tert-butyl 3-[2-[(tert-butylsulfinylamino)methyl]-4-fluoro-phenoxy]-4-[(5- chloropyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]benzoate (7, 400 mg, 649.24 µmol) in dichloromethane (4 mL) at 0 °C, was added HCl/Dioxane (4.5M solution, 3 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the residue which was triturated using diethyl ether to give 3-[2- (aminomethyl)-4-fluoro-phenoxy]-4-[(5-chloropyrazolo[1,5-a]pyrimidine-3- carbonyl)amino]benzoic acid hydrochloride (8, 320 mg, 628.58 µmol, 97% yield) as an off-white solid. LC-MS (ES⁺): m/z 456.2 [M + H] ⁺. Step-6: To a solution of 3-[2-(aminomethyl)-4-fluoro-phenoxy]-4-[(5-chloropyrazolo[1,5-a]pyrimidine-3- carbonyl)amino]benzoic acid hydrochloride (8, 320 mg, 702.02 µmol) in dimethylsulfoxide (5 mL), was added N,N-diisopropylethylamine (453.66 mg, 3.51 mmol, 611.40 µL). The resulting mixture was heated at 100 °C for 3 h. The reaction mixture was cooled to room temperature and treated with cold water (150 mL). The precipitated yellow solid was filtered and dried under vacuum to give 11-fluoro-19-oxo-29-oxa-21,22,23,24,25-pentazapentacyclohexacosa- (2),1(11),3(13),4,6(10),7(15),8(21),12(16),14(22),17-decaene-10-carboxylic acid (9, 300 mg, 594.33 µmol, 85% yield) as a yellow solid. LC-MS (ES⁺): m/z 420.1 [M + H] ⁺. Example 53 Synthesis of (63E,64E)-N-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1- yl)butyl)-14-fluoro-5-oxo-2-oxa-4,7-diaza-6(3,5)-pyrazolo[1,5-a]pyrimidina-1,3(1,2)- dibenzenacyclooctaphane-34-carboxamide (Compound 43)

To a solution of 11-fluoro-19-oxo-29-oxa-21,22,23,24,25-pentazapentacyclohexacosa- (2),1(11),3(12),4,6(10),7(15),8(21),13(16),14(22),17-decaene-10-carboxylic acid (1, 40 mg, 95.38 µmol) and 3-[4-[4-(4-aminobutyl)piperazin-1-yl]anilino]piperidine-2,6-dione;trihydrochloride (2, 44.72 mg, 95.38 µmol) in N,N-dimethylformamide (1 mL), were added HATU (54.40 mg, 143.07 µmol) and N,N-diisopropylethylamine (36.98 mg, 286.15 µmol, 49.84 µL). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was treated with cold water (10 mL). The precipitated solid was filtered and washed with water (10 mL) and dried under vacuum. The crude product was purified by mass-directed preparative HPLC [Column: Sunfire C18 OBD (19 x 100 mm, 5micron); Mobile phase: A, 0.1% formic Acid in water; B, acetonitrile; Wavelength: 215 nm] to give N-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1- yl]butyl]-27-fluoro-37-oxo-54-oxa-40,41,42,43,47-pentazapentacyclohexacosa- 4(6),5(27),7(28),8,10(26),11(31),12(40),29(32),30(41),33-decaene-26-carboxamide formate (Compound 43, 12 mg, 15% yield) as a yellow solid. LC-MS (ES⁺): m/z 761.3 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.20 (s, 1H), 10.77 (s, 1H), 9.22-9.17 (m, 2H), 8.67 (d, J = 7.6 Hz, 1H), 8.55 (t, J = 5.6 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (d, J = 8.40 Hz, 1H), 7.17 (dd, J = 9.0, 3.2 Hz, 1H), 6.93 (td, J = 8.6, 2.4 Hz, 1H), 6.94-6.92 (m, 2H), 6.60 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 7.6 Hz, 1H), 6.43 (dd, J = 9.2, 4.4 Hz, 1H), 5.38 (d, J = 7.2 Hz, 1H), 5.15-5.10 (m, 1H), 4.26-4.17 (m, 2H), 2.94 (s, 4H), 2.68-2.51 (m, 4H), 2.38-2.33 (m, 4H), 2.13-2.08 (m, 1H), 1.91-1.81 (m, 1H), 1.59-1.53 (m, 6H) ppm. Example 54 N-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-2-oxo-ethyl]-14-fluoro-2- oxo-10-oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-7-carboxamide (Compound 44)

LC-MS (ES⁺): m/z 747.2 [M + H] ⁺.

N-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-2-oxo-ethyl]-14-fluoro-2- oxo-10-oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-6-carboxamide (Compound 45)

LC-MS (ES⁺): m/z 747.3 [M + H] ⁺. N-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]ethyl]-14-fluoro-2-oxo-10- oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-6-carboxamide (Compound 46)

LC-MS (ES⁺): m/z 733.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 11.20 (s, 1H), 10.77 (s, 1H), 9.20 (dd, J = 10.2, 2.4 Hz, 2H), 8.67 (d, J = 7.6 Hz, 1H), 8.49 (t, J = 5.6 Hz, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 7.61 (dd, J = 8.2, 2.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.17 (dd, J = 9.2, 3.2 Hz, 1H), 6.95-6.90 (m, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 6.53 (d, J = 7.6 Hz, 1H), 6.44 (dd, J = 9.2, 4.4 Hz, 1H), 5.39 (d, J = 7.2 Hz, 1H), 5.15-5.10 (m, 1H), 4.27-4.17 (m, 2H), 3.46-3.43 (m, 3H), 2.97 (s, 4H), 2.60-2.50 (m, 7H), 2.14-2.03 (m, 1H), 1.85-1.76 (m, 1H) ppm. N-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]butyl]-14-fluoro-2-oxo-10- oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-7-carboxamide (Compound 47)

LC-MS (ES⁺): m/z 761.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 11.23 (s, 1H), 10.76 (s, 1H), 9.24 (br s, 1H), 8.76 (d, J = 6.8 Hz, 1H), 8.66 (d, J = 7.6 Hz, 1H), 8.46 (t, J = 5.2 Hz, 1H), 8.22 (s, 2H), 7.89-7.87 (m, 2H), 7.18 (dd, J = 9.0, 2.8 Hz, 1H), 6.92 (td, J = 8.4, 3.2 Hz, 1H), 6.74 (d, J = 9.2 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 7.6 Hz, 1H), 6.47 (t, J = 4.8 Hz, 1H), 5.43 (br s, 1H), 5.16-5.11 (m, 1H), 4.26-4.18 (m, 2H), 2.93 (s, 4H), 2.72-2.59 (m, 2H), 2.56-2.50 (m, 2H), 2.37-2.34 (m, 2H), 2.12-2.08 (m, 2H), 1.89-1.76 (m, 2H), 1.61-1.45 (m, 6H) ppm. N-[6-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]hexyl]-14-fluoro-2-oxo-10- oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-6-carboxamide (Compound 48)

LC-MS (ES⁺): m/z 789.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 11.20 (s, 1H), 10.76 (s, 1H), 9.24 (br s, 1H), 9.17 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 7.6 Hz, 1H), 8.52 (t, J = 5.6 Hz, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 9.2, 3.2 Hz, 1H), 6.94-6.89 (m, 1H), 6.74 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 7.6 Hz, 1H), 6.43 (dd, J = 9.2, 4.4 Hz, 1H), 5.37 (d, J = 7.2 Hz, 1H), 5.15-5.10 (m, 1H), 4.26- 4.17 (m, 4H), 2.92 (s, 4H), 2.72-2.60 (m, 2H), 2.58-2.50 (m, 2H), 2.34-2.29 (m, 2H), 2.13-2.07 (m, 2H), 1.91-1.81 (m, 1H), 1.58-1.55 (m, 2H), 1.51-1.45 (m, 2H), 1.36 (br s, 4H) ppm. N-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]ethyl]-14-fluoro-2-oxo-10- oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-7-carboxamide (Compound 49)

LC-MS (ES⁺): m/z 733.3 [M + H] ⁺. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]octyl]-14-fluoro-2-oxo-10- oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-6-carboxamide (Compound 50)

LC-MS (ES⁺): m/z 817.4 [M + H] ⁺. N-[6-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-6-oxo-hexyl]-14-fluoro-2- oxo-10-oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-6-carboxamide (Compound 51)

LC-MS (ES⁺): m/z 803.3 [M + H] ⁺. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-8-oxo-octyl]-14-fluoro-2- oxo-10-oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-6-carboxamide (Compound 52)

LC-MS (ES⁺): m/z 831.4 [M + H] ⁺. N-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butyl]-14-fluoro-2- oxo-10-oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-6-carboxamide (Compound 53)

LC-MS (ES⁺): m/z 775.3 [M + H] ⁺. N-[6-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-6-oxo-hexyl]-14-fluoro-2- oxo-10-oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-7-carboxamide (Compound 54)

LC-MS (ES⁺): m/z 803.2 [M + H] ⁺.

N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-8-oxo-octyl]-14-fluoro-2- oxo-10-oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-7-carboxamide (Compound 55)

LC-MS (ES⁺): m/z 831.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 11.21 (s, 1H), 10.77 (s, 1H), 9.25 (t, J = 6.0 Hz, 1H), 8.76 (t, J = 2.4 Hz, 1H), 8.67 (d, J = 7.6 Hz, 1H), 8.44 (t, J = 5.2 Hz, 1H), 8.22 (s, 1H), 7.89-7.87 (m, 2H), 7.18 (dd, J = 8.8, 3.2 Hz, 1H), 6.93 (td, J = 8.4, 3.2 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 9.2 Hz, 2H), 6.53 (d, J = 7.6 Hz, 1H), 6.46 (dd, J = 9.2, 4.4 Hz, 1H), 5.43 (d, J = 7.2 Hz, 1H), 5.16-5.11 (m, 1H), 4.26-4.20 (m, 2H), 3.56 (s, 4H), 3.55-3.24 (m, 3H), 2.91-2.85 (m, 4H), 2.69-2.60 (m, 1H), 2.53-2.50 (m, 2H), 2.35-2.31 (m, 1H), 2.11-2.02 (m, 1H), 1.84-1.78 (m, 1H), 1.56-1.51 (m, 4H), 1.32 (s, 6H) ppm. N-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butyl]-14-fluoro-2- oxo-10-oxa-3,18,22,23,26-pentazapentacyclo[17.5.2.04,9.011,16.022,25]hexacosa- 1(25),4(9),5,7,11,13,15,19(26),20,23-decaene-7-carboxamide (Compound 56)

LC-MS (ES⁺): m/z 775.2 [M + H] ⁺. Example 55 Synthesis of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-2-(isopropylamino)-4-(piperazin-1- yl)benzamide

Step-1: To a solution of tert-butyl 4-fluoro-2-nitro-benzoate (1, 54 g, 223.87 mmol) in tetrahydrofuran (250 mL), was added piperazine (2, 96.41 g, 1.12 mol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was treated with water (200 mL), the precipitated solid was filtered, washed with water and dried under vacuum to give tert-butyl 2-nitro-4-piperazin-1-yl-benzoate (3, 60 g, 189.36 mmol, 85% yield) as a yellow solid. LC-MS (ES⁺): m/z 252.1 [M- Isobutene + H] ⁺. Step-2: To a solution of tert-butyl 2-nitro-4-piperazin-1-yl-benzoate (3, 60 g, 195.22 mmol) and triethylamine (59.26 g, 585.66 mmol, 81.63 mL) in dichloromethane (42 mL), cooled to 0 °C, was added and trifluoroacetic anhydride (61.50 g, 292.83 mmol, 41.28 mL). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture treated with water (60 mL), extracted with dichloromethane (3 x 30 mL). The combined organics were washed with brine solution (40 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product which was triturated with petroleum ether (60 mL), filtered and dried under vacuum to give tert-butyl 2-nitro-4-[4-(2,2,2- trifluoroacetyl)piperazin-1-yl]benzoate (4, 78 g, 177.91 mmol, 91% yield) as a yellow solid. LC- MS (ES⁺): m/z 404.1 [M + H] ⁺. Step-3: To a solution of tert-butyl 2-nitro-4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]benzoate (4, 50 g, 123.96 mmol) in ethanol (500 mL), was added palladium on carbon (10% dry loading, 13.19 g). The contents were stirred at room temperature under hydrogen atmosphere for 16 h. The reaction mixture was filtered through a pad of celite and washed with ethanol. The filtrate was concentrated under reduced pressure and dried under vacuum to give tert-butyl 2-amino-4-[4-(2,2,2- trifluoroacetyl)piperazin-1-yl]benzoate (5, 44 g, 103.70 mmol, 84% yield) as an off-white solid. LC-MS (ES⁺): m/z 374.1 [M + H] ⁺. Step-4: To a solution of tert-butyl 2-amino-4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]benzoate (5, 27 g, 72.31 mmol) and acetone (21.00 g, 361.57 mmol, 26.55 mL) in dichloromethane (270 mL), were added tetramethylammonium triacetoxyborohydride (47.56 g, 180.79 mmol) and trifluoroacetic acid (20.61 g, 180.79 mmol, 13.93 mL). The resulting mixture was stirred at room temperature for 6 h. The reaction mixture was treated with water (300 mL) and extracted with dichloromethane (2 x 200 mL). The combined organics were washed with 10% aqueous sodium bicarbonate solution (100 mL), brine solution (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give tert-butyl 2-(isopropylamino)-4-[4-(2,2,2- trifluoroacetyl)piperazin-1-yl]benzoate (6, 25 g, 57.77 mmol, 80% yield) as a colorless oil. LC- MS (ES⁺): m/z 416.2 [M + H] ⁺. Step-5: To a solution of tert-butyl 2-(isopropylamino)-4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]benzoate (6, 25 g, 60.18 mmol) in dichloromethane (270 mL), cooled to 0 °C, were added triethylamine (18.27 g, 180.53 mmol, 25.16 mL) and trifluoroacetic anhydride (18.96 g, 90.26 mmol, 12.72 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture treated with water (250 mL) and extracted with dichloromethane (3 x 250 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert- butyl 2-[isopropyl-(2,2,2-trifluoroacetyl)amino]-4-[4-(2,2,2-trifluoroacetyl)piperazin-1- yl]benzoate (7, 28 g, 48.18 mmol, 80% yield) as a colorless liquid. LC-MS (ES⁺): m/z 456.0 [M - Isobutene + H] ⁺. Step-6: To a solution of tert-butyl 2-[isopropyl-(2,2,2-trifluoroacetyl)amino]-4-[4-(2,2,2- trifluoroacetyl)piperazin-1-yl]benzoate (7, 28 g, 54.75 mmol) in dichloromethane (280 mL), was added trifluoroacetic acid (93.63 g, 821.18 mmol, 63.27 mL). The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was triturated with diethyl ether, the solid was filtered and dried under vacuum to give 2-[isopropyl-(2,2,2-trifluoroacetyl)amino]-4-[4-(2,2,2- trifluoroacetyl)piperazin-1-yl]benzoic acid (8, 25 g, 48.86 mmol, 89% yield) as a brown solid. LC- MS (ES-): m/z 454.1 [M - H] -. Step-7: To a solution of 2-[isopropyl-(2,2,2-trifluoroacetyl)amino]-4-[4-(2,2,2-trifluoroacetyl)piperazin- 1-yl]benzoic acid (8, 10 g, 21.96 mmol) in dichloromethane (100 mL), were added N,N- dimethylformamide (321.03 mg, 4.39 mmol, 340.07 µL) and oxalyl chloride (5.30 g, 41.73 mmol, 3.63 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure in a nitrogen atmosphere and co-evaporated with toluene to give 2-(2,2,2-trifluoro-N-isopropylacetamido)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoyl chloride (crude) as a brown solid. The crude product was taken to next step. To a solution of 5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amine (9, 5.69 g, 21.96 mmol) in pyridine (60 mL), cooled to -40 °C, was added 2-(2,2,2-trifluoro-N-isopropylacetamido)-4-(4- (2,2,2-trifluoroacetyl)piperazin-1-yl)benzoyl chloride (crude) in dichloromethane (100 mL) dropwise over a period of 10 min. The resulting mixture was stirred at -40 °C for 2 h. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was treated with brine solution (50 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 80% ethyl acetate in petroleum ether to give N-[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]-2-[isopropyl-(2,2,2-trifluoroacetyl)amino]-4-[4-(2,2,2- trifluoroacetyl)piperazin-1-yl]benzamide (10, 12 g, 16.09 mmol, 73% yield) as a red solid. LC- MS (ES⁺): m/z 697.2 [M + H] ⁺. Step-8: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[isopropyl-(2,2,2- trifluoroacetyl)amino]-4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]benzamide (10, 12 g, 17.23 mmol) in methanol (100 mL), was added potassium carbonate (7.14 g, 51.68 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was treated with water (200 mL). The precipitated solid was filtered and washed with water and dried under vacuum to give N-[5-[(3,5-difluorophenyl)methyl]-1H- indazol-3-yl]-2-(isopropylamino)-4-piperazin-1-yl-benzamide (11, 8 g, 15.13 mmol, 88% yield) as a pale red solid. LC-MS (ES⁺): m/z 505.2 [M + H] ⁺.

Example 56 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-2-(methylamino)-4-(piperazin-1-yl)benzamide

Prepared substantially following the synthesis of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol- 3-yl]-2-(isopropylamino)-4-piperazin-1-yl-benzamide. LC-MS (ES⁺): m/z 477.1 [M + H] ⁺. N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(piperazin-1-yl)-2-((tetrahydro-2H-pyran-4- yl)amino)benzamide

Prepared substantially following the synthesis of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol- 3-yl]-2-(isopropylamino)-4-piperazin-1-yl-benzamide. LC-MS (ES⁺): m/z 547.1 [M + H] ⁺.

Example 57 Synthesis of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazin-1-yl)-2- (piperidin-3-ylamino)benzamide

Step-1: To a solution of tert-butyl 4-fluoro-2-nitro-benzoate (1, 6.0 g, 24.87 mmol) in tetrahydrofuran (60 mL), was added 1-methylpiperazine (2, 12.46 g, 124.37 mmol, 13.80 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, the residue was treated with water (100 mL) and stirred for 30 min. The precipitated solid was filtered, washed with water and dried under vacuum to give tert-butyl 4-(4-methylpiperazin- 1-yl)-2-nitro-benzoate (3, 7.5 g, 23.16 mmol, 93% yield) as a yellow solid. LC-MS (ES⁺): m/z 322.1 [M + H] ⁺. Step-2: To a solution of tert-butyl 4-(4-methylpiperazin-1-yl)-2-nitro-benzoate (3, 7.5 g, 23.34 mmol) in ethanol (80 mL), was added palladium on carbon (10% wt. dry loading, 3.0 g). The contents were stirred at room temperature under hydrogen atmosphere for 16 h. The reaction mixture was filtered through a pad of celite and washed with ethanol. The filtrate was concentrated under reduced pressure and the crude residue was triturated with diethyl ether. The precipitated solid was filtered and dried under vacuum to give tert-butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate (4, 6.2 g, 21.06 mmol, 90% yield) as an off-white solid. LC-MS (ES⁺): m/z 292.1 [M + H] ⁺. Step-3: To a solution of tert-butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate (4, 3.0 g, 10.30 mmol) and tert-butyl 3-oxopiperidine-1-carboxylate (5, 2.05 g, 10.30 mmol) in dichloromethane (40 mL), were added tetramethylammonium triacetoxyborohydride (5.42 g, 20.59 mmol) and trifluoroacetic acid (2.35 g, 20.59 mmol, 1.59 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was treated with water (100 mL) and extracted with dichloromethane (2 x 200 mL). The combined organics were washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give tert-butyl 3-[2-tert-butoxycarbonyl-5-(4-methylpiperazin-1-yl)anilino]piperidine-1- carboxylate (6, 4.0 g, 8.21 mmol, 80% yield) as a pale yellow oil. LC-MS (ES⁺): m/z 475.3 [M + H] ⁺. Step-4: To a solution of tert-butyl 3-[2-tert-butoxycarbonyl-5-(4-methylpiperazin-1-yl)anilino]piperidine- 1-carboxylate (6, 4.00 g, 8.43 mmol) in dichloromethane (10 mL), cooled to 0 °C, was added HCl in dioxane (4 M, 10 mL). The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and co-evaporated with dichloromethane to give the crude product. The crude product was triturated with diethyl ether to give an inseparable mixture of 4-(4-methylpiperazin-1-yl)-2-(3-piperidylamino)benzoic acid hydrochloride and tert-butyl 4-(4-methylpiperazin-1-yl)-2-(3-piperidylamino)benzoate hydrochloride (7, 3.5 g, 7.40 mmol, 88% yield) as a brown oil. The inseparable mixture of products was taken to next step without purification. LC-MS (ES⁺): m/z 319.2 [M + H] ⁺. Step-5: To a solution of 4-(4-methylpiperazin-1-yl)-2-(3-piperidylamino)benzoic acid hydrochloride (3.5 g, 10.99 mmol) and tert-butyl 4-(4-methylpiperazin-1-yl)-2-(3-piperidylamino)benzoate hydrochloride (7, 3.50 g, 9.35 mmol) in dichloromethane (40 mL), cooled to 0 °C, were added triethylamine (3.34 g, 32.98 mmol, 4.6 mL) and trifluoroacetic anhydride (3.46 g, 16.49 mmol, 2.32 mL). The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was treated water (100 mL) and extracted with dichloromethane (2 x 200 mL). The combined organics were washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give an inseparable mixture of 4-(4-methylpiperazin-1-yl)-2- [(2,2,2-trifluoroacetyl)-[1-(2,2,2-trifluoroacetyl)-3-piperidyl]amino]benzoic acid and tert-butyl 4- (4-methylpiperazin-1-yl)-2-[(2,2,2-trifluoroacetyl)-[1-(2,2,2-trifluoroacetyl)-3- piperidyl]amino]benzoate (8, 6.3 g, 9.26 mmol, 84% yield) as a brown gum. The inseparable mixture of products was taken to next step without purification. LC-MS (ES⁺): m/z 511.1 [M + H] ⁺. Step-6: To a solution of 4-(4-methylpiperazin-1-yl)-2-[(2,2,2-trifluoroacetyl)-[1-(2,2,2-trifluoroacetyl)-3- piperidyl]amino]benzoic acid and tert-butyl 4-(4-methylpiperazin-1-yl)-2-[(2,2,2-trifluoroacetyl)- [1-(2,2,2-trifluoroacetyl)-3-piperidyl]amino]benzoate (8, 6.3 g, 12.34 mmol) in dichloromethane (50 mL), cooled to 0 °C, was added trifluoroacetic acid (14.80 g, 129.80 mmol, 10 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, the residue was triturated with dichloromethane (2 x 20 mL) to give 4-(4- methylpiperazin-1-yl)-2-[(2,2,2-trifluoroacetyl)-[1-(2,2,2-trifluoroacetyl)-3- piperidyl]amino]benzoic acid trifluoroacetate (9, 5.5 g, 6.61 mmol, 59% yield) as a brown gum. The crude product was taken to next step without purification. LC-MS (ES⁺): m/z 511.1 [M + H] ⁺. Step-7: To a solution of 4-(4-methylpiperazin-1-yl)-2-[(2,2,2-trifluoroacetyl)-[1-(2,2,2-trifluoroacetyl)-3- piperidyl]amino]benzoic acid (9, 3.5 g, 6.86 mmol) in dichloromethane (40 mL), were added oxalyl chloride (1.74 g, 13.71 mmol, 1.19 mL) followed by N,N-dimethylformamide (50.12 mg, 685.70 µmol, 53.09 µL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure in a nitrogen atmosphere and co- distilled with toluene (10 mL) to give 4-(4-methylpiperazin-1-yl)-2-(2,2,2-trifluoro-N-(1-(2,2,2- trifluoroacetyl)piperidin-3-yl)acetamido)benzoyl chloride as a brown semi-solid. To a solution of 4-(4-methylpiperazin-1-yl)-2-(2,2,2-trifluoro-N-(1-(2,2,2- trifluoroacetyl)piperidin-3-yl)acetamido)benzoyl chloride in tetrahydrofuran (50 mL), cooled to - 40 °C, was added 5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amine (10, 1.78 g, 6.86 mmol) and N,N-diisopropylethylamine (2.66 g, 20.57 mmol, 3.58 mL) in tetrahydrofuran (20 mL) drop- wise. The resulting mixture was stirred at -40 °C for 2 h. The reaction mixture was treated with cold water (100 mL) and extracted with dichloromethane (2 x 200 mL). The combined organics were washed with brine solution (150 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-15% methanol in dichloromethane to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4- methylpiperazin-1-yl)-2-[(2,2,2-trifluoroacetyl)-[1-(2,2,2-trifluoroacetyl)-3- piperidyl]amino]benzamide (11, 2.7 g, 2.84 mmol, 41% yield) as a brown solid. LC-MS (ES⁺): m/z 752.2 [M + H] ⁺. Step-8: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)- 2-[(2,2,2-trifluoroacetyl)-[1-(2,2,2-trifluoroacetyl)-3-piperidyl]amino]benzamide (11, 1.70 g, 2.26 mmol) in methanol (20 mL), cooled to 0 °C, was added potassium carbonate (1.56 g, 11.31 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was treated with cold water (80 mL) and stirred for 30 min. The precipitated solid was filtered, washed with water (30 mL) and dried under vacuum to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(3- piperidylamino)benzamide (12, 840 mg, 1.01 mmol, 44% yield) as a pale brown solid. LC-MS (ES⁺): m/z 560.2 [M + H] ⁺. Example 58 N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(4- piperidylamino)benzamide

Prepared substantially following the synthesis of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4- (4-methylpiperazin-1-yl)-2-(piperidin-3-ylamino)benzamide. LC-MS (ES⁺): m/z 560.2 [M + H] ⁺. Example 59 Synthesis of N-(5-(3,5-difluorobenzyl)-1H-indol-3-yl)-4-(4-(2,2,2-trifluoroacetyl)piperazin- 1-yl)benzamide

Step-1: To a solution of 4-piperazin-1-ylbenzoic acid hydrochloride (1, 11 g, 45.32 mmol) in dichloromethane (110 mL), cooled to 0 °C, was added triethylamine (22.93 g, 226.62 mmol, 31.59 mL) followed by trifluoroacetic anhydride (12.38 g, 58.92 mmol, 8.31 mL). The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was treated with water (100 mL) and extracted with dichloromethane (3 × 500 mL). The combined organics were washed with water (400 mL), brine solution (300 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 60-120 mesh) eluted with 35-50% ethyl acetate in petroleum ether to give 4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]benzoic acid (2, 10.5 g, 27.92 mmol, 62% yield) as an off-white solid. LC-MS (ES⁺): m/z 301.9 [M + H] ⁺. Step-2: To a solution of 4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]benzoic acid (2, 5 g, 16.54 mmol) in dichloromethane (50 mL), were added oxalyl chloride (4.20 g, 33.09 mmol, 2.88 mL) followed by N,N-dimethylformamide (241.83 mg, 3.31 mmol, 256.18 µL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and co- distilled with toluene to give 4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoyl chloride (crude) as a pale yellow semi-solid. To a solution of 5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amine (3, 3.73 g, 14.39 mmol) in pyridine (40 mL), cooled to -40 °C, was added 4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoyl chloride (crude) in dichloromethane (40 mL) drop-wise. The resulting mixture was stirred at -30 °C for 1 h. The reaction mixture was warmed to room temperature and concentrated under reduced pressure. The obtained residue was taken in dichloromethane (100 mL), methanol (10 mL) and methyl tert-butyl ether (100mL). The precipitated solid was filtered, washed with mixture of dichloromethane / methyl tert-butyl ether / methanol (10:10:1 ratio, 100 mL) and dried under vacuum to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-(2,2,2- trifluoroacetyl)piperazin-1-yl]benzamide (4, 5.5 g, 8.49 mmol, 51% yield) as an off-white solid. LC-MS (ES⁺): m/z 544.2 [M + H] ⁺. Step-3: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-(2,2,2- trifluoroacetyl)piperazin-1-yl]benzamide (4, 2.5 g, 4.60 mmol) in methanol (20 mL), cooled to 0 °C, was added potassium carbonate (1.91 g, 13.80 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was treated with water (20 mL), the precipitated solid was filtered, washed with water and dried under vacuum to give N-[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]-4-piperazin-1-yl-benzamide (5, 1.8 g, 3.97 mmol, 86% yield) as an off-white solid. LC-MS (ES⁺): m/z 448.2 [M + H] ⁺. Example 60 Synthesis of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 57)

To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-piperazin-1-yl-2- (tetrahydropyran-4-ylamino)benzamide (1, 25 mg, 45.74 µmol) and 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid bis(trifluoroacetate) (2, 28.19 mg, 45.74 µmol) in N,N-dimethylformamide (0.5 mL), were added COMU (23.51 mg, 54.88 µmol) and DIPEA (29.55 mg, 228.68 µmol, 39.83 µL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was treated with water (1 mL) and extracted with ethyl acetate (3 x 1.5 mL). The combined organics were washed with brine solution (2 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under Genevac at 50 °C to give the crude product. The crude product was purified by mass-directed preparative HPLC [Column: Sunfire C18 OBD, (19 x 100 mm), 5 micron; Mobile phase A: 0.1% TFA in water, Mobile phase B: Acetonitrile, Wavelength: 215 nm] and the fractions containing the product was lyophilized to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[4-[4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide trifluoroacetate (Compound 57, 3.55 mg, 8% yield) as an off-white solid. LC-MS (ES⁺): m/z 917.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.67 (s, 1H), 10.85 (s, 1H), 10.14 (s, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.49 (s, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.26 (dd, J = 8.6, 1.4 Hz, 2H), 7.17 (br s, 2H), 7.04-6.99 (m, 3H), 6.98-6.75 (m, 2H), 6.27 (d, J = 7.5 Hz, 1H), 6.17 (s, 1H), 4.37-4.34 (m, 1H), 4.05 (s, 2H), 3.84-3.80 (m, 6H), 3.52-3.47 (m, 5H), 3.28-3.17 (m, 10H), 2.74 (s, 5H), 2.10-2.06 (m, 2H), 1.96-1.88 (m, 3H), 1.39-1.32 (m, 2H) ppm. Example 61 N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-

propoxy]ethoxy]ethoxy]ethoxy]propanoyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 58)

Compound 58 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1094.2 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[2-[2-[2-[2-[2-[2-[4-[[[2-(2,6- dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 59)

Compound 59 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1221.1 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[2-[2-[2-[2-[3-[4-[4-[(2,6-dioxo- 3-piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 60)

Compound 60 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1138.2 [M + H] ⁺.

N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[4-[[[2-(2,6-dioxo-3-piperidyl)- 1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]propanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 61)

Compound 61 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 955.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[12-[4-[[[2-(2,6-dioxo-3-piperidyl)- 1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]dodecanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 62)

Compound 62 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1082.2 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[10-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-10-oxo-decanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 63)

Compound 63 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 1001.4 [M + H] ⁺.

N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[15-[4-[[[2-(2,6-dioxo-3-piperidyl)- 1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]pentadecanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 64)

Compound 64 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1124.1 [M + H] ⁺.

N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[2-[2-[2-[2-[2-[3-[4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 65)

Compound 65 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1182.2 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[12-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-12-oxo-dodecanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 66)

Compound 66 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 1029.4 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[6-[4-[[[2-(2,6-dioxo-3-piperidyl)- 1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]hexanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 67)

Compound 67 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 998.0 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[9-[4-[[[2-(2,6-dioxo-3-piperidyl)- 1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]nonanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 68)

Compound 68 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1040.0 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[7-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo-heptanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 69)

Compound 69 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 959.4 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[2-[2-[4-[[[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]ethoxy]ethoxy]propanoyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (Compound 70)

Compound 70 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1044.0 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]propanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 71)

Compound 71 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 962.0 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[2-[2-[2-[4-[[[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]ethoxy]ethoxy]ethoxy]propanoyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 72)

Compound 72 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1088.1 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]ethoxy]propanoyl]piperazin-1-yl]- 2-(tetrahydropyran-4-ylamino)benzamide (Compound 73)

Compound 73 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1006.1 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[2-[4-[[[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]ethoxy]propanoyl]piperazin- 1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (Compound 74)

Compound 74 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1000.0 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[14-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-14-oxo-tetradecanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 75)

Compound 75 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1058.2 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[2-[2-[2-[2-[4-[[[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]ethoxy]ethoxy]ethoxy]ethoxy]propanoyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 76)

Compound 76 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1132.1 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[2-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]propanoyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 77)

Compound 77 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1050.1 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[3-[2-[2-[2-[2-[2-[4-[[[2-(2,6-dioxo- 3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 78)

Compound 78 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1176.1 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[7-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo-heptanoyl]-4-piperidyl]amino]-4-(4- methylpiperazin-1-yl)benzamide (Compound 79)

Compound 79 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 972.4 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[15-[4-[[[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]pentadecanoyl]-4- piperidyl]amino]-4-(4-methylpiperazin-1-yl)benzamide (Compound 80)

Compound 80 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1137.1 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]-4-piperidyl]amino]-4-(4- methylpiperazin-1-yl)benzamide (Compound 81)

Compound 81 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 931.0 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[3-[2-[2-[2-[2-[2-[4-[[[2-(2,6-dioxo- 3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoyl]-4-piperidyl]amino]-4-(4- methylpiperazin-1-yl)benzamide (Compound 82)

Compound 82 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1189.9 [M + H] ⁺; 1211.0 [M + Na] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[3-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]ethoxy]propanoyl]-4- piperidyl]amino]-4-(4-methylpiperazin-1-yl)benzamide (Compound 83)

Compound 83 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 1019.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[12-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-12-oxo-dodecanoyl]-4-piperidyl]amino]-4-(4- methylpiperazin-1-yl)benzamide (Compound 84)

Compound 84 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1143.0 [M + H] ⁺; 1167.0 [M + Na] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[3-[2-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]ethoxy]ethoxy]propanoyl]-4- piperidyl]amino]-4-(4-methylpiperazin-1-yl)benzamide (Compound 85)

Compound 85 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 1062.4 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[14-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-14-oxo-tetradecanoyl]-4-piperidyl]amino]-4-(4- methylpiperazin-1-yl)benzamide (Compound 86)

Compound 86 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1071.1 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[3-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]propanoyl]-4-piperidyl]amino]-4- (4-methylpiperazin-1-yl)benzamide (Compound 87)

Compound 87 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 975.0 [M + H] ⁺, 996.9 [M + Na] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[10-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-10-oxo-decanoyl]-4-piperidyl]amino]-4-(4- methylpiperazin-1-yl)benzamide (Compound 88)

Compound 88 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 1014.4 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.68 (s, 1H), 10.78 (s, 1H), 10.20 (s, 1H), 9.64 (s, 1H), 8.37 (s, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.45 (s, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 9.5 Hz, 1H), 7.02-6.97 (m, 3H), 6.83 (s, 2H), 6.64 (d, J = 8.2 Hz, 2H), 6.31 (d, J = 9.0 Hz, 1H), 6.24 (s, 1H), 4.23-4.19 (m, 1H), 4.03 (s, 6H), 3.75-3.68 (m, 3H), 3.57- 3.49 (m, 6H), 3.17-3.13 (m, 3H), 3.06-3.00 (m, 5H), 2.88 (s, 6H), 2.33-2.27 (m, 4H), 2.12-2.08 (m, 2H), 1.94-1.84 (m, 2H), 1.47 (s, 4H), 1.25 (s, 12H) ppm. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[12-[4-[[[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]dodecanoyl]-4- piperidyl]amino]-4-(4-methylpiperazin-1-yl)benzamide (Compound 89)

Compound 89 was prepared substantially following the synthesis of Compound 57. UPLC (ES⁺): m/z 1096.2 [M + H] ⁺.

N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[3-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]propanoyl]- 4-piperidyl]amino]-4-(4-methylpiperazin-1-yl)benzamide (Compound 90)

Compound 90 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 1106.4 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]-3-piperidyl]amino]-4-(4- methylpiperazin-1-yl)benzamide (Compound 91)

Compound 91 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 930.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[7-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo-heptanoyl]-3-piperidyl]amino]-4-(4- methylpiperazin-1-yl)benzamide (Compound 92)

Compound 92 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 972.4 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[10-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-10-oxo-decanoyl]-3-piperidyl]amino]-4-(4- methylpiperazin-1-yl)benzamide (Compound 93)

Compound 93 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 1014.5 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.67 (s, 1H), 10.77 (s, 1H), 10.12 (d, J = 12.4 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.86-7.79 (m, 1H), 7.51 (d, J = 4.4 Hz, 1H), 7.41 (d, J = 3.2 Hz, 1H), 7.39 (d, J = 3.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.04-6.98 (m, 3H), 6.77 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 6.28-6.20 (m, 2H), 5.46-5.44 (m, 1H), 4.23-4.16 (m, 1H), 4.05 (d, J = 8.0 Hz, 2H), 3.71-3.65 (m, 2H), 3.55-3.51 (m, 4H), 3.21-3.08 (m, 6H), 2.89 (s, 2H), 2.85 (s, 2H), 2.53-2.50 (m, 4H), 2.34-2.29 (m, 6H), 2.28-2.23 (m, 3H), 1.95- 1.81 (m, 3H), 1.50-1.32 (m, 6H), 1.24-1.13 (m, 9H) ppm. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[3-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]propanoyl]-3-piperidyl]amino]-4- (4-methylpiperazin-1-yl)benzamide (Compound 94)

Compound 94 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 974.3 [M + H] ⁺.

N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[9-[4-[[[2-(2,6-dioxo-3-piperidyl)- 1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]nonanoyl]-3-piperidyl]amino]-4-(4- methylpiperazin-1-yl)benzamide (Compound 95)

Compound 95 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 1052.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[3-[2-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]ethoxy]propanoyl]-3- piperidyl]amino]-4-(4-methylpiperazin-1-yl)benzamide (Compound 96)

Compound 96 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 1040.4 [M + Na] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[12-[4-[[[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]dodecanoyl]-3- piperidyl]amino]-4-(4-methylpiperazin-1-yl)benzamide (Compound 97)

Compound 97 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 1095.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-2-(isopropylamino)benzamide

Compound 98 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 830.3 [M - H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 12.65 (s, 1H), 10.77 (s, 1H), 10.10 (s, 1H), 8.16 (s, 1H), 8.12 (d, J = 7.3 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.48 (s, 2H), 7.41 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.03-6.94 (m, 5H), 6.60 (d, J = 8.2 Hz, 2H), 6.26 (d, J = 8.4 Hz, 1H), 6.11 (s, 1H), 5.66 (d, J = 7.4 Hz, 1H), 4.25-4.18 (m, 1H), 4.04 (s, 2H), 3.74 (s, 4H), 3.60 (s, 4H), 3.22 (s, 4H), 3.02-2.92 (m, 2H), 2.73-2.67 (m, 2H), 2.13-2.08 (m, 2H), 1.87- 1.81 (m, 1H), 1.73-1.69 (m, 3H), 1.16 (d, J = 6.0 Hz, 6H) ppm. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-2-(methylamino)benzamide (Compound 99)

Compound 99 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 804.2 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.64 (s, 1H), 10.77 (s, 1H), 10.12 (s, 1H), 8.16 (s, 1H), 8.10 (d, J = 4.8 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.04-6.95 (m, 5H), 6.61 (d, J = 8.3 Hz, 2H), 6.27 (d, J = 8.7 Hz, 1H), 6.06 (s, 1H), 5.66 (d, J = 7.4 Hz, 1H), 4.29-4.23 (m, 1H), 4.04 (s, 2H), 3.75 (s, 2H), 3.61 (s, 2H), 3.23 (s, 4H), 3.02-2.92 (m, 2H), 2.82 (d, J = 4.8 Hz, 4H), 2.33-2.25 (m, 3H), 2.14-2.08 (m, 3H), 1.83-1.55 (m, 6H) ppm. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]benzamide (Compound 100)

Compound 100 was prepared substantially following the synthesis of Compound 57. LC-MS (ES⁺): m/z 775.4 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.70 (s, 1H), 10.77 (s, 1H), 10.44 (s, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.59 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.26-7.23 (m, 1H), 7.08-6.95 (m, 7H), 6.61 (d, J = 8.4 Hz, 2H), 5.66 (d, J = 7.6 Hz, 1H), 4.29-4.23 (m, 1H), 4.05 (s, 2H), 3.77 (s, 2H), 3.63 (s, 2H), 3.41 (s, 2H), 3.37 (s, 2H), 2.95-2.90 (m, 2H), 2.74-2.68 (m, 1H), 2.61-2.50 (m, 2H), 2.34-2.29 (m, 2H), 2.12-2.08 (m, 3H), 1.88-1.83 (m, 1H), 1.73-1.70 (m, 2H), 1.60-1.57 (m, 2H) ppm. Example 62 Synthesis of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4- yl)amino)benzamide (Compound 101)

Step-1: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-piperazin-1-yl-2- (tetrahydropyran-4-ylamino)benzamide (1, 530 mg, 969.61 µmol) in methanol (10 mL), were added 2,2-dimethoxyacetaldehyde (2, 121.13 mg, 1.16 mmol), MP-cyanoborohydride (Biotage^®, 1.1 g) and acetic acid (5.82 mg, 96.96 µmol, 5.55 µL). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with diethyl ether to give N-[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-(2,2-dimethoxyethyl)piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (3, 520 mg, 696.38 µmol, 72% yield) as an off-white solid. LC-MS (ES⁺): m/z 635.2 [M + H] ⁺. Step-2: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-(2,2- dimethoxyethyl)piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (3, 520 mg, 819.27 µmol) in tetrahydrofuran (8 mL), was added 3 N HCl in water (8 mL). The resulting mixture was heated at 70 °C for 12 h. The reaction mixture was purged in an inert atmosphere of nitrogen for 30 minutes to remove volatiles, triturated with diethyl ether (3 x 20 mL) and dried under vacuum to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-(2-oxoethyl)piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide hydrochloride (4, 500 mg, 535.91 µmol, 65% yield) as an off-white solid. The crude product was taken to next step without purification. LC-MS (ES⁺): m/z 589.2 [M + H] ⁺. Step-3: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-(2-oxoethyl)piperazin- 1-yl]-2-(tetrahydropyran-4-ylamino)benzamide hydrochloride (4, 197.96 mg, 316.68 µmol) in methanol (6 mL), were added 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione hydrochloride (5, 70 mg, 243.60 µmol), MP-cyanoborohydride (Biotage^®, 300 mg) and acetic acid (1.46 mg, 24.36 µmol, 1.39 µL). The resulting mixture was stirred at 65 °C for 5 h. The reaction mixture was filtered, and filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by mass directed preparative HPLC [Column: Sunfire C18 (19 x 100 mm), 5 microns; Mobile phase: A, 0.1% TFA in water; B: acetonitrile; Wavelength: 215 nm]. The fractions containing the product was lyophilized to give N-[5-[(3,5-difluorophenyl)methyl]-1H- indazol-3-yl]-4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]ethyl]piperazin-1- yl]-2-(tetrahydropyran-4-ylamino)benzamide trifluoroacetate (Compound 101, 6 mg, 6.15 µmol, 3% yield) as an off-white solid. LC-MS (ES⁺): m/z 860.4 [M + H] ⁺.¹H NMR (400 MHz, DMSO- d₆): δ 12.68 (s, 1H), 10.80 (s, 1H), 10.17 (s, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.47 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.27 (dd, J = 8.6, 1.6 Hz, 1H), 7.05-6.98 (m, 6H), 6.66 (d, J = 8.4 Hz, 2H), 6.32 (d, J = 8.8 Hz, 1H), 6.21 (s, 1H), 4.23-4.15 (m, 1H), 4.05 (s, 2H), 3.85-3.81 (m, 3H), 3.41-3.33 (m, 4H), 3.12-3.01 (m, 4H), 2.69-2.61 (m, 6H), 2.53-2.50 (m, 4H), 2.48 (s, 1H), 2.13-2.01 (m, 2H), 1.96-1.86 (m, 8H), 1.38-1.24 (m, 3H) ppm.

Example 63 N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-[(2,4-dioxo-3- azabicyclo[3.1.1]heptan-1-yl)amino]phenyl]-1-piperidyl]ethyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 102)

Compound 102 was prepared substantially following the synthesis of Compound 101. LC-MS (ES⁺): m/z 872.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]ethyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 103)

Compound 103 was prepared substantially following the synthesis of Compound 101. LC-MS (ES⁺): m/z 878.3 [M + H] ⁺. Example 64 Synthesis of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 104)

Step-1: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-piperazin-1-yl-2- (tetrahydropyran-4-ylamino)benzamide (1, 150 mg, 274.42 µmol) and oxaldehydic acid (2, 20.32 mg, 274.42 µmol, 15.16 µL) in methanol (3 mL), were added MP-cyanoborohydride (Biotage^®, 250 mg) and acetic acid (16.48 mg, 274.42 µmol, 15.69 µL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a pad of celite, washed with methanol and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was washed with 50% diethyl ether in hexanes, filtered and dried under vacuum to give 2-[4-[4-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]-3-(tetrahydropyran-4- ylamino)phenyl]piperazin-1-yl]acetic acid (3, 130 mg, 175.42 µmol, 64% yield) as an off-white solid. LC-MS (ES⁺): m/z 605.3 [M + H] ⁺. Step-2: To a solution of 2-[4-[4-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]-3- (tetrahydropyran-4-ylamino)phenyl]piperazin-1-yl]acetic acid (3, 60 mg, 99.23 µmol) and 3-[4- (4-piperidyl)anilino]piperidine-2,6-dione (4, 34.22 mg, 119.08 µmol) in N,N-dimethylformamide (2 mL), were added DIPEA (64.13 mg, 496.16 µmol, 86.42 µL) and PyBOP (61.97 mg, 119.08 µmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was treated with cold water (2 mL) and extracted with ethyl acetate (3 x 3 mL). The combined organics were washed brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase C18 column [60 g ISCO C18 column; Mobile phase: A, 0.1% ammonium acetate in water; B: acetonitrile]. The fractions containing the product was lyophilized to give N-[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]- 1-piperidyl]-2-oxo-ethyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (Compound 104, 7.22 mg, 7.78 µmol, 8% yield) as an off-white solid. LC-MS (ES⁺): m/z 874.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.64 (s, 1H), 10.77 (s, 1H), 10.10 (s, 1H), 8.29 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.48 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.25 (dd, J = 8.6, 1.4 Hz, 1H), 7.03-6.94 (m, 6H), 6.61 (d, J = 8.6 Hz, 2H), 6.24 (d, J = 9.0 Hz, 1H), 6.14 (s, 1H), 5.68 (d, J = 7.4 Hz, 1H), 4.50 (d, J = 11.6 Hz, 1H), 4.29-4.26 (m, 1H), 4.25-4.23 (m, 1H), 4.04 (s, 2H), 3.82-3.79 (m, 2H), 3.69-3.64 (m, 1H), 3.53-3.46 (m, 2H), 3.39-3.31 (m, 3H), 3.10-3.03 (m, 4H), 2.51-2.49 (m, 4H), 2.11-2.07 (m, 4H), 1.94-1.80 (m, 5H), 1.57-1.55 (m, 1H), 1.35-1.23 (m, 3H) ppm.

Example 65 Synthesis of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 105)

To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-piperazin-1-yl-2- (tetrahydropyran-4-ylamino)benzamide (1, 75.00 mg, 137.21 µmol) and 2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]acetic acid (2, 47.39 mg, 137.21 µmol) in N,N- dimethylformamide (2 mL), were added PyBOP (107.10 mg, 205.81 µmol) and DIPEA (53.20 mg, 411.63 µmol, 71.70 µL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was treated with water (20 mL), the precipitated solid was filtered and washed with water and dried under vacuum. The crude product was purified by mass-directed preparative HPLC [Column: Sunfire C18 OBD, (19 x 100 mm), 5 micron; Mobile phase: A, 0.1% ammonium acetate in water; B, acetonitrile; Wavelength: 215 nm] and the fractions containing the product was lyophilized to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 105, 21 mg, 23.52 µmol, 17.14% yield) as an off-white solid. LC-MS (ES⁺): m/z 874.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.67 (s, 1H), 10.78 (s, 1H), 10.13 (s, 1H), 8.31 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 8.6, 1.2 Hz, 1H), 7.04-6.94 (m, 5H), 6.60 (d, J = 8.4 Hz, 2H), 6.27 (d, J = 9.2 Hz, 1H), 6.18 (s, 1H), 5.67 (d, J = 7.2 Hz, 1H), 4.26-4.21 (m, 1H), 4.04 (s, 2H), 3.83-3.69 (m, 6H), 3.60 (s, 2H), 3.49 (t, J = 9.6 Hz, 2H), 3.27 (s, 2H), 3.21 (s, 2H), 2.92 (d, J = 10.8 Hz, 2H), 2.73-2.67 (m, 1H), 2.37-2.31 (m, 2H), 2.12-2.07 (m, 3H), 1.86-1.72 (m, 4H), 1.69-1.61 (m, 2H), 1.39-1.34 (m, 2H) ppm. Example 66 N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-[(2,4-dioxo-3- azabicyclo[3.1.1]heptan-1-yl)amino]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 106)

Compound 106 was prepared substantially following the synthesis of Compound 105. LC-MS (ES⁺): m/z 886.3 [M + H] ⁺.

N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-[(2,4- dioxohexahydropyrimidin-1-yl)methyl]phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 107)

Compound 107 was prepared substantially following the synthesis of Compound 105. LC-MS (ES⁺): m/z 874.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[2-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]ethyl]piperazin-1-yl]acetyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 108)

Compound 108 was prepared substantially following the synthesis of Compound 105. LC-MS (ES⁺): m/z 903.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-(2,6-dioxo-3- piperidyl)phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 109)

Compound 109 was prepared substantially following the synthesis of Compound 105. LC-MS (ES⁺): m/z 859.4 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 110)

Compound 110 was prepared substantially following the synthesis of Compound 105. LC-MS (ES⁺): m/z 892.3 [M + H] ⁺.

N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[3-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]propyl]piperazin-1-yl]acetyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 111)

Compound 111 was prepared substantially following the synthesis of Compound 105. LC-MS (ES⁺): m/z 917.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[4-[[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]methyl]piperazin-1-yl]acetyl]piperazin-1-yl]-2-(tetrahydropyran- 4-ylamino)benzamide (Compound 112)

Compound 112 was prepared substantially following the synthesis of Compound 105. LC-MS (ES⁺): m/z 889.3 [M + H] ⁺. Example 67 N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[4-[4-[4-[(2,6-dioxo-3- piperidyl)carbamoyl]phenyl]-1-piperidyl]-4-oxo-butanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 113)

Step-1: An oven dried round bottom flask was charged with N-[5-[(3,5-difluorophenyl)methyl]-1H- indazol-3-yl]-4-piperazin-1-yl-2-(tetrahydropyran-4-ylamino)benzamide (1, 400 mg, 731.78 µmol) and 4-tert-butoxy-4-oxo-butanoic acid (2, 127.47 mg, 731.78 µmol) in DMF (3 mL) before DIPEA (283.73 mg, 2.20 mmol, 382.39 µL) and T3P (417.37 mg, 1.10 mmol) were added at room temperature and the resulting mixture was stirred at this temperature for 16 hours. The reaction mixture was then diluted with water (15 mL) and the solid precipitation was dried under reduced pressure to give tert-butyl 4-[4-[4-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]- 3-(tetrahydropyran-4-ylamino)phenyl]piperazin-1-yl]-4-oxo-butanoate (3, 330 mg, 441.38 µmol, 60% yield) as an off-white solid. LC-MS (ES-): m/z 701.2 [M - H] -. Step-2: An oven dried round bottom flask was charged with tert-butyl 4-[4-[4-[[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]-3-(tetrahydropyran-4- ylamino)phenyl]piperazin-1-yl]-4-oxo-butanoate (3, 330 mg, 469.56 µmol) in DCM (5 mL) and 4M HCl in dioxane (85.69 mg, 2.35 mmol) was added at 0 °C and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was co-distilled with diethyl ether to afford 4-[4-[4-[[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]-3-(tetrahydropyran-4- ylamino)phenyl]piperazin-1-yl]-4-oxo-butanoic acid hydrochloride (4, 300 mg, 395.23 µmol, 84% yield) as a white color solid. LC-MS (ES⁺): m/z 647.2 [M + H] ⁺. Step-3: An oven dried round bottom flask was charged with 4-[4-[4-[[5-[(3,5-difluorophenyl)methyl]-1H- indazol-3-yl]carbamoyl]-3-(tetrahydropyran-4-ylamino)phenyl]piperazin-1-yl]-4-oxo-butanoic acid (4, 40 mg, 61.85 µmol) and N-(2,6-dioxo-3-piperidyl)-4-(4-piperidyl)benzamide hydrochloride (5, 19.51 mg, 55.44 µmol) in DMF (1 mL) before DIPEA (31.98 mg, 247.42 µmol, 43.10 µL) and HATU (35.28 mg, 92.78 µmol) were added at room temperature. The resulting mixture was stirred at room temperature for 0.5 hour. After completion of the reaction, the reaction mixture was diluted with water (15 mL), and the solid precipitation was filtered and dried under reduced pressure to give the crude product, which was purified by prep-HPLC[Mobile-phase A: 0.1% HCOOH in H₂O, Mobile-phase B: ACN] and lyophilized to afford N-[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[4-[4-[4-[(2,6-dioxo-3- piperidyl)carbamoyl]phenyl]-1-piperidyl]-4-oxo-butanoyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide formate (Compound 113, 16 mg, 16.14 µmol, 26% yield) as an off- white solid. LC-MS (ES⁺): m/z 944.2 [M + H] ⁺. Example 68 N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[4-[4-[4-[2-[(2,6-dioxo-3- piperidyl)amino]-2-oxo-ethyl]phenyl]-1-piperidyl]-4-oxo-butanoyl]piperazin-1-yl]-2- (tetrahydropyran-4-ylamino)benzamide (Compound 114)

Compound 114 was prepared substantially following the synthesis of Compound 113. LC-MS (ES⁺): m/z 958.3 [M + H] ⁺. Example 69 Synthesis of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperidine-1-carbonyl]piperazin-1-yl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 115)

Step-1: To a solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione trifluoroacetate (1, 150 mg, 373.71 µmol) and DIPEA (241.50 mg, 1.87 mmol, 325.47 µL) in N,N-dimethylformamide (5 mL), was added (4-nitrophenyl) carbonochloridate (2, 82.86 mg, 411.08 µmol). The resulting mixture was heated at 80 °C for 16 h. The reaction mixture was treated with water (8 mL) and extracted with ethyl acetate (3 x 7 mL). The combined organics were washed with water, brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 40-60% ethyl acetate in petroleum ether to give (4-nitrophenyl) 4- [4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperidine-1-carboxylate (3, 160 mg, 341.96 µmol, 92% yield) as a pale green solid. LC-MS (ES⁺): m/z 453.1 [M + H] ⁺. Step-2: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-piperazin-1-yl-2- (tetrahydropyran-4-ylamino)benzamide (4, 159.47 mg, 291.74 µmol) and (4-nitrophenyl) 4-[4- [(2,6-dioxo-3-piperidyl)amino]phenyl]piperidine-1-carboxylate (3, 110 mg, 243.12 µmol) in N,N- dimethylformamide (3 mL), were added DIPEA (94.26 mg, 729.35 µmol, 127.04 µL) and DMAP (2.97 mg, 24.31 µmol). The resulting mixture was stirred at 100 °C for 24 h. The reaction mixture was treated with water (2 mL), the precipitated solid was filtered to give the crude product. The crude product was purified by reverse phase C18 column [30 g ISCO C18 column; Mobile phase: A, 0.1% ammonium acetate in water; B, acetonitrile] to give N-[5-[(3,5-difluorophenyl)methyl]- 1H-indazol-3-yl]-4-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperidine-1- carbonyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (Compound 115, 15.81 mg, 17.10 µmol, 7% yield) as a light brown solid. LC-MS (ES⁺): m/z 860.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.65 (s, 1H), 10.78 (s, 1H), 10.13 (s, 1H), 8.31 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.49 (s, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.26 (dd, J = 8.6, 1.3 Hz, 1H), 7.04-6.96 (m, 6H), 6.62 (d, J = 8.6 Hz, 2H), 6.26 (d, J = 9.1 Hz, 1H), 6.16 (s, 1H), 5.69 (d, J = 7.6 Hz, 1H), 4.30-4.26 (m, 1H), 4.04 (s, 2H), 3.83-3.69 (m, 6H), 3.49 (t, J = 9.9 Hz, 2H), 3.33-3.23 (m, 7H), 2.87-2.81 (m, 2H), 2.76-2.73 (m, 1H), 2.51-2.48 (m, 1H), 2.12-2.08 (m, 1H), 1.96-1.84 (m, 3H), 1.76-1.71 (m, 2H), 1.57-1.52 (m, 2H), 1.38-1.31 (m, 2H) ppm. Example 70 Synthesis of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[1-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 116)

Step-1: To a solution of 4-bromo-2-nitro-benzoic acid (1, 5 g, 20.32 mmol) in dichloromethane (50 mL) was added oxalyl chloride (5.16 g, 40.65 mmol, 3.53 mL) followed by N,N-dimethylformamide (297.10 mg, 4.06 mmol, 314.72 µL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure in a nitrogen and co-evaporated with toluene to give 4-bromo-2-nitrobenzoyl chloride as a brown solid. The crude product was taken to next step. The obtained 4-bromo-2-nitrobenzoyl chloride was taken in tetrahydrofuran (5 mL), cooled to -40 °C, was added a solution mixture of 5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amine (2, 5.27 g, 20.32 mmol) and N,N-diisopropylethylamine (10.51 g, 81.30 mmol, 14.16 mL) in tetrahydrofuran (50 mL). The resulting mixture was stirred at -40 °C for 2 h. The reaction mixture was warmed to room temperature, treated with saturated brine solution (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was triturated with diethyl ether and ethyl acetate. The precipitated solid was filtered and dried under vacuum to give 4-bromo-N-[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]-2-nitro-benzamide (3, 7 g, 14.22 mmol, 70% yield) as an off-white solid. LC-MS (ES⁺): m/z 487.0 [M + H] ⁺. Step-2: To a solution of 4-bromo-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-nitro-benzamide (3, 2 g, 4.10 mmol) in tetrahydrofuran (20 mL), was added sodium dithionite (3.57 g, 20.52 mmol) in water (10 mL). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under vacuum to give the crude product. The crude product was triturated with 50% diethyl ether in petroleum ether to give 2-amino-4-bromo- N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]benzamide (4, 1.6 g, 3.35 mmol, 82% yield) as an off-white solid. LC-MS (ES-): m/z 455.0 [M - H] -. Step-3: To a solution of 2-amino-4-bromo-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]benzamide (4, 2 g, 4.37 mmol) and tetrahydro-4H-pyran-4-one (5, 656.83 mg, 6.56 mmol, 608.17 µL) in dichloromethane (20 mL) were added tetramethylammonium triacetoxyborohydride (2.88 g, 10.93 mmol) and trifluoroacetic acid (1.25 g, 10.93 mmol, 842.40 µL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was treated with water (50 mL) and extracted with dichloromethane (2 x 50 mL). The combined organics were washed with 10% aqueous sodium bicarbonate solution (30 mL), washed with brine solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude compound, which was dissolved in methanol (20 mL). To this solution were added acetic acid (656.64 mg, 10.93 mmol, 625.37 µL) and sodium cyanoborohydride (2.75 g, 43.74 mmol). The resulting mixture was heated at 80 °C for 16 h. The crude mixture was concentrated under reduced pressure, the residue was treated with water (50 mL) and extracted with dichloromethane (2 x 50 mL). The combined organics were washed with 10% sodium bicarbonate solution, washed with brine solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 70% ethyl acetate in petroleum ether to give 4-bromo-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2- (tetrahydropyran-4-ylamino)benzamide (6, 1.4 g, 2.59 mmol, 59% yield) as an off-white solid. LC-MS (ES⁺): m/z 541.0 [M + H] ⁺. Step-4: To a solution of 4-bromo-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2- (tetrahydropyran-4-ylamino)benzamide (6, 100 mg, 184.71 µmol) and tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (7, 85.67 mg, 277.07 µmol) in 1,4-dioxane (3 mL), was added sodium carbonate (58.73 mg, 554.13 µmol) in water (1 mL) and the solution was purged with nitrogen for 5 min. Subsequently, bis(triphenylphosphine)palladium chloride (12.96 mg, 18.47 µmol) was added. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered through a pad of celite, the filtrate was treated with cold water and extracted with ethyl acetate (2 x 20 mL). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 100-200 mesh) eluted with 40-50% ethyl acetate in petroleum ether to give tert-butyl 4-[4-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]carbamoyl]-3-(tetrahydropyran-4-ylamino)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (8, 90 mg, 132.99 µmol, 72% yield) as a pale brown solid. LC-MS (ES⁺): m/z 644.2 [M + H] ⁺. Step-5: To a solution of tert-butyl 4-[4-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]-3- (tetrahydropyran-4-ylamino)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (8, 90 mg, 139.81 µmol) in methanol (5 mL), was added palladium on carbon (10% dry loading, 45 mg). The contents were stirred at room temperature under hydrogen atmosphere for 16 h. The crude mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure and dried under vacuum to give tert-butyl 4-[4-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]carbamoyl]-3-(tetrahydropyran-4-ylamino)phenyl]piperidine-1-carboxylate (9, 70 mg, 104.64 µmol, 75% yield) as an off-white solid. LC-MS (ES⁺): m/z 645.1 [M + H] ⁺. Step-6: To a solution of tert-butyl 4-[4-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]-3- (tetrahydropyran-4-ylamino)phenyl]piperidine-1-carboxylate (9, 70 mg, 108.40 µmol) in dichloromethane (3 mL), cooled to 0 °C, was added HCl in dioxane (4 M, 2 mL). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was co-evaporated with toluene to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-piperidyl)-2- (tetrahydropyran-4-ylamino)benzamide hydrochloride (10, 50 mg, 77.83 µmol, 72% yield) as a brown solid. LC-MS (ES⁺): m/z 546.2 [M + H] ⁺. Step-7: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-piperidyl)-2- (tetrahydropyran-4-ylamino)benzamide hydrochloride (10, 50 mg, 85.90 µmol) and 2-[4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetic acid hydrochloride (11, 32.80 mg, 85.90 µmol) in N,N-dimethylformamide (2 mL), were added DIPEA (33.30 mg, 257.70 µmol, 44.88 µL) and PyBOP (67.05 mg, 128.85 µmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was treated with water (15 mL), precipitated solid was filtered and dried under vacuum to give the crude product. The crude product was crystallized using diethyl ether in dichloromethane to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[1-[2-[4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]-2-(tetrahydropyran-4- ylamino)benzamide (Compound 116, 25 mg, 27.54 µmol, 32% yield) as an off-white solid. LC- MS (ES⁺): m/z 873.2 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.72 (s, 1H), 10.77 (s, 1H), 10.39 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 8.6, 1.2 Hz, 1H), 7.04-6.93 (m, 5H), 6.65-6.60 (m, 3H), 6.52 (s, 1H), 5.66 (d, J = 7.6 Hz, 1H), 4.53-4.49 (m, 1H), 4.25-4.22 (m, 2H), 4.04 (s, 2H), 3.81-3.60 (m, 3H), 3.53-3.48 (m, 1H), 3.09-3.06 (m, 4H), 2.95 (br s, 2H), 2.79-2.60 (m, 4H), 2.35-2.33 (m, 4H), 2.12- 2.07 (m, 3H), 1.93-1.70 (m, 8H), 1.60-1.57 (m, 2H) ppm. Example 71 Synthesis of 3-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-4-((tetrahydro-2H- pyran-4-yl)amino)benzoic acid

Step-1: To a solution of 5-methoxycarbonyl-2-nitro-benzoic acid (1, 4 g, 17.77 mmol) in dichloromethane (60 mL), were added N,N-dimethylformamide (129.85 mg, 1.78 mmol, 137.55 µL) followed by oxalyl chloride (4.51 g, 35.53 mmol, 3.09 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure in a nitrogen atmosphere and co-evaporated with toluene (60 mL) to give methyl 3-(chlorocarbonyl)-4- nitrobenzoate (crude) as a brown semi-solid. The above prepared methyl 3-(chlorocarbonyl)-4-nitrobenzoate (crude) was taken in tetrahydrofuran (60 mL), cooled to -40 °C, was added a solution mixture of 5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-amine (2, 4.61 g, 17.77 mmol) and N,N- diisopropylethylamine (9.18 g, 71.06 mmol, 12.38 mL) in tetrahydrofuran (10 mL) drop-wise. The resulting mixture was stirred at 10 °C for 2 h. The reaction mixture was cooled to 0 °C, treated with cold water (250 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organics were washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was triturated with methanol / dichloromethane / diethyl ether (1 : 1: 2 ratio, 20 mL) and washed with petroleum ether (50 mL), filtered and dried under vacuum to give methyl 3-[[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]-4-nitro-benzoate (3, 4 g, 7.72 mmol, 43% yield) as an off-white solid. LC-MS (ES⁺): m/z 467.0 [M + H] ⁺. Step-2: To a solution of methyl 3-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]-4-nitro- benzoate (3, 4 g, 8.58 mmol) in ethanol (200 mL) and tetrahydrofuran (30 mL), was added palladium on carbon (10% dry loading, 2.5 g). The contents were stirred at room temperature under hydrogen atmosphere for 20 h. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated under reduced pressure to give methyl 4-amino-3-[[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]benzoate (4, 3.2 g, 6.97 mmol, 81% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 437.0 [M + H] ⁺. Step-3: To a solution of methyl 4-amino-3-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]carbamoyl]benzoate (4, 3.6 g, 8.25 mmol) and tetrahydropyran-4-one (5, 2.48 g, 24.75 mmol, 2.29 mL) in 1,2-dichloroethane (100 mL), were added tetramethylammonium triacetoxyborohydride (6.51 g, 24.75 mmol) and trifluoroacetic acid (4.70 g, 41.25 mmol, 3.18 mL). The resulting mixture was stirred at 80 °C for 26 h. The reaction mixture was cooled to 0 °C, treated with cold water (100 mL) and extracted with dichloromethane (2 x 150 mL). The combined organics were washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude compound. The crude compound was dissolved in methanol (40 mL), cooled to 0 °C, were added sodium cyanoborohydride (8.97 g, 142.81 mmol) and acetic acid (94.97 mg, 1.58 mmol, 90.45 µL). The resulting mixture was stirred at 80 °C for 28 h. The reaction mixture was concentrated under reduced pressure, cooled to 0 °C, treated with water (200 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organics were washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give methyl 3-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]-4-(tetrahydropyran- 4-ylamino)benzoate (6, 3.5 g, 4.89 mmol, 62% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 521.2 [M + H] ⁺. Step-4: To a solution of methyl 3-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]-4- (tetrahydropyran-4-ylamino)benzoate (6, 3.5 g, 6.72 mmol) in methanol / tetrahydrofuran / water (1: 1 : 1 ratio, 60 mL), cooled to 0 °C, was added lithium hydroxide monohydrate (1.41 g, 33.62 mmol). The resulting mixture was heated at 80 °C for 5 h. The reaction mixture was concentrated under reduced pressure, cooled to 0 °C and neutralized using 1.5N aqueous hydrochloric acid. The precipitated solid was filtered, washed with water (30 mL) and dried under vacuum to give 3-[[5- [(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]-4-(tetrahydropyran-4- ylamino)benzoic acid dihydrochloride (7, 3.1 g, 4.95 mmol, 74% yield) as an off-white solid. LC- MS (ES⁺): m/z 507.0 [M + H] ⁺. Example 72 Synthesis of N3-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-N1-(4-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperazin-1-yl)butyl)-4-((tetrahydro-2H-pyran-4-yl)amino)isophthalamide (Compound 117)

To a solution of 3-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]-4- (tetrahydropyran-4-ylamino)benzoic acid dihydrochloride (1, 40 mg, 69.03 µmol) and 3-[4-[4-(4- aminobutyl)piperazin-1-yl]anilino]piperidine-2,6-dione dihydrochloride (2, 24.82 mg, 69.03 µmol) in N,N-dimethylformamide (0.6 mL), were added DIPEA (35.69 mg, 276.14 µmol, 48.10 µL) and HATU (31.50 mg, 82.84 µmol). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was treated with water (10 mL), precipitated solid was filtered and dried under vacuum to give the crude product. The crude product was purified by mass-directed preparative HPLC [Column: Sunfire C18 OBD, (19 x 100 mm), 5 micron; Mobile phase: A, 10 mM ammonium acetate in water; B, acetonitrile; Wavelength: 215 nm] and the fractions containing the product was lyophilized to give N3-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]-N1-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]butyl]-4-(tetrahydropyran- 4-ylamino)benzene-1,3-dicarboxamide (Compound 117, 19 mg, 31% yield) as an yellow solid. LC-MS (ES⁺): m/z 848.1 [M + H] ⁺, RT = 2.62 min.¹H NMR (400 MHz, DMSO-d₆): δ 12.79 (s, 1H), 10.77 (s, 1H), 10.56 (s, 1H), 8.38 (d, J = 1.6 Hz, 1H), 8.12-8.07 (m, 2H), 7.83 (dd, J = 9.0, 1.2 Hz, 1H), 7.56 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 8.6, 1.6 Hz, 1H), 7.04-6.99 (m, 3H), 6.91 (d, J = 9.2 Hz, 1H), 6.72 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 5.38 (d, J = 7.2 Hz, 1H), 4.20-4.18 (m, 1H), 4.05 (s, 2H), 3.86-3.83 (m, 2H), 3.74-3.72 (m, 1H), 3.51-3.46 (m, 2H), 3.33-3.25 (m, 4H), 2.92 (br s, 4H), 2.70-2.55 (m, 3H), 2.37-2.33 (m, 2H), 2.11-2.08 (m, 1H), 1.96-1.91 (m, 2H), 1.86-1.82 (m, 1H), 1.55 (br s, 4H), 1.43-1.38 (m, 2H) ppm.

Example 73 N3-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-N1-[6-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]hexyl]-4-(tetrahydropyran-4-ylamino)benzene-1,3- dicarboxamide (Compound 118)

Compound 118 was prepared substantially following the synthesis of Compound 117. LC-MS (ES⁺): m/z 876.3 [M + H] ⁺. N3-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-N1-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]octyl]-4-(tetrahydropyran-4-ylamino)benzene-1,3- dicarboxamide (Compound 119)

Compound 119 was prepared substantially following the synthesis of Compound 117. LC-MS (ES⁺): m/z 904.0 [M + H] ⁺. N3-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-N1-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-8-oxo-octyl]-4-(tetrahydropyran-4- ylamino)benzene-1,3-dicarboxamide (Compound 120)

Compound 120 was prepared substantially following the synthesis of Compound 117. LC-MS (ES⁺): m/z 918.2 [M + H] ⁺. N3-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-N1-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]ethyl]-4-(tetrahydropyran-4-ylamino)benzene-1,3- dicarboxamide (Compound 121)

Compound 121 was prepared substantially following the synthesis of Compound 117. LC-MS (ES⁺): m/z 820.1 [M + H] ⁺. Example 74 Synthesis of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)ethyl)benzamide (Compound 122)

Step-1: To a solution of 4-(carboxymethyl)benzoic acid (1, 5 g, 27.75 mmol) in methanol (30 mL), was added thionyl chloride (165.09 mg, 1.39 mmol, 100.67 µL). The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 25-30% ethyl acetate in petroleum ether to give 4-(2-methoxy-2-oxo- ethyl)benzoic acid (2, 4.5 g, 23.13 mmol, 83% yield) as an off-white solid. LC-MS (ES-): m/z 193.2 [M - H] -. Step-2: To a solution of 4-(2-methoxy-2-oxo-ethyl)benzoic acid (2, 4.52 g, 23.28 mmol) in dichloromethane (20 mL), were added N,N-dimethylformamide (340.25 mg, 4.66 mmol, 360.44 µL) followed by oxalyl chloride (5.91 g, 46.55 mmol, 4.05 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and co-evaporated with toluene to give methyl 2-(4-(chlorocarbonyl)phenyl)acetate (crude) as a pale yellow semi-solid. To a solution of 5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amine (3, 5.25 g, 20.25 mmol) in pyridine (10 mL), cooled to -40 °C, was added methyl 2-(4-(chlorocarbonyl)phenyl)acetate (crude) dissolved in dichloromethane (20 mL) drop-wise. The resulting mixture was stirred at -40 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 60- 80% ethyl acetate in petroleum ether to give methyl 2-[4-[[5-[(3,5-difluorophenyl)methyl]-1H- indazol-3-yl]carbamoyl]phenyl]acetate (4, 4 g, 9.15 mmol, 39% yield) as an off-white solid. LC- MS (ES⁺): m/z 436.2 [M + H] ⁺. Step-3: To a solution of methyl 2-[4-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]carbamoyl]phenyl]acetate (4, 2 g, 4.59 mmol) in tetrahydrofuran (15 mL), cooled to 0 °C, was added lithium borohydride (2 M, 9.33 mL). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was treated with cold water and extracted with ethyl acetate (3 x 40 mL). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 100-200 mesh) eluted with 4-5% methanol in dichloromethane to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]-4-(2-hydroxyethyl)benzamide (5, 1.4 g, 3.42 mmol, 74% yield) as an off-white solid. LC-MS (ES⁺): m/z 408.0 [M + H] ⁺. Step-4: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(2- hydroxyethyl)benzamide (5, 120 mg, 294.54 µmol) in tetrahydrofuran (2 mL), were added tetrabromomethane (195.36 mg, 589.08 µmol) and triphenylphosphine (154.51 mg, 589.08 µmol). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was treated with water (2 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with water, brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 35-40% ethyl acetate in petroleum ether to give 4-(2-bromoethyl)-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]benzamide (6, 70 mg, 124.01 µmol, 42% yield) as an off white solid. LC-MS (ES-): m/z 468.0 [M - H] -. Step-5: To a solution of 4-(2-bromoethyl)-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]benzamide (6, 70 mg, 148.84 µmol) and 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione trifluoroacetate (71.69 mg, 178.61 µmol) in N,N-dimethylformamide (1.5 mL), was added DIPEA (96.18 mg, 744.19 µmol, 129.62 µL). The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC [Column: X-select C18, (19 x 150 mm), 5 micron; Mobile phase: A, 0.1% formic acid in water; B, acetonitrile) and the fractions containing the product was lyophilized to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]ethyl]benzamide formate (Compound 122, 16.12 mg, 22.24 µmol, 14.94% yield, 99.70% purity) as an off-white solid. LC-MS (ES⁺): m/z 677.2 [M + H] ⁺. Example 75 N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[2-[4-[4-[(2,6-dioxo-3- piperidyl)oxy]phenyl]-1-piperidyl]ethyl]benzamide (Compound 123)

Compound 123 was prepared substantially following the synthesis of Compound 122. LC-MS (ES⁺): m/z 678.2 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.79 (s, 1H), 10.93 (s, 1H), 10.66 (s, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.66 (s, 1H), 7.45-7.40 (m, 3H), 7.26 (dd, J = 8.6, 1.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.03-6.93 (m, 4H), 5.18-5.14 (m, 1H), 4.05 (s, 1H), 3.06 (d, J = 10.8 Hz, 2H), 2.85 (t, J = 8.4 Hz, 2H), 2.69-2.60 (m, 2H), 2.35-2.06 (m, 4H), 1.77 (s, 11H), 1.73- 1.61 (m, 2H) ppm. Example 76 Synthesis of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)- 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)ethyl)benzamide formate (Compound 124)

Step-1: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(2- hydroxyethyl)benzamide (1, 1.4 g, 3.44 mmol) in tetrahydrofuran (15 mL), were added triethylamine (1.04 g, 10.31 mmol, 1.44 mL), di-tert-butyl dicarbonate (974.96 mg, 4.47 mmol, 1.03 mL) and DMAP (41.98 mg, 343.63 µmol). The resulting mixture was stirred at room temperature for 8 h. The reaction mixture was treated with water and extracted with ethyl acetate (3 x 30 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 100- 200 mesh) eluted with 40-50% ethyl acetate in petroleum ether to give tert-butyl 5-[(3,5- difluorophenyl)methyl]-3-[[4-(2-hydroxyethyl)benzoyl]amino]indazole-1-carboxylate (2, 1.1 g, 2.08 mmol, 60% yield) as an off-white solid. LC-MS (ES⁺): m/z 508.0 [M + H] ⁺. Step-2: To a solution of tert-butyl 5-[(3,5-difluorophenyl)methyl]-3-[[4-(2- hydroxyethyl)benzoyl]amino]indazole-1-carboxylate (2, 200 mg, 394.07 µmol) in dichloromethane (6 mL), were added tetrabromomethane (196.03 mg, 591.10 µmol) followed by triphenylphosphine (155.04 mg, 591.10 µmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture treated with water and extracted with dichloromethane (3 x 5 mL). The combined organics were washed with brine solution (5 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 100- 200 mesh) eluted with 30-40% ethyl acetate in petroleum ether to give tert-butyl 3-[[4-(2- bromoethyl)benzoyl]amino]-5-[(3,5-difluorophenyl)methyl]indazole-1-carboxylate (3, 100 mg, 172.63 µmol, 44% yield) as an off-white solid. LC-MS (ES⁺): m/z 570.0 [M + H] ⁺. Step-3: To a solution of tert-butyl 3-[[4-(2-bromoethyl)benzoyl]amino]-5-[(3,5- difluorophenyl)methyl]indazole-1-carboxylate (3, 74.99 mg, 131.46 µmol) and 3-[3-methyl-2- oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione trifluoroacetate (50 mg, 109.55 µmol, 115.76 µL) in acetonitrile (3 mL), were added 4Å molecular sieves (150 mg) and DIPEA (70.79 mg, 547.75 µmol, 95.41 µL). The resulting mixture was heated at 70 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude tert-butyl 5-[(3,5- difluorophenyl)methyl]-3-[[4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]ethyl]benzoyl]amino]indazole-1-carboxylate (80 mg, 49.09 µmol, 45% yield) as an off-white solid. LC-MS (ES⁺): m

z 832.3 [M + H] ⁺. To a solution of tert-butyl 5-[(3,5-difluorophenyl)methyl]-3-[[4-[2-[4-[1-(2,6-dioxo-3-piperidyl)- 3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethyl]benzoyl]amino]indazole-1-carboxylate (80 mg, 96.16 µmol) in dichloromethane (3 mL), cooled to 0 °C, was added HCl in 1,4-dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 h. The volatiles were concentrated under reduce pressure to give the crude product. The crude product was purified by preparative HPLC [Column: X BRIDGE C8, 19 x 150 mm, 5 microns; Mobile phase: A, 0.1% HCOOH in water; B, acetonitrile) and the fractions containing the product was lyophilized to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3- methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethyl]benzamide formate (Compound 124, 10 mg, 12.83 µmol, 13% yield) as an off-white solid. LC-MS (ES⁺): m/z 732.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.76 (s, 1H), 11.10 (s, 1H), 10.67 (s, 1H), 8.15 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.61 (s, 1H), 7.44 (t, J = 7.2 Hz, 3H), 7.26 (dd, J = 8.6, 1.6 Hz, 1H), 7.12 (s, 1H), 7.05-6.93 (m, 5H), 5.37-5.33 (m, 1H), 4.05 (s, 2H), 3.16 (d, J = 10.0 Hz, 3H), 2.90 (br s, 3H), 2.73-2.60 (m, 4H), 2.35-2.33 (m, 4H), 2.03-1.98 (m, 2H), 1.82-1.73 (m, 4H) ppm. Example 77 Synthesis of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(2-(4-(4-((2,6-dioxopiperidin-3- yl)amino)benzyl)piperazin-1-yl)ethyl)benzamide trifluoroacetate (Compound 125)

Step-1: To a solution of tert-butyl 5-[(3,5-difluorophenyl)methyl]-3-[[4-(2- hydroxyethyl)benzoyl]amino]indazole-1-carboxylate (1, 200 mg, 394.07 µmol) in dichloromethane (5 mL) was added Dess-Martin periodinane (334.28 mg, 788.13 µmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with aqueous sodium bicarbonate solution (4 mL). The organic phase was washed with brine solution and dried using anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product tert-butyl 5-[(3,5-difluorophenyl)methyl]-3-[[4-(2-oxoethyl)benzoyl]amino]indazole-1-carboxylate (2, 220 mg, 253.46 µmol, 64% yield). The crude product was directly taken to next step without purification. LCMS (ES⁺): 506.0 [M + H] ⁺. Step-2: To a solution of 3-[4-(piperazin-1-ylmethyl)anilino]piperidine-2,6-dione (3, 70 mg, 231.50 µmol) and tert-butyl 5-[(3,5-difluorophenyl)methyl]-3-[[4-(2-oxoethyl)benzoyl]amino]indazole-1- carboxylate (2, 140.43 mg, 277.80 µmol) in methanol (2 mL), were added acetic acid (1.39 mg, 23.15 µmol, 1.32 µL) followed by MP-cyanoborohydride (Biotage^®, 150 mg). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was triturated with petroleum ether / diethyl ether and dried under vacuum to give tert-butyl 5-[(3,5-difluorophenyl)methyl]-3-[[4-[2-[4-[[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]methyl]piperazin-1-yl]ethyl]benzoyl]amino]indazole-1-carboxylate (4, 100 mg, 79.15 µmol, 34% yield) as an off-white solid. LC-MS (ES⁺): m/z 792.3 [M + H] ⁺. Step-3: To a solution of tert-butyl 5-[(3,5-difluorophenyl)methyl]-3-[[4-[2-[4-[[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]methyl]piperazin-1-yl]ethyl]benzoyl]amino]indazole-1-carboxylate (4, 100 mg, 126.28 µmol) in dichloromethane (5 mL), cooled to 0 °C, was added HCl in dioxane (4 M, 1 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with petroleum ether / diethyl ether to give the crude product. The crude product was purified by preparative HPLC [0.1% TFA in water : acetonitrile] and the fractions containing the compound was lyophilized to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[2-[4-[[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]methyl]piperazin-1-yl]ethyl]benzamide trifluoroacetate (Compound 125, 18.96 mg, 22.40 µmol, 18% yield) as an off-white solid. LC-MS (ES⁺): m/z 692.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.71 (s, 1H), 10.83 (s, 1H), 10.70 (s, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.45-7.43 (m, 3H), 7.27 (dd, J = 8.6, 1.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.05-6.96 (m, 3H), 6.72 (d, J = 8.4 Hz, 2H), 4.40-4.36 (m, 1H), 4.05 (s, 2H), 3.79 (br s, 5H), 2.96 (br s, 7H), 2.81-2.72 (m, 2H), 2.68-2.61 (m, 1H), 2.13-2.05 (m, 2H), 1.94-1.86 (m, 2H) ppm. Example 78 Synthesis of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-2-(piperidin-4-ylamino)benzamide

Step-1: To a solution of 5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amine (2, 698.55 mg, 2.69 mmol) and DIPEA (1.04 g, 8.08 mmol, 1.41 mL) in tetrahydrofuran (5 mL), cooled to -40 °C, was added 2-nitrobenzoyl chloride (1, 500 mg, 2.69 mmol) in tetrahydrofuran (2 mL) drop-wise. The resulting mixture was stirred at -40 °C for 1 h. The reaction mixture was treated with cold water (20 mL) and extracted with dichloromethane (2 x 50 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted using 0-60% ethyl acetate in petroleum ether to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-nitro-benzamide (3, 600 mg, 1.39 mmol, 52% yield) as a yellow solid. LC-MS (ES⁺): m/z 409.1 [M + H] ⁺. Step-2: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-nitro-benzamide (3, 600.00 mg, 1.47 mmol) in tetrahydrofuran (6 mL), was added sodium dithionate (1.51 g, 7.35 mmol) in water (3 mL). The contents were stirred at room temperature for 2 h. The reaction mixture was partitioned between ethyl acetate / water (50 mL / 25 mL) and the organic phase was separated. The aqueous phase was again extracted with ethyl acetate (2 x 30 mL), the combined organic layers were washed with brine solution (40 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was triturated with diethyl ether (10 mL) and dried under vacuum to give 2-amino-N-[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]benzamide (4, 520 mg, 962.01 µmol, 65% yield) as an off white solid. LC-MS (ES⁺): m/z 379.1 [M + H] ⁺. Step-3: To a solution of 2-amino-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]benzamide (4, 530.00 mg, 1.40 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (5, 279.09 mg, 1.40 mmol) in dichloromethane (5 mL), were added tetramethylammonium triacetoxyborohydride (737.05 mg, 2.80 mmol), trifluoroacetic acid (319.43 mg, 2.80 mmol, 215.83 µL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was treated with water (50 mL) and extracted with dichloromethane (2 x 50 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted using 0-60% ethyl acetate in petroleum ether to give tert-butyl 4-[2-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]carbamoyl]anilino]piperidine-1-carboxylate (6, 350 mg, 411.31 µmol, 29% yield) as a pale yellow oil. LC-MS (ES-): m/z 560.3 [M - H]-. Step-4: To a solution of tert-butyl 4-[2-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]carbamoyl]anilino]piperidine-1-carboxylate (6, 350.00 mg, 623.20 µmol) in dichloromethane (5 mL), cooled to 0 °C, was added trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL). The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, the residue was co-distilled with dichloromethane (2 x 10 mL) to give the crude product. The crude product was purified by mass-directed preparative HPLC [Column: Sunfire C18 OBD, 19 x 100 mm, 5 micron; Mobile phase: A, 0.1% TFA in water, B, acetonitrile; Wavelength: 215 nm] to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2- (4-piperidylamino)benzamide trifluoroacetate (7, 115 mg, 197.82 µmol, 32% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 462.2 [M + H) ⁺.

Example 79 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-fluoro-2-(piperidin-4-ylamino)benzamide

Prepared substantially similar to the synthesis of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-2- (piperidin-4-ylamino)benzamide, except the reduction of the nitro group was performed with hydrogen, Pd/C in EtOH and tetrahydrofuran at room temperature for 4 h. LC-MS (ES⁺): m/z 480.2 [M + H) ⁺. Example 80 Synthesis of 4-cyano-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-2-(piperidin-4- ylamino)benzamide

Step-1: To a solution of4-methyl-3-nitro-benzonitrile (1, 3 g, 18.50 mmol) and potassium dichromate (8.16 g, 27.75 mmol, 3.05 mL) in water (7 mL), was added sulfuric acid (20 mL). The resulting mixture was stirred at room temperature for 5 h. The reaction mixture diluted with water (50 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organics were washed with brine solution (5 mL) and dried over anhydrous sodium sulfate. The solution was filtered, concentrated under reducing pressure and the solid was washed with diethyl ether to give 4-cyano-2-nitro-benzoic acid (2, 2.4 g, 12.37 mmol, 67% yield) as a green solid. LC-MS (ES-): m/z 191.9 [M - H] -. Step-2: To a solution of 4-cyano-2-nitro-benzoic acid (2, 2 g, 10.41 mmol) in dichloromethane (20 mL), were added N,N-dimethylformamide (760.85 mg, 10.41 mmol, 805.98 µL) followed by oxalyl chloride (1.98 g, 15.61 mmol, 1.36 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure in a nitrogen and the residue was co-evaporated with toluene to give 4-cyano-2-nitrobenzoyl chloride as a pale-yellow solid. To a solution of 5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amine (3, 2.16 g, 8.33 mmol) and DIPEA (4.04 g, 31.23 mmol, 5.44 mL) in tetrahydrofuran (20 mL), cooled to -40 °C, was added 4-cyano-2-nitrobenzoyl chloride in tetrahydrofuran (20 mL) drop-wise. The resulting mixture was stirred at -40 °C for 2 h. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was treated with saturated brine solution (10 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230- 400 mesh) eluted with 0-60% ethyl acetate in petroleum ether to give 4-cyano-N-[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]-2-nitro-benzamide (4, 1.8 g, 3.90 mmol, 38% yield) as a yellow solid. LC-MS (ES⁺): m/z 434.1 [M + H] ⁺. Step-3: To a solution of 4-cyano-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-nitro-benzamide (4, 800 mg, 1.85 mmol) in ethanol (5 mL), were added iron (515.50 mg, 9.23 mmol) followed by ammonium chloride (493.72 mg, 9.23 mmol) in water (3 mL). The contents were heated at 90 °C for 3 h. The reaction mixture was cooled and filtered through a pad of celite bed and washed with ethyl acetate (50 mL). The organic phase was separated, and the aqueous phase was extracted further with ethyl acetate (2 x 20 mL). The combined organics were washed with brine solution (40 mL) and dried over with anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with of 0-65% ethyl acetate in petroleum ether to give 2-amino-4-cyano-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]benzamide (5, 630 mg, 1.28 mmol, 69% yield) as a yellow solid. LC-MS (ES⁺): m/z 404.1 [M + H] ⁺. Step-4: To a solution of 2-amino-4-cyano-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]benzamide (5, 600 mg, 1.49 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (6, 296.36 mg, 1.49 mmol) dichloromethane (10 mL), were added tetramethylammonium triacetoxyborohydride (587.00 mg, 2.23 mmol) and trifluoroacetic acid (424.00 mg, 3.72 mmol, 286.49 µL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was treated with water (20 mL) and extracted with dichloromethane (2 x 30 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude product was purified by reverse phase C18 column [30 g, ISCO C18 column, Mobile phase A: 0.1% HCOOH in water; Mobile phase B: Acetonitrile] and the fractions containing the compound was lyophilized to give tert-butyl 4-[5-cyano-2-[[5-[(3,5-difluorophenyl)methyl]-1H- indazol-3-yl]carbamoyl]anilino]piperidine-1-carboxylate (7, 130 mg, 212.74 µmol, 14.30% yield, 96.41% purity) as a pale yellow solid. LC-MS (ES⁺): m/z 487.1 [M - COOtBu + H] ⁺. Step-5: To a solution of tert-butyl 4-[5-cyano-2-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]carbamoyl]anilino]piperidine-1-carboxylate (7, 50 mg, 85.23 µmol) in dichloromethane (1 mL), cooled to 0 °C, was added HCl in dioxane (4M, 1 mL). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was co-distilled with dichloromethane to give 4-cyano-N-[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]-2-(4-piperidylamino)benzamide hydrochloride (8, 45 mg, 27.53 µmol, 32% yield) as an off-white solid. LC-MS (ES⁺): m/z 487.1 [M + H] ⁺. Example 81 Synthesis of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-3-(piperidin-4- ylamino)isonicotinamide

Step-1: To a solution mixture of 3-fluoropyridine-4-carboxylic acid (1, 1 g, 7.09 mmol) in DMSO (5 mL), were added tert-butyl 4-aminopiperidine-1-carboxylate (2.13 g, 10.63 mmol) and DIPEA (4.58 g, 35.44 mmol, 6.17 mL). The contents were heated at 140 °C for 16 h. The reaction mixture was treated cold water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organics were washed brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase C18 column [60 g, ISCO C18 column, Mobile phase A: 0.1% HCOOH in water; Mobile phase B: Acetonitrile] to give 3-[(1-tert-butoxycarbonyl-4-piperidyl)amino]pyridine-4- carboxylic acid (2, 400 mg, 1.23 mmol, 17% yield) as an off-white solid. LC-MS (ES⁺): m/z 322.3 [M + H] ⁺. Step-2: To a solution of 3-[(1-tert-butoxycarbonyl-4-piperidyl)amino]pyridine-4-carboxylic acid (2, 350 mg, 1.09 mmol) in dichloromethane (10 mL), were added N,N-dimethylformamide (79.60 mg, 1.09 mmol, 84.32 µL) followed by oxalyl chloride (207.36 mg, 1.63 mmol, 142.02 µL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure in a nitrogen and co-evaporated with toluene to give tert-butyl 4-((4- (chlorocarbonyl)pyridin-3-yl)amino)piperidine-1-carboxylate (crude) as a brown solid. To a solution of 5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amine (3, 282.35 mg, 1.09 mmol) and DIPEA (563.01 mg, 4.36 mmol, 758.78 µL) in tetrahydrofuran (15 mL), cooled to -40 °C, was added tert-butyl 4-((4-(chlorocarbonyl)pyridin-3-yl)amino)piperidine-1-carboxylate (crude) in tetrahydrofuran (15 mL) drop-wise. The resulting mixture was stirred at -40 °C for 2 h. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was treated with brine solution (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified column chromatography (silica gel, 230-400 mesh) eluted with 60% ethyl acetate in petroleum ether to give tert-butyl 4-[[4-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]carbamoyl]-3-pyridyl]amino]piperidine-1-carboxylate (4, 120 mg, 172.77 µmol, 16% yield) as a yellow solid. LC-MS (ES⁺): m/z 563.2 [M + H] ⁺. Step-3: To a solution of 3-[(1-tert-butoxycarbonyl-4-piperidyl)amino]pyridine-4-carboxylic acid (4, 50 mg, 155.58 µmol) in dichloromethane (2 mL), cooled to 0 °C, was added HCl in dioxane (4M, 2 mL). The resulting mixture was stirred at room temperature for 1 h. The volatiles were concentrated under reduce pressure and dried under vacuum to give 3-(4-piperidylamino)pyridine- 4-carboxylic acid hydrochloride (5, 60 mg, 121.06 µmol, 78% yield). The crude product was taken to next step without any further purification. LC-MS (ES⁺): m/z 222.2 [M + H] ⁺. Example 82 Synthesis of 4-cyano-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[4-[4-[4- [(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]-4- piperidyl]amino]benzamide (Compound 126)

To a solution of 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid (2, 23.95 mg, 61.66 µmol) and 4-cyano-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]-2-(4-piperidylamino)benzamide (1, 30 mg, 61.66 µmol) in N,N-dimethylformamide (1 mL), were added DIPEA (23.91 mg, 184.99 µmol, 32.22 µL) followed by HATU (35.17 mg, 92.49 µmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (0.5 mL) and the precipitated solid was filtered to give the crude product. The solid was purified by reverse phase C18 column [30 g, ISCO C18 column, Mobile phase A: 0.1% ammonium acetate in water; Mobile phase B: Acetonitrile] and the fractions containing the product was lyophilized to give 4-cyano-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2- [[1-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]-4- piperidyl]amino]benzamide (Compound 126, 3.5 mg, 3.81 µmol, 6% yield). LCMS (ES-): m/z 855.3 [M - H].¹H NMR (400 MHz, DMSO-d₆): δ 12.81 (s, 1H), 10.80 (s, 1H), 10.77 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H), 7.27 (dd, J = 8.4, 1.2 Hz, 1H), 7.04-6.98 (m, 4H), 6.77 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 9.2 Hz, 2H), 5.45 (d, J = 6.4 Hz, 1H), 4.23-4.17 (m, 2H), 4.05 (s, 2H), 3.84-3.77 (m, 4H), 3.58-3.54 (m, 5H), 2.93-2.85 (m, 6H), 2.76-2.67 (m, 2H), 2.52-2.50 (m, 3H), 2.12-2.05 (m, 1H), 1.89-1.76 (m, 2H) ppm. Example 83 N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[3-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]propanoyl]-4- piperidyl]amino]benzamide (Compound 127)

Compound 127 was prepared substantially following the synthesis of Compound 126. LC-MS (ES⁺): m/z 876.2 [M + H] ⁺.

N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]-4-piperidyl]amino]benzamide (Compound 128)

Compound 128 was prepared substantially following the synthesis of Compound 126. LC-MS (ES⁺): m/z 832.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[7-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo-heptanoyl]-4-piperidyl]amino]benzamide (Compound 129)

Compound 129 was prepared substantially following the synthesis of Compound 126. LC-MS (ES⁺): m/z 874.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]-4-piperidyl]amino]-4-fluoro- benzamide (Compound 130)

Compound 130 was prepared substantially following the synthesis of Compound 126. LC-MS (ES⁺): m/z 850.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[7-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo-heptanoyl]-4-piperidyl]amino]-4-fluoro- benzamide (Compound 131)

Compound 131 was prepared substantially following the synthesis of Compound 126. LC-MS (ES⁺): m/z 892.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[3-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]propanoyl]-4-piperidyl]amino]-4- fluoro-benzamide (Compound 132)

Compound 132 was prepared substantially following the synthesis of Compound 126. LC-MS (ES⁺): m/z 894.3 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-3-[[1-[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]-4-piperidyl]amino]pyridine-4- carboxamide (Compound 133)

Compound 133 was prepared substantially following the synthesis of Compound 126. LC-MS (ES⁺): m/z 833.3 [M + H] ⁺. 4-cyano-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[7-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo-heptanoyl]-4-piperidyl]amino]benzamide (Compound 134)

Compound 134 was prepared substantially following the synthesis of Compound 126. LC-MS (ES⁺): m/z 899.5 [M + H] ⁺. 4-cyano-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[3-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo-propoxy]propanoyl]-4- piperidyl]amino]benzamide (Compound 135)

Compound 135 was prepared substantially following the synthesis of Compound 126. LC-MS (ES⁺): m/z 901.3 [M + H] ⁺. Example 84 Synthesis of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butyl]-4-piperidyl]amino]benzamide (Compound 136)

Step-1: To a solution of 2-amino-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]benzamide (1, 100 mg, 264.29 µmol) and tert-butyl 4-(4-oxo-1-piperidyl)butanoate (2, 63.78 mg, 264.29 µmol) in dichloromethane (5 mL), were added tetramethylammonium triacetoxyborohydride (139.07 mg, 528.58 µmol) and trifluoroacetic acid (60.27 mg, 528.58 µmol, 40.72 µL). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was treated with water (20 mL) and extracted with dichloromethane (2 x 20 mL). The combined organics were washed with brine solution (20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-60% ethyl acetate in petroleum ether to give tert-butyl 4-[4-[2-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]carbamoyl]anilino]-1-piperidyl]butanoate (3, 80 mg, 124.02 µmol, 47% yield) as a pale yellow oil. LC-MS (ES⁺): m/z 604.2 [M + H) ⁺. Step-2: To a solution of tert-butyl 4-[4-[2-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]carbamoyl]anilino]-1-piperidyl]butanoate (3, 80 mg, 132.52 µmol) in dichloromethane (2 mL), cooled to 0 °C, was added HCl in Dioxane (4 M, 1 mL). The resulting mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was concentrated under reduced pressure and co-distilled with dichloromethane to give 4-[4-[2-[[5-[(3,5-difluorophenyl)methyl]- 1H-indazol-3-yl]carbamoyl]anilino]-1-piperidyl]butanoic acid hydrochloride (4, 70 mg, 97.62 µmol, 74% yield) as a pale grey solid. LC-MS (ES⁺): m/z 548.1 [M + H] ⁺. Step-3: To a solution of 4-[4-[2-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]anilino]-1- piperidyl]butanoic acid (4, 50 mg, 91.31 µmol) and 3-(4-piperazin-1-ylanilino)piperidine-2,6- dione (5, 26.33 mg, 91.31 µmol) in N,N-dimethylformamide (1 mL), were added HATU (52.08 mg, 136.96 µmol) and DIPEA (35.40 mg, 273.93 µmol, 47.71 µL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was treated with water (2 mL), the precipitated solid was filtered and washed with water and dried. The crude product was purified by mass-directed preparative HPLC [Column: Sunfire C18 OBD, (19 x 100 mm), 5 micron, Mobile phase: A, 0.1% ammonium acetate in water; B, acetonitrile; Wavelength: 215 nm] to give N-[5- [(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[[1-[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butyl]-4-piperidyl]amino]benzamide (Compound 136, 12.0 mg, 14.50 µmol, 16% yield) as an off-white solid. LC-MS (ES⁺): m/z 818.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 12.74 (s, 1H), 10.77 (s, 1H), 10.45 (s, 1H), 7.88 (d, J = 7.6 Hz, 2H), 7.52 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.04- 6.98 (m, 3H), 6.81-6.76 (m, 3H), 6.62-6.54 (m, 3H), 5.44 (d, J = 6.8 Hz, 1H), 4.20-4.17 (m, 1H), 4.04 (s, 2H), 3.61-3.53 (m, 10H), 3.02-2.85 (m, 7H), 2.17-2.09 (m, 3H), 1.91-1.82 (m, 4H), 1.66 (br s, 2H), 1.42 (br s, 2H) ppm. Example 85 Synthesis of ethyl 1-(2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl)-1H-pyrazole-3- carboxylate and ethyl 1-(2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl)-1H-pyrazole-5- carboxylate

Step-1: To a solution of 2-(2-aminoethoxy)ethanol (1, 5.0 g, 47.56 mmol) and triethylamine (7.22 g, 71.34 mmol, 9.94 mL) in methanol (100 mL), cooled to 0 °C, was added benzyl chloroformate (7.71 g, 45.18 mmol) drop-wise. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated under reduced pressure. The residue was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 70-90% ethyl acetate in petroleum ether to give benzyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (2, 8 g, 30.06 mmol, 63% yield) as a colorless oil. LC-MS (ES⁺): m/z 240.2 [M + H] ⁺. Step-2: To a solution of benzyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (2, 3 g, 12.54 mmol) in dichloromethane (30 mL), were added carbon tetrabromide (6.24 g, 18.81 mmol) and triphenylphosphine (4.93 g, 18.81 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was treated with water (20 mL) and extracted with dichloromethane (3 x 50 mL). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 15-25% ethyl acetate in petroleum ether to give benzyl N-[2-(2- bromoethoxy)ethyl]carbamate (3, 3.5 g, 11.13 mmol, 89% yield) as a colorless liquid. LC-MS (ES⁺): m/z 303.2 [M + H] ⁺. Step-3: To a solution of ethyl 1H-pyrazole-3-carboxylate (4, 1.3 g, 9.28 mmol) and benzyl N-[2-(2- bromoethoxy)ethyl]carbamate (3, 3.5 g, 11.58 mmol) in N,N-dimethylformamide (15 mL), was added cesium carbonate (4.53 g, 13.91 mmol). The contents were stirred at room temperature for 3 h. The reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with water (50 mL), brine solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 25-35% ethyl acetate in petroleum ether to give the fast eluting regio- isomer, ethyl 2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethyl]pyrazole-3-carboxylate (5, 1.5 g, 4.04 mmol, 44% yield) as a colorless oil. LC-MS (ES⁺): m/z 362.0 [M + H] ⁺. The late eluting regio-isomer was eluted at 50-60% ethyl acetate in petroleum ether to give ethyl 1-[2-[2-(benzyloxycarbonylamino)ethoxy]ethyl]pyrazole-3-carboxylate (6, 0.9 g, 2.37 mmol, 26% yield) as a colorless oil. LC-MS (ES⁺): m/z 361.9 [M + H] ⁺. Example 86 Synthesis of 1-(2-(2-aminoethoxy)ethyl)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-1H- pyrazole-5-carboxamide

Step-1: To a solution of ethyl 2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethyl]pyrazole-3-carboxylate (1, 1.5 g, 4.15 mmol) in methanol (15 mL), was added lithium hydroxide monohydrate (522.48 mg, 12.45 mmol) in water (5 mL). The resulting solution was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to remove volatiles. The suspension was treated with water (20 mL) and extracted with ethyl acetate (10 mL) to remove organic impurities. The aqueous layer was acidified using 1.5N hydrogen chloride solution and extracted with ethyl acetate (3 x 20 mL). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethyl]pyrazole-3-carboxylic acid (2, 1.2 g, 3.19 mmol, 77% yield) as colorless sticky solid. LC-MS (ES⁺): m/z 333.9 [M + H] ⁺. Step-2: To a solution of 2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethyl]pyrazole-3-carboxylic acid (2, 600 mg, 1.80 mmol) in toluene (6 mL), was added thionyl chloride (428.29 mg, 3.60 mmol) drop- wise. The resulting mixture was heated at 100 °C for 3 h. The resulting mixture was concentrated under reduced pressure and co-distilled with toluene to benzyl (2-(2-(5-(chlorocarbonyl)-1H- pyrazol-1-yl)ethoxy)ethyl)carbamate (crude) as a pale yellow semi-solid. To a solution of 5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amine (3, 466.65 mg, 1.80 mmol) and DIPEA (1.16 g, 9.00 mmol, 1.57 mL) in tetrahydrofuran (5 mL), cooled to -40 °C, was added the above prepared acid chloride, benzyl (2-(2-(5-(chlorocarbonyl)-1H-pyrazol-1- yl)ethoxy)ethyl)carbamate, dissolved in dichloromethane (5 mL). The reaction mixture was stirred at -20 °C for 2 h. The reaction mixture was treated with cold water (5 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase C18 column [60 g, ISCO C18 column; Mobile phase: A, 0.1% ammonium acetate in water; B, acetonitrile] and the fractions containing the compound was lyophilized to give a desired regio-isomer benzyl N-[2-[2-[5-[[5- [(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]pyrazol-1-yl]ethoxy]ethyl]carbamate (160 mg, 260.76 µmol, 14.49% yield, 93.64% purity) as pale brown solid. LC-MS (ES⁺): m/z 573.0 [M - H] ^–, RT = 2.34 min and an undesired regio-isomer, benzyl N-[2-[2-[5-[3-amino-5-[(3,5- difluorophenyl)methyl]indazole-1-carbonyl]pyrazol-1-yl]ethoxy]ethyl]carbamate (4, 250 mg, 183.35 µmol, 10% yield). LC-MS (ES-): m/z 573.0 [M - H] -. Step-3: Benzyl N-[2-[2-[5-[[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]carbamoyl]pyrazol-1- yl]ethoxy]ethyl]carbamate (4, 160 mg, 278.47 µmol) was taken in trifluoroacetic acid (4.44 g, 38.94 mmol, 3 mL). The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was triturated using diethyl ether to give 2-[2-(2-aminoethoxy)ethyl]-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]pyrazole-3-carboxamide trifluoroacetate (5, 110 mg, 190.45 µmol, 68% yield) as an off-white solid. LCMS (ES⁺): m/z 440.9 [M + H] ⁺.

Example 87 Synthesis of 1-[2-(2-aminoethoxy)ethyl]-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]pyrazole-3-carboxamide trifluoroacetate

Step-1: To a solution of 5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amine (1, 2 g, 7.71 mmol) in dichloromethane (20 mL) and triethylamine (2.34 g, 23.14 mmol, 3.23 mL), cooled to -40 °C, was added trifluoroacetic anhydride (2.43 g, 11.57 mmol, 1.63 mL). The resulting mixture was stirred at -40 °C for 3 h. The reaction mixture was treated with water (10 mL) and extracted with dichloromethane (3 x 20 mL). The combined organics were washed with saturated sodium bicarbonate solution (15 mL), brine solution (20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 40- 50% ethyl acetate in petroleum ether to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]- 2,2,2-trifluoro-acetamide (2, 2 g, 3.73 mmol, 48% yield) as an off-white solid. LC-MS (ES⁺): m/z 356.2 [M + H] ⁺. Step-2: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide (2, 1 g, 2.81 mmol) in dichloromethane (10 mL), cooled to 0 °C, were added DBU (1.06 g, 4.22 mmol) and trityl chloride (941.63 mg, 3.38 mmol). The resulting mixture was stirred at 0 °C for 3 h. The resulting mixture was treated with water (10 mL) and extracted with dichloromethane (3 x 20 mL). The combined organics were washed with brine solution (20 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 5-10% ethyl acetate in petroleum ether to give N-[5-[(3,5-difluorophenyl)methyl]-1-trityl-indazol-3-yl]-2,2,2- trifluoro-acetamide (3, 1.1 g, 942.29 µmol, 33% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 619.7 [M + Na] ⁺. Step-3: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1-trityl-indazol-3-yl]-2,2,2-trifluoro- acetamide (3, 1.2 g, 2.01 mmol) in methanol (6 mL), was added triethylamine (2.90 g, 28.70 mmol, 4 mL). The resulting mixture was heated at 80 °C for 3 h. The resulting mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 18-25% ethyl acetate in petroleum ether to give 5-[(3,5-difluorophenyl)methyl]-1-trityl-indazol-3-amine (4, 650 mg, 1.24 mmol, 62% yield) as an off-white solid. LC-MS (ES⁺): m/z 502.1 [M + H] ⁺. Step-4: To a solution of 1-[2-[2-(benzyloxycarbonylamino)ethoxy]ethyl]pyrazole-3-carboxylic acid (5, 250 mg, 749.99 µmol) and 5-[(3,5-difluorophenyl)methyl]-1-trityl-indazol-3-amine (4, 501.57 mg, 749.99 µmol) in N,N-dimethylformamide (4 mL), was added DIPEA (290.79 mg, 2.25 mmol, 391.89 µL) followed by HATU (570.34 mg, 1.50 mmol). The resulting mixture was heated at 80 °C for 3 h. The reaction mixture was cooled to room temperature, treated with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with water (10 mL), brine solution (15 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 45-55% ethyl acetate in petroleum ether to give benzyl N-[2-[2-[3-[[5-[(3,5-difluorophenyl)methyl]-1-trityl-indazol-3- yl]carbamoyl]pyrazol-1-yl]ethoxy]ethyl]carbamate (6, 185 mg, 187.06 µmol, 25% yield) as an off- white solid. LC-MS (ES⁺): m/z 838.7 [M + Na] ⁺. Step-5: Benzyl N-[2-[2-[3-[[5-[(3,5-difluorophenyl)methyl]-1-trityl-indazol-3-yl]carbamoyl]pyrazol-1- yl]ethoxy]ethyl]carbamate (6, 185 mg, 226.47 µmol) was taken in trifluoroacetic acid (4.44 g, 38.94 mmol, 3 mL), was added triisopropylsilane (773.00 mg, 4.88 mmol, 1 mL). The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was triturated with 50% petroleum ether in diethyl ether to give 1-[2-(2-aminoethoxy)ethyl]-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]pyrazole-3-carboxamide trifluoroacetate (7, 100 mg, 160.57 µmol, 71% yield) as an off-white solid. LC-MS (ES⁺): m/z 441.0 [M + H] ⁺.

Example 88 Synthesis of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[2-[2-[[4-[4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo- butanoyl]amino]ethoxy]ethyl]pyrazole-3-carboxamide trifluoroacetate (Compound 137)

To a solution of 2-[2-(2-aminoethoxy)ethyl]-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3- yl]pyrazole-3-carboxamide (35 mg, 63.12 µmol) and 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoic acid;2,2,2-trifluoroacetic acid (41.57 mg, 63.12 µmol) in N,N-dimethylformamide (1 mL), were added HATU (28.80 mg, 75.75 µmol) and DIPEA (40.79 mg, 315.62 µmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was treated with water (1 mL) and extracted with ethyl acetate (3 x 1 mL). The combined organics were evaporated under Genevac at 50 °C for 1 h to give the crude product. The crude product was purified by mass-directed preparative HPLC [Column: X BRIDGE C18 , 19 x 150 mm, 5 microns; Mobile phase A: 0.1% TFA in water, Mobile phase B: Acetonitrile; Wavelength: 215 nm] and the fractions containing the compound was lyophilized to give N-[5- [(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[2-[2-[[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]amino]ethoxy]ethyl]pyrazole-3- carboxamide trifluoroacetate (Compound 137, 5.49 mg, 9% yield) as a yellow solid. LC-MS (ES⁺): m/z 810.7 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.76 (s, 1H), 10.83 (s, 1H), 10.77 (s, 1H), 7.84 (t, J = 5.60 Hz, 1H), 7.60 (t, J = 3.2 Hz, 2H), 7.44 (d, J = 8.8 Hz, 1H), 7.28-7.25 (m, 1H), 7.18 (s, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.05-6.96 (m, 4H), 6.73 (d, J = 7.6 Hz, 2H), 4.72 (t, J = 5.6 Hz, 2H), 4.36-4.29 (m, 1H), 4.06 (s, 2H), 3.78-3.67 (m, 3H), 3.38 (t, J = 5.6 Hz, 2H), 3.16- 3.14 (m, 7H), 2.77-2.71 (m, 2H), 2.69-2.67 (m, 3H), 2.34-2.31 (m, 3H), 2.09-2.03 (m, 1H), 1.90- 1.81 (m, 1H) ppm. Example 89 N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[2-[2-[[7-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo-heptanoyl]amino]ethoxy]ethyl]pyrazole-3- carboxamide (Compound 138)

Compound 138 was prepared substantially following the synthesis of Compound 137. LC-MS (ES⁺): m/z 852.7 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-2-[2-[2-[3-[3-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]propanoylamino]ethoxy]ethyl]pyrazole-3-carboxamide (Compound 139)

Compound 139 was prepared substantially following the synthesis of Compound 137. LC-MS (ES⁺): m/z 854.8 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-1-[2-[2-[[7-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-7-oxo-heptanoyl]amino]ethoxy]ethyl]pyrazole-3- carboxamide (Compound 140)

Compound 140 was prepared substantially following the synthesis of Compound 137. LC-MS (ES⁺): m/z 853.2 [M + H] ⁺. N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-1-[2-[2-[[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoyl]amino]ethoxy]ethyl]pyrazole-3- carboxamide (Compound 141)

Compound 141 was prepared substantially following the synthesis of Compound 137. LC-MS (ES⁺): m/z 811.3 [M + H] ⁺. Example 90 Synthesis of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-((4-(4-((2,6-dioxopiperidin-3- yl)amino)benzyl)piperazin-1-yl)methyl)benzamide trifluoroacetate (Compound 142)

Step-1: To a solution of 4-formylbenzoic acid (1, 300 mg, 2.00 mmol) in pyridine (5 mL), was added thionyl chloride (2.38 g, 19.98 mmol, 1.45 mL) drop-wise. The resulting mixture was heated at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure in a nitrogen and co-evaporated with toluene to give 4-formylbenzoyl chloride (crude) as an off-white solid. To a solution of 5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amine (2, 518.05 mg, 2.00 mmol) in pyridine (5 mL), cooled to -40 °C, was added the above prepared 4-formylbenzoyl chloride (crude) in dichloromethane (5 mL) drop-wise. The reaction was stirred at -40 °C for 20 min. The reaction mixture was treated with brine solution (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 60% ethyl acetate in petroleum ether to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol- 3-yl]-4-formyl-benzamide (3, 220 mg, 491.92 µmol, 25% yield) as an off-white solid. LC-MS (ES⁺): m/z 392.0 [M + H] ⁺. Step-2: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-formyl-benzamide (3, 100 mg, 255.51 µmol) in methanol (2 mL), cooled to at 0 °C, was added sodium borohydride (14.50 mg, 383.27 µmol, 13.55 µL). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was treated with cold water and extracted with ethyl acetate (31x 1 mL). The combined organics were washed with brine solution (1 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give N-[5- [(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(hydroxymethyl)benzamide (4, 110 mg, 252.58 µmol, 99% yield) as an off-white solid. LC-MS (ES⁺): m/z 394.4 [M + H] ⁺. Step-3: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4- (hydroxymethyl)benzamide (4, 100 mg, 254.20 µmol) in tetrahydrofuran (2 mL), cooled to 0 °C, was added phosphorus tribromide (103.21 mg, 381.31 µmol, 35.84 µL). The resulting mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was treated with aqueous sodium bicarbonate solution (1 mL) and extracted with ethyl acetate (3 x 1 mL). The combined organics were washed with brine solution (1.5 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 4- (bromomethyl)-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]benzamide (5, 150 mg, 253.92 µmol, 99% yield) as a colorless gum. The crude product was taken to next step without purification. LC-MS (ES⁺): m/z 456.0 [M + H] ⁺. Step-4: To a solution of 4-(bromomethyl)-N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]benzamide (5, 40 mg, 87.67 µmol) and 3-[4-(piperazin-1-ylmethyl)anilino]piperidine-2,6-dione (6, 29.16 mg, 96.44 µmol) in N,N-dimethylformamide (1 mL), was added DIPEA (11.33 mg, 87.67 µmol, 15.27 µL). The resulting mixture was heated at 60 °C for 4 h. The reaction mixture was partitioned with ethyl acetate / water (2 mL / 1 mL), the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2 x 1 mL). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase C18 column [30 g ISCO C18 column, Mobile phase A: 0.1% TFA in water; Mobile phase B: Acetonitrile] and the fractions containing the compound was lyophilized to give N-[5-[(3,5-difluorophenyl)methyl]- 1H-indazol-3-yl]-4-[[4-[[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]piperazin-1- yl]methyl]benzamide trifluoroacetate (Compound 142, 4 mg, 4.93 µmol, 6% yield) as an off- white solid. LC-MS (ES⁺): m/z 678.2 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.76 (s, 1H), 10.79 (s, 1H), 10.68 (s, 1H), 8.26 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H), 7.46-7.42 (m, 3H), 7.26 (dd, J = 8.4, 1.6 Hz, 1H), 7.04-6.98 (m, 5H), 6.62 (d, J = 8.8 Hz, 2H), 4.33-4.25 (m, 1H), 4.04 (s, 2H), 3.68 (s, 2H), 2.74-2.67 (m, 1H), 2.59-2.50 (m, 5H), 2.39-2.33 (m, 6H), 2.13-2.08 (m, 1H), 1.89-1.85 (m, 1H) ppm. Example 91 Synthesis of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-3-(((8-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperazin-1-yl)-8-oxooctyl)amino)methyl)benzamide formate (Compound 143)

Step-1: To a solution of 3-formylbenzoic acid (1, 150 mg, 999.13 µmol) in toluene (5 mL), was added thionyl chloride (1.19 g, 9.99 mmol) drop-wise. The resulting mixture was heated at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure in a nitrogen and co-evaporated with toluene to give 3-formylbenzoyl chloride (crude) as an off-white solid. To a solution of 5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amine (2, 259.03 mg, 999.13 µmol) and DIPEA (129.13 mg, 999.13 µmol, 174.03 µL) in tetrahydrofuran (5 mL), cooled to -40 °C, was added the above prepared 3-formylbenzoyl chloride (crude) dissolved in tetrahydrofuran (5 mL) drop-wise. The resulting mixture was stirred at -40 °C for 20 min. The reaction mixture was treated with brine solution (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 60% ethyl acetate in petroleum ether to give N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-3-formyl-benzamide (3, 230 mg, 546.54 µmol, 55% yield) as an off-white solid. LC-MS (ES⁺): m/z 392.1 [M + H] ⁺. Step-2: To a solution of N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-3-formyl-benzamide (3, 90 mg, 229.96 µmol) and 3-[4-[4-(8-aminooctanoyl)piperazin-1-yl]anilino]piperidine-2,6-dione hydrochloride (4, 98.78 mg, 211.97 µmol) in dichloromethane (4 mL), was added tetramethylammonium triacetoxyborohydride (121.00 mg, 459.92 µmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (3 mL) and extracted with dichloromethane (2 x 2 mL). The combined organics were washed with brine (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase [Column: ISCO, 15 g; Mobile phase A: 0.1% HCOOH in water, Mobile phase B: Acetonitrile] and the fractions containing the compound was lyophilized to give N-[5-[(3,5- difluorophenyl)methyl]-1H-indazol-3-yl]-3-[[[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-8-oxo-octyl]amino]methyl]benzamide formate (Compound 143, 15 mg, 17.04 µmol, 7% yield) as a pale grey solid. LC-MS (ES⁺): m/z 805.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12.81 (s, 1H), 10.75 (s, 2H), 8.29 (s, 1H), 8.10 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 6.8 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.27 (dd, J = 8.6, 1.2 Hz, 1H), 7.05-6.98 (m, 3H), 6.96 (d, J = 6.4 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 5.42 (br s, 1H), 4.19 (br s, 2H), 4.05 (s, 2H), 3.92 (s, 2H), 3.55 (s, 4H), 2.85 (d, J = 4.4 Hz, 4H), 2.70-2.61 (m, 3H), 2.31 (t, J = 7.6 Hz, 2H), 2.12-2.08 (m, 1H), 1.86-1.82 (m, 1H), 1.51 (br s, 4H), 1.28 (s, 6H) ppm. Example 92 N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[[[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperazin-1-yl]-8-oxo-octyl]amino]methyl]benzamide (Compound 144)

Compound 144 was synthesized analogously to Compound 143 except starting with 4- formylbenzoic acid. LC-MS (ES⁺): m/z 805.3 [M + H] ⁺. Example 93 Synthesis of (R)-N-(3-aminopropyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide

Step-1: To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1, 1 g, 4.43 mmol) and (2R)-2-(2,5-difluorophenyl)pyrrolidine (2, 811.93 mg, 4.43 mmol) in n-butanol (1.5 mL), was added DIPEA (2.29 g, 17.73 mmol, 3.09 mL). The resulting mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature and the precipitated solid was filtered. The solid was washed with methanol followed by petroleum ether and dried under vacuum to give ethyl 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate (3, 1.3 g, 3.35 mmol, 76% yield) as a pale orange solid. LC-MS (ES⁺): m/z 373.1 [M + H] ⁺. Step-2: To a solution of ethyl 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carboxylate (3, 1.3 g, 3.49 mmol) in ethanol (13 mL), was added lithium hydroxide monohydrate (732.51 mg, 17.46 mmol) in water (4 mL) drop-wise. The contents were heated at 90 °C for 16 h. The volatiles were concentrated under reduced pressure and the reaction mixture was acidified using 2N aqueous HCl until the reaction mixture became pH 4. The precipitated solid was filtered and dried under vacuum to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxylic acid (4, 950 mg, 2.68 mmol, 77% yield) as an off-white solid. LC-MS (ES⁺): m/z 345.1 [M + H] ⁺. Step-3: To a solution of 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carboxylic acid (4, 950 mg, 2.76 mmol) and tert-butyl N-(3-aminopropyl)carbamate (5, 624.97 mg, 3.59 mmol, 626.22 µL) in N,N-dimethylformamide (8 mL), were added DIPEA (1.43 g, 11.04 mmol, 1.92 mL) and HATU (1.57 g, 4.14 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 80-90% ethyl acetate in petroleum ether to give tert-butyl N-[3-[[5- [(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carbonyl]amino]propyl]carbamate (6, 1.1 g, 2.04 mmol, 74% yield) as a colorless oil. LC-MS (ES⁺): m/z 501.2 [M + H] ⁺. Step-4: To a solution of tert-butyl N-[3-[[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carbonyl]amino]propyl]carbamate (6, 1.1 g, 2.20 mmol) in dichloromethane (5 mL), cooled 0 °C, was added HCl in dioxane (4.5M, 5 mL) drop-wise. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was triturated with diethyl ether, the solid was filtered and dried under vacuum to give N-(3-aminopropyl)-5-[(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (7, 800 mg, 1.78 mmol, 81% yield) as an off-white solid. LC-MS (ES⁺): m/z 401.1 [M + H] ⁺.

Example 94 Synthesis of 3-((4-(3-((8-aminooctyl)(methyl)amino)propyl)phenyl)amino)piperidine-2,6- dione

Step-1: To a solution of tert-butyl N-allylcarbamate (1, 4 g, 25.44 mmol) in N,N-dimethylformamide (20 mL), was added sodium hydride (60% dispersion in mineral oil, 760.44 mg, 33.08 mmol). The suspension was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, was added methyl iodide (4.69 g, 33.08 mmol, 2.06 mL). The contents were warmed to room temperature and stirred for 1 h. The reaction mixture was treated with cold water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organics were washed with brine solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give tert-butyl N-allyl-N-methyl-carbamate (2, 4 g, 23.36 mmol, 91.81% yield) as a colorless oil.¹H NMR (400 MHz, CDCl₃): δ 5.71-5.81 (m, 1H), 5.15-5.10 (m, 2H), 3.81 (br s, 2H), 2.86 (s, 3H), 1.46 (s, 9H) ppm. Step-2: tert-Butyl N-allyl-N-methyl-carbamate (2, 1.36 g, 7.92 mmol) and 1-bromo-4-nitro-benzene (3, 1 g, 4.95 mmol, 512.82 µL) were taken in triethylamine (10.02 g, 99.01 mmol, 13.80 mL) and the resulting mixture was degassed in an inert atmosphere of nitrogen for 5 min. To this mixture, were added tris(o-tolyl)phosphine (60.27 mg, 198.01 µmol) and palladium(II) acetate (11.11 mg, 49.50 µmol). The resulting mixture was heated at 110 °C for 20 h. The reaction mixture was cooled to room temperature, treated with cold water (200 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organics were washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 20-30% ethyl acetate in petroleum ether to give tert-butyl N-methyl-N-[(E)-3-(4- nitrophenyl)allyl]carbamate (4, 600 mg, 2.05 mmol, 41% yield) as a pale yellow liquid. LC-MS (ES⁺): m/z 258.2 [M - Isobutene + Na] ⁺. Step-3: To a solution of tert-butyl N-methyl-N-[(E)-3-(4-nitrophenyl)allyl]carbamate (4, 600 mg, 2.05 mmol) in ethanol (4 mL), was added palladium on carbon (10% dry loading, 436.85 mg). The resulting mixture was stirred under hydrogen atmosphere at room temperature for 16 h. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated under reduced pressure and dried under vacuum to give tert-butyl N-[3-(4-aminophenyl)propyl]-N-methyl- carbamate (5, 500 mg, 1.59 mmol, 77% yield) as an off-white solid. LC-MS (ES⁺): m/z 165.2 [M - COOtBu + H] ⁺. Step-4: To a solution of tert-butyl N-[3-(4-aminophenyl)propyl]-N-methyl-carbamate (5, 600 mg, 2.27 mmol) and 3-bromopiperidine-2,6-dione (522.95 mg, 2.72 mmol) in N,N-dimethylformamide (5 mL), was added sodium bicarbonate (571.99 mg, 6.81 mmol). The contents were heated at 85 °C for 16 h. The reaction mixture was cooled to room temperature, treated with cold water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 80-90% ethyl acetate in petroleum ether to give tert-butyl N-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]propyl]-N-methyl- carbamate (6, 500 mg, 972.14 µmol, 43% yield) as pale yellow liquid. LC-MS (ES-): 374.2 [M - H] -. Step-5: To a solution of tert-butyl N-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]propyl]-N-methyl- carbamate (6, 500 mg, 1.33 mmol) in dichloromethane (5 mL), cooled to 0 °C, was added trifluoroacetic acid (303.69 mg, 2.66 mmol, 205.19 µL). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was triturated with diethyl ether to give 3- [4-[3-(methylamino)propyl]anilino]piperidine-2,6-dione trifluoroacetate (7, 510 mg, 1.31 mmol, 98% yield) as a grey gum. LC-MS (ES⁺): m/z 276.2 [M + H] ⁺. Step-6: To a solution of 3-[4-[3-(methylamino)propyl]anilino]piperidine-2,6-dione trifluoroacetate (250 mg, 642.07 µmol) and tert-butyl N-(8-bromooctyl)carbamate (7, 197.92 mg, 642.07 µmol) in acetonitrile (4 mL), was added DIPEA (248.95 mg, 1.93 mmol, 335.51 µL). The resulting mixture was heated at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230- 400 mesh) eluted with 0-10% methanol in ethyl acetate to give tert-butyl N-[8-[3-[4-[(2,6-dioxo- 3-piperidyl)amino]phenyl]propyl-methyl-amino]octyl]carbamate (8, 150 mg, 286.46 µmol, 45% yield) as a colorless oil. LC-MS (ES⁺): m/z 503.4 [M + H] ⁺. Step-7: To a solution of tert-butyl N-[8-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]propyl-methyl- amino]octyl]carbamate (8, 200 mg, 397.86 µmol) in dichloromethane (2 mL), cooled to 0 °C, was added 4 M HCl in dioxane (2 mL) drop-wise. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was co-evaporated with diethyl ether to give 3-[4-[3- [8-aminooctyl(methyl)amino]propyl]anilino]piperidine-2,6-dione hydrochloride (9, 120 mg, 246.00 µmol, 62% yield) as a colorless oil. LC-MS (ES⁺): m/z 403.3 [M + H] ⁺. Example 95 Synthesis of 3-((4-(1-(8-amino-2-hydroxyoctyl)piperidin-4-yl)phenyl)amino)piperidine-2,6- dione

Step-1: To a solution of 8-bromooct-1-ene (1, 5 g, 26.16 mmol, 4.39 mL) in N,N-dimethylformamide (20 mL), were added cesium carbonate (12.79 g, 39.24 mmol) and di-tert-butyl iminodicarboxylate (2, 6.82 g, 31.40 mmol). The contents were heated at 90 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give the residue and partitioned between ethyl acetate and water (150 mL / 50 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with brine solution (75 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted using 15-10% ethyl acetate in petroleum ether to give tert-butyl N-tert- butoxycarbonyl-N-oct-7-enyl-carbamate (3, 6 g, 18.14 mmol, 69% yield) as a colorless liquid. LC- MS (ES⁺): m/z 216.2 [M - (2 x Isobutene) + H] ⁺. Step-2: To a solution of tert-butyl N-tert-butoxycarbonyl-N-oct-7-enyl-carbamate (3, 6 g, 18.32 mmol) in dichloromethane (60 mL), cooled to 0 °C, was added m-chloroperoxybenzoic acid (4.74 g, 27.48 mmol). The resulting mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was treated with saturated sodium bicarbonate solution (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organics were washed with sodium sulfite solution (2 x 250 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give tert-butyl N-tert-butoxycarbonyl-N-[6-(oxiran-2-yl)hexyl]carbamate (4, 5.5 g, 15.85 mmol, 87% yield) as a colorless liquid. LC-MS (ES⁺): m/z 232.2 [M - (2 x Isobutene) + H] ⁺. Step-3: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[6-(oxiran-2-yl)hexyl]carbamate (4, 727.34 mg, 2.12 mmol) and 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione trifluoroacetate (5, 500 mg, 1.25 mmol) in 2-propanol (10 mL), was added sodium bicarbonate (523.26 mg, 6.23 mmol). The contents were heated at 80 °C for 24 h. The reaction mixture was concentrated under reduced pressure and portioned between ethyl acetate and water (40 mL / 20 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x 25 mL). The combined organics were washed with brine solution (40 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-10% methanol in dichloromethane to give tert-butyl N-tert-butoxycarbonyl-N-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-7-hydroxy-octyl]carbamate (6, 240 mg, 346.22 µmol, 28% yield) as a colorless liquid. LC-MS (ES⁺): m/z 631.4 [M + H] ⁺. Step-4: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-7-hydroxy-octyl]carbamate (6, 250 mg, 396.31 µmol) dichloromethane (5 mL), cooled resulting mixture to 0 °C, was added HCl in dioxane (4M, 5 mL) drop-wise. The was warmed to room temperature and stirred for 2 h. The volatiles were removed under reduce pressure and dried to give 3-[4-[1-(8-amino-2-hydroxy-octyl)-4- piperidyl]anilino]piperidine-2,6-dione hydrochloride (7, 170 mg, 243.87 µmol, 62% yield) as a colorless gum. The crude product was taken to next step without purification. LC-MS (ES⁺): m/z 431.4 [M + H] ⁺. Example 96 Synthesis of 3-((4-(1-(8-amino-2-fluorooctyl)piperidin-4-yl)phenyl)amino)piperidine-2,6- dione

Step-1: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-7-hydroxy-octyl]carbamate (1, 150 mg, 237.79 µmol) in tetrahydrofuran (1 mL), were added triethylamine (72.19 mg, 713.37 µmol, 99.43 µL), triethylamine trihydrofluoride (76.67 mg, 475.58 µmol, 77.44 µL) and perfluorobutanesulfonyl fluoride (143.67 mg, 475.58 µmol, 82.10 µL). The contents were stirred at room temperature for 24 h. The reaction mixture was filtered through a pad of silica, the filtrate was concentrated under reduced pressure to give tert-butyl N-tert-butoxycarbonyl-N-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-7-fluoro-octyl]carbamate (2, 200 mg, 151.71 µmol, 64% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 633.4 [M + H] ⁺. Step-2: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-7-fluoro-octyl]carbamate (2, 184.00 mg, 290.77 µmol) in dichloromethane (5 mL), cooled to 0 °C, was added HCl in dioxane (4M, 3 mL) drop-wise. The resulting mixture was warmed to room temperature and stirred for 2 h. The volatiles were concentrated under reduce pressure and dried to give 3-[4-[1-(8-amino-2-fluoro-octyl)-4- piperidyl]anilino]piperidine-2,6-dione hydrochloride (3, 100 mg, 135.06 µmol, 46% yield) as an off-white solid. The crude product was taken to next step without any further purification. LC-MS (ES⁺): m/z 433.4 [M + H] ⁺. Example 97 Synthesis of 3-(5-(1-(8-amino-2-hydroxyoctyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

Step-1: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[6-(oxiran-2-yl)hexyl]carbamate (1, 906.57 mg, 2.64 mmol) and 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (2, 500 mg, 1.32 mmol) in acetonitrile / IPA (20 mL / 5 mL, 4:1), was added sodium bicarbonate (554.37 mg, 6.60 mmol). The contents were heated at 75 °C for 36 h. The reaction mixture was concentrated and partitioned between ethyl acetate and water (100 mL / 40 mL). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (2 x 40 mL). The combined organics were washed with brine solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduce pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) using 5% methanol in dichloromethane to give tert-butyl N-tert-butoxycarbonyl-N-[8-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-7-hydroxy-octyl]carbamate (3, 200 mg, 265.34 µmol, 20% yield) as a yellow gum. LC-MS (ES⁺): m/z 686.5 [M + H] ⁺. Step-2: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[8-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2- oxo-benzimidazol-5-yl]-1-piperidyl]-7-hydroxy-octyl]carbamate (3, 70 mg, 102.06 µmol) in dichloromethane (2 mL), cooled to 0 °C, was added HCl in dioxane (4M, 1.2 mL) drop-wise. The reaction mixture was warmed to room temperature and stirred for 2 h. The volatiles were removed under reduce pressure and dried under vacuum to give 3-[5-[1-(8-amino-2-hydroxy-octyl)-4- piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (4, 50 mg, 69.91 µmol, 69% yield) as a yellow solid. The crude product was taken to next step without further purification. LC-MS (ES⁺): m/z 486.4 [M + H] ⁺. Example 98 3-(5-(1-(8-amino-2-fluorooctyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione

Prepared substantially similar to the synthesis of 3-((4-(1-(8-amino-2-fluorooctyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione, except replacing HCl in dioxane with TFA during the Boc- deprotection step. LC-MS (ES⁺): m/z 488.5 [M + H] ⁺. Example 99 Synthesis of 3-((4-(12-aminododecyl)phenyl)amino)piperidine-2,6-dione

Step-1: To a solution of tert-butyl N-(12-bromododecyl)carbamate (1, 1 g, 2.74 mmol) in DMSO (20 mL), was added TBAF (1M in THF, 27.54 g, 105.52 mmol, 105.5 mL). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was treated with water (200 mL), the precipitated solid was filtered and dried under vacuum to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-10 % ethyl acetate in petroleum ether to give tert-butyl N-dodec-11-enylcarbamate (2, 530 mg, 448.76 µmol, 16% yield) as an off-white solid. LC-MS (ES⁺): m/z 228.3 [M - Isobutene +H] ⁺. Step-2: 1-Bromo-4-nitro-benzene (2, 181.30 mg, 897.52 µmol, 92.98 µL) and tert-butyl N-dodec-11- enylcarbamate (530 mg, 448.76 µmol) was taken in triethylamine (4 mL) and the contents were degassed in an inert atmosphere of nitrogen. To this mixture, were added tri(o-tolyl)phosphine (5.46 mg, 17.95 µmol) and palladium(II) acetate (1.01 mg, 4.49 µmol). The contents were stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature, treated with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were washed with brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 30-40% ethyl acetate in petroleum ether to give tert-butyl N-[(E)-12-(4-nitrophenyl)dodec-11-enyl]carbamate (3, 200 mg, 405.40 µmol, 90% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 305.3 [M - COOtBu + H] ⁺. Step-3: To a solution of tert-butyl N-[(E)-12-(4-nitrophenyl)dodec-11-enyl]carbamate (3, 200 mg, 410.34 µmol) in ethanol (20 mL), was added palladium on carbon (10% dry loading, 100 mg). The contents were stirred under hydrogen pressure at room temperature for 5 h. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated under reduced pressure to give tert-butyl N-[12-(4-aminophenyl)dodecyl]carbamate (4, 150 mg, 350.53 µmol, 85% yield) as an off-white solid. LC-MS (ES⁺): m/z 377.4 [M + H] ⁺. Step-4: To a solution of tert-butyl N-[12-(4-aminophenyl)dodecyl]carbamate (4, 150 mg, 262.90 µmol) and 3-bromopiperidine-2,6-dione (5, 100.96 mg, 525.79 µmol) in N,N-dimethylformamide (4 mL), was added sodium bicarbonate (66.26 mg, 788.69 µmol). The contents were stirred at 60 °C for 14 h. The reaction mixture was cooled to room temperature, treated with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organics were washed with brine solution (20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 30-60 % ethyl acetate in petroleum ether to give tert-butyl N-[12-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]dodecyl]carbamate (6, 120 mg, 142.72 µmol, 54% yield) as an off-white solid. LC-MS (ES⁺): m/z 488.4 [M + H] ⁺. Step-5: To a solution of tert-butyl N-[12-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]dodecyl]carbamate (6, 120 mg, 246.07 µmol) in dichloromethane (3 mL), cooled to 0 °C, was added HCl in dioxane (4M, 5 mL). The resulting mixture was warmed room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and dried under vacuum to give 3-[4-(12- aminododecyl)anilino]piperidine-2,6-dione hydrochloride (7, 110 mg, 238.67 µmol, 97% yield) as an off-white solid. LC-MS (ES⁺): m/z 388.5 [M + H] ⁺. Example 100 Synthesis of 3-(5-(12-aminododecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione

Step-1: To a solution of 12-bromododec-1-ene (1, 1 g, 4.05 mmol, 438.60 µL) in N,N-dimethylformamide (10 mL), were added cesium carbonate (1.98 g, 6.07 mmol) and di-tert-butyl iminodicarboxylate (2, 1.05 g, 4.85 mmol). The contents were heated at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and water (100 mL / 40 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230- 400 mesh) eluted with 10-15% ethyl acetate in petroleum ether to give tert-butyl N-tert- butoxycarbonyl-N-dodec-11-enyl-carbamate (3, 1 g, 2.35 mmol, 58% yield) as a colorless oil. LC- MS (ES⁺): m/z 272.2 [M - (2 x Isobutene) + H] ⁺. Step-2: To a solution of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (4, 200 mg, 591.44 µmol) and tert-butyl N-tert-butoxycarbonyl-N-dodec-11-enyl-carbamate (3, 294.91 mg, 768.88 µmol) in N,N-dimethylformamide (5 mL), was added triethylamine (598.48 mg, 5.91 mmol, 824.35 µL). The contents were degassed in an atmosphere of nitrogen for 5 min, was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (48.30 mg, 59.14 µmol). The contents were heated at 95 °C for 16 h. The reaction mixture was filtered through a pad of celite, the filtrate was treated with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organics were washed with brine solution (20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 75-100% ethyl acetate in petroleum ether to give E/Z mixture of tert- butyl N-tert-butoxycarbonyl-N-[12-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]dodec-11-enyl]carbamate (5, 150 mg, 208.33 µmol, 35% yield) as a yellow gum. LC-MS (ES⁺): m/z 441.3 [M - (2 x COOtBu) + H] ⁺. Step-3: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[12-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2- oxo-benzimidazol-5-yl]dodec-11-enyl]carbamate (5, 150 mg, 234.08 µmol) in ethanol (10 mL), was added palladium on carbon (10% dry loading, 50.15 mg). The contents were stirred at room temperature 16 h. The reaction was filtered through a pad of celite, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was triturated using diethyl ether, the solid was filtered and dried under vacuum to give tert-butyl N-tert-butoxycarbonyl-N- [12-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]dodecyl]carbamate (6, 120 mg, 69% yield) an off-white solid. LC-MS (ES⁺): m/z 443.4 [M - (2 x COOtBu) + H] ⁺. Step-4: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[12-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2- oxo-benzimidazol-5-yl]dodecyl]carbamate (6, 120 mg, 186.68 µmol) in dichloromethane (5 mL), cooled to 0 °C, was added HCl in dioxane (4M, 2.1 mL) dropwise. The resulting mixture was warmed to room temperature and stirred for 2 h. The volatiles were concentrated under reduce pressure and dried under vacuum to give 3-[5-(12-aminododecyl)-3-methyl-2-oxo-benzimidazol- 1-yl]piperidine-2,6-dione hydrochloride (7, 85 mg, 165.07 µmol, 88% yield) as a pale yellow gum. The crude product was taken to next step without purification. LC-MS (ES⁺): m/z 443.4 [M + H] ⁺. Example 101 Synthesis of 3-((4-(1-(8-amino-2-oxooctyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione

Step-1: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-7-hydroxy-octyl]carbamate (1, 240 mg, 380.46 µmol) in dichloromethane (3 mL) and DMSO (3 mL), were added DIPEA (147.51 mg, 1.14 mmol, 198.80 µL) and sulfur trioxide-pyridine complex (302.47 mg, 1.90 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine solution (20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 10% methanol in ethyl acetate to give tert- butyl N-tert-butoxycarbonyl-N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-7- oxo-octyl]carbamate (2, 90 mg, 113.07 µmol, 30% yield) as a yellow solid. LC-MS (ES⁺): m/z 629.4 [M + H] ⁺. Step-2: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-7-oxo-octyl]carbamate (2, 80 mg, 127.23 µmol) in dichloromethane (4 mL), cooled to 0 °C, was added HCl in dioxane (4M, 2 mL) drop-wise. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The residue was co-evaporated with diethyl ether to give 3-[4-[1-(8-amino-2-oxo-octyl)-4-piperidyl]anilino]piperidine-2,6-dione hydrochloride (3, 54 mg, 70.83 µmol, 56% yield) as a grey semi-solid. LC-MS (ES⁺): m/z 429.4 [M + H] ⁺. Example 102 3-(5-(1-(8-amino-2-oxooctyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione

Prepared substantially similar to the synthesis of 3-[4-[1-(8-amino-2-oxo-octyl)-4- piperidyl]anilino]piperidine-2,6-dione. LC-MS (ES⁺): m/z 429.4 [M + H] +. Example 103 Synthesis of 3-(5-(3-((8-aminooctyl)(methyl)amino)propyl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione

Step-1: To a solution of tert-butyl N-allyl-N-methyl-carbamate (2, 265.85 mg, 1.55 mmol) and 3-(5- bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1, 2350 mg, 1.04 mmol) in N,N- dimethylformamide (10 mL), was added triethylamine (1.05 g, 10.35 mmol, 1.44 mL). The contents were degassed in an inert atmosphere of nitrogen for 5 minutes, was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (84.52 mg, 103.50 µmol). The contents were heated at 110 °C for 16 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to give the residue. The residue was partitioned with ethyl acetate and water (100 mL / 40 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organics were washed with brine solution (40 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 75-100% ethyl acetate in petroleum ether to give E/Z mixture of tert-butyl N-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]allyl]-N-methyl-carbamate (3, 250 mg, 490.10 µmol, 47% yield) as a yellow gum. LC-MS (ES-): m/z 427.2 [M - H] -. Step-2: To a solution of tert-butyl N-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]allyl]-N-methyl-carbamate (3, 200 mg, 466.77 µmol) in ethanol (10 mL), was added palladium on carbon (10% dry loading, 100 mg). The contents were stirred at room temperature 16 h. The reaction was filtered through a pad of celite, the filtrate was concentrated under reduced pressure and dried under vacuum to give tert-butyl N-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]propyl]-N-methyl-carbamate (4, 200 mg, 83% yield) as a yellow gum. LC-MS (ES⁺): m/z 375.2 [M - Isobutene + H] ⁺. Step-3: To a solution of tert-butyl N-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]propyl]-N-methyl-carbamate (4, 200 mg, 464.58 µmol) in dichloromethane (7 mL), cooled to 0 °C, was added trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL). The resulting mixture was warmed to room temperature and stirred for 2 h. The volatiles were concentrated under reduce pressure and dried under vacuum to give 3-[3-methyl-5-[3-(methylamino)propyl]-2-oxo-benzimidazol-1- yl]piperidine-2,6-dione trifluoroacetate (5, 170 mg, 233.35 µmol, 50% yield) as a brown gum. The crude product was taken to next step without purification. LC-MS (ES⁺): m/z 331.2 [M + H] ⁺. Step-4: To a solution of 3-[3-methyl-5-[3-(methylamino)propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6- dione trifluoroacetate (5, 200 mg, 545.19 µmol) and tert-butyl N-(8-bromooctyl)carbamate (6, 201.67 mg, 654.23 µmol) in acetonitrile (5 mL), was added DIPEA (352.31 mg, 2.73 mmol, 474.81 µL). The resulting mixture was heated at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to get the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-10% methanol in ethyl acetate to give tert-butyl N-[8-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl-methyl- amino]octyl]carbamate (7, 150 mg, 207.82 µmol, 38% yield) as a yellow syrup. LC-MS (ES⁺): m/z 558.3 [M + H] ⁺. Step-5: To a solution of tert-butyl N-[8-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]propyl-methyl-amino]octyl]carbamate (7, 150 mg, 268.95 µmol) in dichloromethane (5 mL), cooled to 0 °C, was added HCl in dioxane (4M, 3 mL) drop-wise. The resulting mixture was warmed to room temperature and stirred for 2 h. The volatiles were concentrated under reduced pressure and dried under vacuum to give 3-[5-[3-[8-aminooctyl(methyl)amino]propyl]-3-methyl- 2-oxo-benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (8, 80 mg, 148.61 µmol, 55% yield) as a yellow gum. LC-MS (ES⁺): m/z 458.2 [M + H] ⁺. Example 104 Synthesis of 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]octyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 145)

To a solution of 3-[4-[1-(8-aminooctyl)-4-piperidyl]anilino]piperidine-2,6-dione (2, 50 mg, 120.60 µmol) and 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carboxylic acid (1, 10 mg, 29.04 µmol) in N,N-dimethylformamide (1 mL), were added DIPEA (3.75 mg, 29.04 µmol, 5.06 µL) and PyBOP (22.67 mg, 43.56 µmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was treated with water (3 mL), the precipitated solid was filtered and dried under vacuum to give the crude product. The crude product was purified by preparative HPLC [Mobile phase A: 0.1% ammonium bicarbonate in water, Mobile phase B: ACN] and the fractions containing the product was lyophilized to give 5-[(2R)- 2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]octyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 145, 8 mg, 10.59 µmol, 36% yield) as an off-white solid. LC-MS (ES⁺): m/z 741.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO- d₆): δ 10.78 (s, 1H), 8.81 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.32-7.25 (m, 2H), 7.15-7.08 (m, 1H), 7.02-6.93 (m, 4H), 6.68 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.64 (d, J = 7.6 Hz, 1H), 5.47 (d, J = 6.8 Hz, 1H), 4.31-4.23 (m, 1H), 4.01-3.99 (m, 1H), 3.69-3.61 (m, 1H), 2.92-2.85 (m, 2H), 2.74-2.67 (m, 2H), 2.34-2.22 (m, 4H), 2.11-2.07 (m, 4H), 1.91-1.85 (m, 5H), 1.66-1.63 (m, 3H), 1.58-1.53 (m, 3H), 1.42 (br s, 4H), 1.27 (br s, 6H) ppm.

Example 105 N-[6-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-6-oxo-hexyl]-5-[rac-(2R)-2- (2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 146)

Compound 146 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 727.9 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 1H), 8.80 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.35-7.26 (m, 2H), 7.16-7.11 (m, 1H), 7.05-7.01 (m, 1H), 6.78-6.67 (m, 2H), 6.63-6.54 (m, 3H), 5.46-5.42 (m, 2H), 4.23-4.16 (m, 1H), 4.03-3.97 (m, 1H), 3.55-3.65 (m, 1H), 3.56 (s, 4H), 3.19-3.14 (m, 1H), 2.90 (br s, 2H), 2.85 (br s, 2H), 2.68-2.59 (m, 2H), 2.35-2.32 (m, 2H), 2.10-2.06 (m, 3H), 1.92- 1.85 (m, 2H), 1.58-1.50 (m, 3H), 1.30-1.24 (m, 4H) ppm. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-8-oxo-octyl]-5-[rac-(2R)-2- (2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 147)

Compound 147 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 755.8 [M + H] ⁺. N-[6-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]hexyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 148)

Compound 148 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 713.9 [M + H] ⁺. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]octyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 149)

Compound 149 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 741.9 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 1H), 8.81 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.33-7.25 (m, 2H), 7.15-7.11 (m, 1H), 7.05-6.98 (m, 1H), 6.73 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 9.2 Hz, 2H), 5.47 (d, J = 7.2 Hz, 1H), 5.37 (d, J = 7.6 Hz, 1H), 4.19-4.11 (m, 1H), 4.10-4.03 (m, 1H), 3.38-3.30 (m, 1H), 2.91 (s, 5H), 2.73-2.67 (m, 1H), 2.61-2.51 (m, 2H), 2.45 (s, 5H), 2.34-2.26 (m, 2H), 2.10-2.01 (m, 4H), 1.91-1.86 (m, 3H), 1.43 (s, 3H), 1.27 (s, 6H) ppm. N-[8-[4-[[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]piperazin-1-yl]octyl]-5-[rac-(2R)- 2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 150)

Compound 150 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 756.3 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d): δ 10.78 (s, 1H), 8.80 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.32-7.25 (m, 2H), 7.21 (s, 1H), 7.01-6.96 (m, 3H), 6.67 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 8.4 Hz, 2H), 5.75 (d, J = 7.6 Hz, 1H), 5.46 (d, J = 7.6 Hz, 1H), 4.30-4.24 (m, 1H), 4.05-3.97 (m, 1H), 3.66-3.49 (m, 3H), 3.25-3.16 (m, 4H), 2.93-2.85 (m, 2H), 2.72-2.51 (m, 2H), 2.33-2.29 (m, 6H), 2.20-2.13 (m, 3H), 2.12-2.02 (m, 4H), 1.89-1.76 (m, 3H), 1.37 (s, 3H), 1.24 (s, 6H) ppm. N-[8-[4-[[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]piperazin-1-yl]-8-oxo-octyl]-5- [rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 151)

Compound 151 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 770.2 [M + H] ⁺. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-8-oxo-octyl]-5-[rac-(2R)-2- (2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 152)

Compound 152 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 754.8 [M + H] ⁺. N-[10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]decyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 153)

Compound 153 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 767.4 [M + H] ⁺. N-[10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-10-oxo-decyl]-5-[rac-(2R)-2- (2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 154)

Compound 154 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 782.8 [M + H] ⁺. N-[8-[4-[2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]ethyl]piperazin-1-yl]octyl]-5-[rac-(2R)- 2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 155)

Compound 155 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 770.5 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 1H), 8.81 (d, J = 8.0 Hz, 1H), 8.15 (s, 1H), 7.33-7.24 (m, 2H), 7.20-7.11 (m, 1H), 7..02-6.97 (m, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 8.4 Hz, 2H), 5.65 (d, J = 7.6 Hz, 1H), 5.47 (d, J = 7.6 Hz, 1H), 4.30-4.24 (m, 1H), 4.08-4.01 (m, 1H), 3.69-3.62 (m, 1H), 3.19-3.14 (m, 1H), 2.97-2.90 (m, 1H), 2.77-2.67 (m, 1H), 2.61-2.51 (m, 12H), 2.60-2.51 (m, 2H), 2.13-2.07 (m, 3H), 2.01-1.84 (m, 2H), 1.42 (br s, 4H), 1.26 (br s, 10H) ppm. N-[8-[4-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]propyl]piperazin-1-yl]-8-oxo-octyl]-5- [rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 156)

Compound 156 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 798.3 [M + H] ⁺. N-[8-[4-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]propyl]piperazin-1-yl]octyl]-5-[rac- (2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 157)

Compound 157 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 784.3 [M + H] ⁺. N-[8-[4-[2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]ethyl]piperazin-1-yl]-8-oxo-octyl]-5- [rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 158)

Compound 158 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 784.4 [M + H] ⁺. N-[6-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]hexyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 159)

Compound 159 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 713.2 [M + H] ⁺. N-[5-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]pentyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 160)

Compound 160 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 699.3 [M + H] ⁺. N-[9-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]nonyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 161)

Compound 161 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 755.4 [M + H] ⁺.

N-[7-[4-[[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]piperazin-1-yl]heptyl]-5-[rac- (2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 162)

Compound 162 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 742.4 [M + H] ⁺. N-[6-[4-[[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]piperazin-1-yl]hexyl]-5-[rac-(2R)- 2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 163)

Compound 163 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 728.3 [M + H] ⁺.

N-[5-[4-[[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]piperazin-1-yl]pentyl]-5-[rac- (2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 164)

Compound 164 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 714.3 [M + H] ⁺. N-[3-[[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo- butanoyl]amino]propyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (Compound 165)

Compound 165 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 770.8 [M + H] ⁺. N-[3-[[10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-10-oxo- decanoyl]amino]propyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (Compound 166)

Compound 166 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 854.8 [M + H] ⁺. N-[3-[[12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-12-oxo- dodecanoyl]amino]propyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (Compound 167)

Compound 167 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 882.8 [M + H] ⁺.

N-[3-[[14-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-14-oxo- tetradecanoyl]amino]propyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 168)

Compound 168 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 910.8 [M + H] ⁺. N-[3-[3-[2-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]propanoylamino]propyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 169)

Compound 169 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 858.8 [M + H] ⁺. N-[3-[3-[2-[2-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]propanoylamino]propyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 170)

Compound 170 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 902.8 [M + H] ⁺. N-[3-[3-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]ethoxy]propanoylamino]propyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 171)

Compound 171 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 946.7 [M + H] ⁺. N-[3-[3-[2-[2-[2-[2-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-3-oxo- propoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]propyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 172)

Compound 172 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 990.8 [M + H] ⁺. N-[3-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]butanoylamino]propyl]- 5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide (Compound 173)

Compound 173 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 757.3 [M + H] ⁺. N-[3-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]butanoylamino]propyl]-5- [rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 174)

Compound 174 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 756.3 [M + H] ⁺. N-[7-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]heptyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 175)

Compound 175 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 727.3 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.79 (s, 1H), 8.81 (d, J = 8.0 Hz, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.34-7.25 (m, 3H), 7.17-7.01 (m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.66 (d, J = 7.6 Hz, 1H), 5.47 (d, J = 6.8 Hz, 1H), 4.29-4.22 (m, 1H), 4.07- 3.98 (m, 1H), 3.64-3.59 (m, 2H), 3.19-3.11 (m, 2H), 2.96 (d, J = 8.8 Hz, 3H), 2.74-2.67 (m, 2H), 2.61-2.50 (m, 2H), 2.34-2.31 (m, 3H), 2.12-1.85 (m, 7H), 1.68-1.60 (m, 2H), 1.58-1.52 (m, 2H), 1.44 (br s, 2H), 1.29-1.21 (m, 7H) ppm. N-[8-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]propyl-methyl-amino]octyl]-5-[rac-(2R)-2- (2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 176)

Compound 176 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 729.4 [M + H] ⁺. 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[12-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]dodecyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 177)

Compound 177 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 714.4 [M + H] ⁺.

N-[8-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl-methyl- amino]octyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine- 3-carboxamide (Compound 178)

Compound 178 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 784.1 [M + H] ⁺. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-7-hydroxy-octyl]-5-[rac- (2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 179)

Compound 179 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 757.3 [M + H] ⁺. 1H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H), 8.81 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 7.34-7.25 (m, 2H), 7.16-7.12 (m, 1H), 7.05-7.00 (m, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 8.0 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 5.65 (d, J = 7.2 Hz, 1H), 5.47 (d, J = 7.2 Hz, 1H), 4.28- 4.21 (m, 1H), 4.09-4.01 (m, 1H), 3.59-3.51 (m, 3H), 2.95-2.85 (m, 4H), 2.74-2.67 (m, 1H), 2.61- 2.50 (m, 2H), 2.34-2.31 (m, 3H), 2.11-1.91 (m, 4H), 1.89-1.81 (m, 3H), 1.66-1.56 (m, 5H), 1.41 (br s, 3H), 1.37-1.24 (m, 5H) ppm. N-[8-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-7- hydroxy-octyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (Compound 180)

Compound 180 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 812.6 [M + H] ⁺. N-[8-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-7-fluoro- octyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide (Compound 181)

Compound 181 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 814.4 [M + H] ⁺. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-7-fluoro-octyl]-5-[rac-(2R)-2- (2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 182)

Compound 182 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 759.3 [M + H] ⁺. N-[12-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]dodecyl]-5-[rac-(2R)-2- (2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 183)

Compound 183 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 769.4 [M + H] ⁺. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-7-oxo-octyl]-5-[rac-(2R)-2- (2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 184)

Compound 184 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 755.4 [M + H] ⁺. N-[8-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-7-oxo- octyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide (Compound 185)

Compound 185 was prepared substantially following the synthesis of Compound 145. LC-MS (ES⁺): m/z 810.5 [M + H] ⁺. Example 106 Synthesis of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(5-(2- oxoethoxy)pentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step-1: To a stirred solution of tert-butyl N-(5-hydroxypentyl)carbamate (1, 1.0 g, 4.92 mmol) and 3- bromoprop-1-ene (654.64 mg, 5.41 mmol) in N,N-dimethylformamide (10 mL), cooled to 0 °C, was added sodium hydride (60% dispersion in mineral oil, 376.98 mg, 9.84 mmol) portion-wise. The contents were warmed to room temperature and stirred for 2 h. The reaction mixture was treated with cold water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 20% ethyl acetate in petroleum ether to give tert-butyl N-(5-allyloxypentyl)carbamate (2, 700 mg, 2.85 mmol, 58% yield) as a colorless oil. LC-MS (ES⁺): m/z 144.0 [M - COOtBu + H] ⁺. Step-2: To a solution of tert-butyl N-(5-allyloxypentyl)carbamate (2, 300 mg, 1.23 mmol) in dichloromethane (5 mL), cooled to 0 °C, was added HCl in dioxane (4M, 3 mL). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and triturated with diethyl ether. The solid was filtered and dried under vacuum to give 5-allyloxypentan-1-amine hydrochloride (3, 200 mg, 89% yield) as an off-white solid. LC-MS (ES⁺): m/z 144.3 [M + H] ⁺. Step-3: To a solution of 5-allyloxypentan-1-amine hydrochloride (3, 250.50 mg, 1.39 mmol) and 5-[(2R)- 2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4, 400 mg, 1.16 mmol) in N,N-dimethylformamide (7 mL), were added DIPEA (750.71 mg, 5.81 mmol, 1.01 mL) and PyBOP (725.46 mg, 1.39 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was treated with water (10 mL), the precipitated solid was filtered and dried under vacuum to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 70-100% ethyl acetate in petroleum ether to give N-(5-allyloxypentyl)-5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (5, 400 mg, 826.37 µmol, 71% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 470.2 [M + H] ⁺. Step-4: To a solution of N-(5-allyloxypentyl)-5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (5, 350 mg, 745.43 µmol) in 1,4-dioxane (10 mL) and water (5 mL), were added osmium tetroxide (18.95 mg, 74.54 µmol), sodium periodate (637.76 mg, 2.98 mmol) and 2,6-lutidine (159.75 mg, 1.49 mmol). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was treated with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organics were washed with brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[5-(2-oxoethoxy)pentyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (6, 300 mg, 426.30 µmol, 57% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 472.4 [M + H] ⁺. Example 107 Synthesis of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(5-(methyl(2- oxoethyl)amino)pentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step-1: To a solution of tert-butyl N-(5-aminopentyl)carbamate (1, 4 g, 19.77 mmol) in toluene (50 mL), was added isobenzofuran-1,3-dione (3.22 g, 21.75 mmol, 2.11 mL). The resulting mixture was heated at 125 °C for 3 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 20-30% ethyl acetate in petroleum ether to give tert-butyl N-[5-(1,3-dioxoisoindolin-2-yl)pentyl]carbamate (2, 5.4 g, 15.92 mmol, 81% yield) as an off-white solid. LC-MS (ES⁺): m/z 233.2 [M - COOtBu + H] ⁺. Step-2: To a solution of tert-butyl N-[5-(1,3-dioxoisoindolin-2-yl)pentyl]carbamate (2, 2.9 g, 8.72 mmol) in N,N-dimethylformamide (30 mL), cooled to 0 °C, was added sodium hydride (60% dispersion in mineral oil, 314.06 mg, 13.09 mmol). The contents were stirred at 0 °C for 30 min. To this mixture, was added methyl iodide (1.86 g, 13.09 mmol, 814.71 µL) and the contents were stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C, treated with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 80-90% ethyl acetate in petroleum ether to give tert-butyl N-[5-(1,3-dioxoisoindolin-2-yl)pentyl]-N-methyl- carbamate (3, 1.75 g, 4.75 mmol, 54% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 247.2 [M - COOtBu + H] ⁺. Step-3: To a solution of tert-butyl N-[5-(1,3-dioxoisoindolin-2-yl)pentyl]-N-methyl-carbamate (3, 1.75 g, 5.05 mmol) in ethanol (20 mL), was added hydrazine hydrate (80% in water, 313.58 mg, 9.79 mmol, 0.22 mL). The resulting mixture was heated at 90 °C for 1 h. The reaction mixture was cooled to room temperature and the solid was filtered. The filtrate was concentrated under reduced pressure to give tert-butyl N-(5-aminopentyl)-N-methyl-carbamate (4, 1.2 g, 4.77 mmol, 94% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 217.3 [M + H] ⁺. Step-4: To a solution of tert-butyl N-(5-aminopentyl)-N-methyl-carbamate (4, 502.61 mg, 2.32 mmol) and 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5, 400 mg, 1.16 mmol) in N,N-dimethylformamide (20 mL), cooled to 0 °C, were added DIPEA (450.44 mg, 3.49 mmol, 607.06 µL) and HATU (530.07 mg, 1.39 mmol). The resulting mixture was stirred at 0 °C for 10 min. The reaction mixture was treated with water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 2-5% methanol in ethyl acetate to give tert-butyl N-[5-[[5-[(2R)- 2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]pentyl]-N- methyl-carbamate (6, 320 mg, 542.55 µmol, 47% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 543.2 [M + H] ⁺. Step-5: To a solution of tert-butyl N-[5-[[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carbonyl]amino]pentyl]-N-methyl-carbamate (6, 320 mg, 589.73 µmol) in dichloromethane (5 mL), cooled to 0 °C, was added HCl in 1,4-dioxane (4M, 15 mL). The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was triturated using diethyl ether (5 mL) to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[5- (methylamino)pentyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (7, 285 mg, 583.13 µmol, 99% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 443.2 [M + H] ⁺. Step-6: To a solution of 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[5- (methylamino)pentyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (7, 290 mg, 605.47 µmol) in methanol (5 mL), were added 2,2-dimethoxyacetaldehyde (8, 60% in water, 94.55 mg, 908.21 µmol), MP-cyanoborohydride (580 mg, 605.47 µmol) and acetic acid (3.64 mg, 60.55 µmol, 3.46 µL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure and dried under vacuum to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[5- [2,2-dimethoxyethyl(methyl)amino]pentyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (9, 320 mg, 554.83 µmol, 92% yield) as pale yellow gum. LC-MS (ES⁺): m/z 531.3 [M + H] ⁺. Step-7: To a solution of 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[5-[2,2- dimethoxyethyl(methyl)amino]pentyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (9, 160 mg, 301.54 µmol) in tetrahydrofuran (1.5 mL), was added 6N aqueous HCl (1.5 mL). The resulting mixture was heated at 60 °C for 3 h. The reaction mixture was cooled, purged with an inert atmosphere of nitrogen for 30 min and concentrated. The residue was triturated with diethyl ether (15 mL), filtered and dried under vacuum to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]- N-[5-[methyl(2-oxoethyl)amino]pentyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (10, 160 mg, 196.54 µmol, 65% yield) as an off-white solid. LC-MS (ES⁺): m/z 485.1 [M + H] ⁺. Example 108 Synthesis of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(8-oxooctyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide

Step-1: To a solution of 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carboxylic acid (1, 200.00 mg, 580.86 µmol) and 8-aminooctan-1-ol (2, 84.37 mg, 580.86 µmol) in N,N-dimethylformamide (3 mL), were added DIPEA (225.21 mg, 1.74 mmol, 303.52 µL) and HATU (331.29 mg, 871.30 µmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-10% methanol in dichloromethane to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]- N-(8-hydroxyoctyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (3, 220 mg, 419.15 µmol, 72% yield) as a yellow gum. LC-MS (ES⁺): m/z 472.3 [M + H] ⁺. Step-2: To a solution of 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-(8-hydroxyoctyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide (3, 220.00 mg, 466.55 µmol) in dichloromethane (4 mL), was added pyridinium chlorochromate (201.14 mg, 933.11 µmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture were absorbed with silica gel and the crude product was purified flash chromatography (silica gel, 230-400 mesh) eluted with 0-15% methanol in dichloromethane to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-(8- oxooctyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (4, 130 mg, 100.62 µmol, 22% yield) as a brown solid. LC-MS (ES⁺): m/z 469.9 [M + H] ⁺. Example 109 Synthesis of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-methyl-N-(8- oxooctyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step-1: To a solution of 9-bromonon-1-ene (1 g, 4.87 mmol) and tert-butyl N-tert- butoxycarbonylcarbamate (2, 1.06 g, 4.87 mmol) in N,N-dimethylformamide (8 mL), was added cesium carbonate (2.70 g, 8.29 mmol). The reaction mixture was heated at 90 °C for 2 h. The reaction mixture was treated with water (5 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 2-5% ethyl acetate in petroleum ether to give tert-butyl N-tert-butoxycarbonyl-N-non-8-enyl- carbamate (3, 1.4 g, 4.09 mmol, 84% yield) as a colorless oil. LC-MS (ES⁺): m/z 705.5 [2M + Na] ⁺. Step-2: To a solution of tert-butyl N-tert-butoxycarbonyl-N-non-8-enyl-carbamate (3, 1.4 g, 4.10 mmol) in dichloromethane (15 mL), cooled to 0 °C, was added HCl in dioxane (4M, 10 mL). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and dried under vacuum to give non-8-en-1-amine hydrochloride (4, 700 mg, 3.93 mmol, 96% yield) as a pale brown semi-solid. LC-MS (ES⁺): m/z 142.3 [M + H] ⁺. Step-3: To a solution of non-8-en-1-amine hydrochloride (4, 246.15 mg, 1.74 mmol) and 5-[(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5, 600 mg, 1.74 mmol) in N,N-dimethylformamide (6 mL), were added DIPEA (675.65 mg, 5.23 mmol, 910.58 µL) and PyBOP (1.09 g, 2.09 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was treated with cold water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organics were washed with water (20 mL), brine solution (20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 70-90% ethyl acetate in petroleum ether to give 5-[(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]-N-non-8-enyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide (6, 800 mg, 1.68 mmol, 96% yield) as a pale yellow semi-solid. LC-MS (ES⁺): m/z 468.1 [M + H] ⁺. Step-4: To a solution of 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-non-8-enyl-pyrazolo[1,5- a]pyrimidine-3-carboxamide (6, 110 mg, 235.27 µmol) in N,N-dimethylformamide (2 mL), were added sodium hydride (60% dispersion in mineral oil, 21.64 mg, 941.07 µmol) and methyl iodide (133.57 mg, 941.07 µmol, 58.59 µL). The contents were stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, treated with saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 90-100 % ethyl acetate in petroleum ether to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-methyl-N-non-8-enyl-pyrazolo[1,5- a]pyrimidine-3-carboxamide (7, 60 mg, 105.90 µmol, 45% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 482.3 [M + H] ⁺. Step-5: To a solution of 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-methyl-N-non-8-enyl- pyrazolo[1,5-a]pyrimidine-3-carboxamide (7, 60 mg, 124.59 µmol) in 1,4-dioxane (2 mL) and water (1 mL), cooled to 0 °C, were added osmium(VIII) oxide (2.5 wt. % in tert-butanol, 3.16 mg, 12.45 µmol, 0.15 mL), sodium periodate (106.15 mg, 496.28 µmol) and 2,6-lutidine (26.70 mg, 249.18 µmol, 28.93 µL). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was cooled to 0 °C, treated with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organics were washed with brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-methyl-N-(8-oxooctyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide (8, 60 mg, 80.65 µmol, 65% yield) as a pale yellow oil. LC-MS (ES⁺): m/z 484.2 [M + H] ⁺. Example 110 Synthesis of 5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(5-(2-(4-(1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1- yl)ethoxy)pentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 186)

To a solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (2, 30 mg, 79.19 µmol) in methanol (10 mL), were added 5-[(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]-N-[5-(2-oxoethoxy)pentyl]pyrazolo[1,5-a]pyrimidine-3- carboxamide (1, 37.34 mg, 79.19 µmol), MP-cyanoborohydride (Biotage^®, 100 mg) and acetic acid (4.76 mg, 79.19 µmol, 4.53 µL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by mass-directed preparative HPLC [Column: X-bridge C8, (3 x 150 mm), 5 micron; Mobile phase A: 0.1% HCOOH in water, Mobile phase B: Acetonitrile, Wavelength: 215 nm] and the fractions containing the product was lyophilized to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[5-[2-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethoxy]pentyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide formate (Compound 186, 23 mg, 33% yield) as an off-white solid. LC-MS (ES⁺): m/z 798.4 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 11.09 (s, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.34-7.25 (m, 2H), 7.16-7.09 (m, 1H), 7.08 (s, 1H), 7.02- 6.99 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 5.35 (d, J = 5.2 Hz, 1H), 5.32 (d, J = 5.6 Hz, 1H), 4.05-3.98 (m, 1H), 3.62-3.54 (m, 1H), 3.49 (t, J = 6.0 Hz, 3H), 3.33-3.17 (m, 5H), 3.15-3.03 (m, 2H), 2.99-2.91 (m, 4H), 2.71-2.60 (m, 2H), 2.53-2.50 (m, 2H), 2.05-1.97 (m, 7H), 1.68 (s, 4H), 1.52-1.49 (m, 2H), 1.33-1.27 (m, 3H) ppm. Example 111 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[5-[2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]ethoxy]pentyl]pyrazolo[1,5-a]pyrimidine-3- carboxamide (Compound 187)

Compound 187 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 743.3 [M + H] ⁺. N-[5-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]ethoxy]pentyl]-5-[rac- (2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 188)

Compound 188 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 744.2 [M + H] ⁺. N-[5-[2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1-piperidyl]ethoxy]pentyl]-5-[rac-(2R)-2- (2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 189)

Compound 189 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 744.3 [M + H] ⁺. N-[5-[2-[4-[4-[(2,4-dioxohexahydropyrimidin-1-yl)methyl]phenyl]-1- piperidyl]ethoxy]pentyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (Compound 190)

Compound 190 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 743.3 [M + H] ⁺. N-[5-[2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]ethoxy]pentyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 191)

Compound 191 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 728.2 [M + H] ⁺. N-[5-[2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1-piperidyl]ethyl-methyl-amino]pentyl]- 5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide (Compound 192)

Compound 192 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 757.3 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.92 (s, 1H), 8.80 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.33-7.25 (m, 2H), 7.13-7.02 (m, 3H), 6.91 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 5.47 (d, J = 8.4 Hz, 1H), 5.15-5.12 (m, 1H), 4.06-3.99 (m, 1H), 3.67-3.61 (m, 1H), 3.59-3.41 (m, 4H), 3.20-3.15 (m, 2H), 2.95-2.89 (m, 4H), 2.68-2.60 (m, 2H), 2.53-2.43 (m, 2H), 2.40-2.33 (m, 4H), 2.30-2.26 (m, 2H), 2.17 (s, 3H), 2.15-2.07 (m, 2H), 1.98-1.86 (m, 4H), 1.70 (s, 2H), 1.59- 1.53 (m, 1H), 1.40-1.24 (m, 2H) ppm. N-[5-[2-[4-[4-[(2,4-dioxohexahydropyrimidin-1-yl)methyl]phenyl]-1-piperidyl]ethyl- methyl-amino]pentyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (Compound 193)

Compound 193 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 756.4 [M + H] ⁺. N-[5-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethyl- methyl-amino]pentyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (Compound 194)

Compound 194 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 811.4 [M + H] ⁺. N-[5-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]ethyl-methyl- amino]pentyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (Compound 195)

Compound 195 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 757.3 [M + H] ⁺. N-[5-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]ethyl-methyl- amino]pentyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (Compound 196)

Compound 196 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 756.3 [M + H] ⁺. N-[5-[2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]ethyl-methyl-amino]pentyl]-5-[rac- (2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 197)

Compound 197 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 741.3 [M + H] ⁺. N-[8-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]octyl]-5- [rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 198)

Compound 198 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 796.3 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.09 (s, 1H), 8.81 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 8.16 (s, 1H), 7.32-7.27 (m, 2H), 7.16-7.00 (m, 4H), 6.91 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 5.47 (d, J = 8.0 Hz, 1H), 5.34 (td, J = 12.6, 5.6 Hz, 1H), 4.05-4.01 (m, 1H), 3.69-3.61 (m, 1H), 3.20- 3.15 (m, 3H), 2.98-2.86 (m, 2H), 2.75-2.65 (m, 4H), 2.60-2.51 (m, 2H), 2.34 (br s, 2H), 2.19-2.01 (m, 5H), 2.00-1.78 (m, 4H), 1.49 (br s, 4H), 1.29 (br s, 10H) ppm. N-[8-[4-[4-[(2,4-dioxohexahydropyrimidin-1-yl)methyl]phenyl]-1-piperidyl]octyl]-5-[rac- (2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 199)

Compound 199 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 741.3 [M + H] ⁺. N-[8-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]octyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 200)

Compound 200 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 726.3 [M + H] ⁺. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]octyl]-N-methyl-5-[rac-(2R)- 2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 201)

Compound 201 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 755.4 [M + H] ⁺. 5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[8-[4-[4-[[rac-(3S)-2,6-dioxo-3- piperidyl]amino]phenyl]-1-piperidyl]octyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 202)

Compound 202 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 741.3 [M + H] ⁺. 5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[8-[4-[4-[[rac-(3R)-2,6-dioxo-3- piperidyl]amino]phenyl]-1-piperidyl]octyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 203)

Compound 203 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 741.8 [M + H] ⁺. N-[12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]dodecyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 204)

Compound 204 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 797.3 [M + H] ⁺. N-[8-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]octyl]-5- [rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 205)

Compound 205 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 781.3 [M + H] ⁺. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]octyl]-5-[rac-(2R)-2- (2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 206)

Compound 206 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 759.2 [M + H] ⁺. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-3,3-difluoro-1-piperidyl]octyl]-5-[rac- (2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 207)

Compound 207 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 777.2 [M + H] ⁺. N-[8-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]azetidin-1-yl]octyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 208)

Compound 208 was prepared substantially following the synthesis of Compound 186. LC-MS (ES⁺): m/z 713.3 [M + H] ⁺. Example 112 Synthesis of (R)-8-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamido)octanoic acid

Step-1: To a solution of 8-aminooctanoic acid (1, 500 mg, 3.14 mmol) in methanol (20 mL), cooled 0 °C, was added thionyl chloride (557.60 mg, 4.69 mmol, 0.34 mL). The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was triturated with diethyl ether, filtered and dried under vacuum to give methyl 8-aminooctanoate hydrochloride (2, 350 mg, 1.30 mmol, 41% yield) as an off-white solid. LC-MS (ES⁺): m/z 174.1 [M + H] ⁺. Step-2: To a solution of 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carboxylic acid (3, 300 mg, 787.86 µmol) and methyl 8-aminooctanoate hydrochloride (2, 193.95 mg, 787.86 µmol) in N,N-dimethylformamide (4 mL), were added DIPEA (509.13 mg, 3.94 mmol, 686.16 µL) and HATU (359.48 mg, 945.44 µmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was treated with water (5 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organics were washed with water (10 mL), brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 85-100% ethyl acetate in petroleum ether to give methyl 8-[[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carbonyl]amino]octanoate (4, 250 mg, 360.92 µmol, 46% yield) as a colorless semi-solid. LC-MS (ES⁺): m/z 500.2 [M + H] ⁺. Step-3: To a solution of methyl 8-[[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carbonyl]amino]octanoate (4, 210 mg, 420.38 µmol) in tetrahydrofuran (4 mL) and water (2 mL), was added lithium hydroxide monohydrate (70.56 mg, 1.68 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to give the suspension. The crude mixture was acidified to pH 3-4 using 1.5N aqueous HCl solution and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine solution (10 ml) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 8-[[5-[(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]octanoic acid (5, 151 mg, 276.86 µmol, 66% yield) as an off-white solid. LC-MS (ES⁺): m/z 486.0 [M + H] ⁺. Example 113 Synthesis of 5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(8-(4-(1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-8- oxooctyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 209)

To a solution of 8-[[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carbonyl]amino]octanoic acid (1, 40 mg, 82.39 µmol) and 3-[3-methyl-2-oxo-5-(4- piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (2, 31.21 mg, 82.39 µmol, 021) in N,N- dimethylformamide (1 mL), cooled to -5 °C, was added DIPEA (53.24 mg, 411.93 µmol, 71.75 µL) and HATU (37.59 mg, 98.86 µmol). The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was treated with water (1 mL), the precipitated solid was filtered and dried under vacuum to give the crude product. The crude product was purified by preparative HPLC [Column: X SELECT C18 (19 x 150) mm, 5 microns; Mobile phase A: 0.1% Formic acid in water, Mobile phase B: Acetonitrile; Wavelength: 215 nm] and the fractions containing the compound was lyophilized to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[8-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-8-oxo-octyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide formate (Compound 209, 18.10 mg, 20.51 µmol, 25% yield) as an off-white solid. LC-MS (ES⁺): m/z 810.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 11.10 (s, 1H), 8.80 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.34-7.27 (m, 2H), 7.25-7.14 (m, 2H), 7.12-7.00 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 5.46 (d, J = 7.6 Hz, 1H), 5.34 (td, J = 12.6, 5.6 Hz, 1H), 4.57-4.51 (m, 1H), 4.02-3.96 (m, 2H), 3.66-3.56 (m, 1H), 3.34-3.45 (m, 5H), 3.23- 3.11 (m, 1H), 3.08-2.90 (m, 1H), 2.78-2.68 (m, 2H), 2.64-2.56 (m, 2H), 2.53-2.50 (m, 2H), 2.34 (t, J = 7.2 Hz, 2H), 2.08-2.01 (m, 4H), 1.99-1.97 (m, 2H), 1.77-1.52 (m, 5H), 1.32-1.21 (m, 6H) ppm. Example 114 N-[8-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]-8-oxo-octyl]-5-[rac-(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 210)

Compound 210 was prepared substantially following the synthesis of Compound 209. LC-MS (ES⁺): m/z 739.8 [M + H] ⁺.

N-[8-[4-[4-[(2,4-dioxohexahydropyrimidin-1-yl)methyl]phenyl]-1-piperidyl]-8-oxo-octyl]-5- [rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 211)

Compound 211 was prepared substantially following the synthesis of Compound 209. LC-MS (ES⁺): m/z 755.3 [M + H] ⁺. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)carbamoyl]phenyl]-1-piperidyl]-8-oxo-octyl]-5-[rac-(2R)- 2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 212)

Compound 212 was prepared substantially following the synthesis of Compound 209. LC-MS (ES⁺): m/z 783.3 [M + H] ⁺. N-[8-[4-[4-[2-[(2,6-dioxo-3-piperidyl)amino]-2-oxo-ethyl]phenyl]-1-piperidyl]-8-oxo-octyl]- 5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide (Compound 213)

Compound 213 was prepared substantially following the synthesis of Compound 209. LC-MS (ES-): m/z 795.3 [M - H] -. N-[8-[4-[4-[2-[(2,6-dioxo-3-piperidyl)oxy]ethyl]phenyl]-1-piperidyl]-8-oxo-octyl]-5-[rac- (2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 214)

Compound 214 was prepared substantially following the synthesis of Compound 209. LC-MS (ES⁺): m/z 784.4 [M + H] ⁺. Example 115 Synthesis of 5-[(2,5-difluorophenyl)methylamino]-N-[8-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]octyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 215)

To a solution of 3-[4-[1-(8-aminooctyl)-4-piperidyl]anilino]piperidine-2,6-dione (1, 50 mg, 120.60 µmol) in tetrahydrofuran (0.8 mL) and N,N-dimethylformamide (0.2 mL), was added DIPEA (77.93 mg, 603.02 µmol, 105.03 µL) and 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (2, 26.05 mg, 120.60 µmol). The resulting mixture was stirred at room temperature for 15 h. After consumption of starting materials (as indicated by UPLC), (2,5- difluorophenyl)methanamine (25.89 mg, 180.90 µmol, 21.22 µL) was added and the contents were heated at 100 °C for 1 h. The reaction mixture was cooled to room temperature, the crude reaction mass was directly loaded onto reverse phase C18 column [30 g ISCO C18 column; Mobile-phase A: 0.1% TFA in water, Mobile phase B: Acetonitrile] and the fractions containing the compound were lyophilized to give 5-[(2,5-difluorophenyl)methylamino]-N-[8-[4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]octyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate (Compound 215, 16 mg, 19.56 µmol, 16% yield) as an off-white solid. LC-MS (ES⁺): m/z 701.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.80 (s, 1H), 9.10 (br s, 1H), 8.63 (d, J = 7.6 Hz, 2H), 8.09 (s, 1H), 7.68 (t, J = 5.2 Hz, 1H), 7.34-7.30 (m, 1H), 7.29-7.21 (m, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 6.49 (d, J = 7.6 Hz, 1H), 4.65 (d, J = 5.6 Hz, 2H), 4.31-4.27 (m, 1H), 3.55-3.43 (m, 2H), 3.27-3.22 (m, 3H), 3.04-2.97 (m, 4H), 2.68-2.60 (m, 3H), 2.10-2.07 (m, 1H), 1.96-1.83 (m, 5H), 1.63 (br s, 2H), 1.41 (br s, 2H), 1.23 (s, 8H) ppm. Example 116 5-[1-(2,5-difluorophenyl)ethylamino]-N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]octyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate (Compound 216)

Compound 216 was prepared substantially similar to the synthesis of Compound 215 except replacing (2,5-difluorophenyl)methanamine with 1-(2,5-difluorophenyl)ethan-1-amine. LC-MS (ES⁺): m/z 715.4 [M + H] ⁺. Example 117 Synthesis of 3-[4-[1-[10-[5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidin-3-yl]dec-9-ynyl]-4-piperidyl]anilino]piperidine-2,6-dione formate (Compound 217)

Step-1: To a solution of 5-chloro-3-iodo-pyrazolo[1,5-a]pyrimidine (1.00 g, 3.58 mmol) and (2R)-2-(2,5- difluorophenyl)pyrrolidine (1, 655.53 mg, 3.58 mmol) in n-butanol (10 mL), was added DIPEA (1.39 g, 10.73 mmol, 1.87 mL). The resulting mixture was heated at 110 °C for 2 h. The reaction mixture was cooled to room temperature, treated with cold water (10 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with brine solution (30 ml) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-50% ethyl acetate in petroleum ether to give 5-[(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]-3-iodo-pyrazolo[1,5-a]pyrimidine (2, 300 mg, 632.73 µmol, 18% yield) as a brown solid. LC-MS (ES⁺): m/z 427.0 [M + H] ⁺. Step-2: To a solution of 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-3-iodo-pyrazolo[1,5-a]pyrimidine (2, 300.00 mg, 703.89 µmol) in N,N-dimethylformamide (4 mL), was added triethylamine (356.13 mg, 3.52 mmol, 490.54 µL) and the contents were degassed in an atmosphere of nitrogen gas for 5 min. To this mixture, were added bis(triphenylphosphine)palladium(II) chloride (49.41 mg, 70.39 µmol), copper(I) iodide (13.41 mg, 70.39 µmol, 2.39 µL) and dec-9-yn-1-ol (3, 325.72 mg, 2.11 mmol). The resulting mixture was stirred at 45 °C for 16 h. The reaction mixture was treated with cold water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organics were washed with brine solution (15 ml) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 50-70 % ethyl acetate in petroleum ether to give 10-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidin-3-yl]dec-9-yn-1-ol (4, 130 mg, 201.12 µmol, 29% yield) as a brown solid. LC-MS (ES⁺): m/z 453.2 [M + H] ⁺. Step-3: To a solution of 10-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3- yl]dec-9-yn-1-ol (4, 130 mg, 287.27 µmol) in dichloromethane (5 mL), was added Dess-Martin periodinane (134.03 mg, 316.00 µmol). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with diethyl ether (15 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 45-55% ethyl acetate in petroleum ether to give 10-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidin-3-yl]dec-9-ynal (5, 100 mg, 119.86 µmol, 42% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 451.2 [M + H] ⁺. Step-4: To a solution of 10-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3- yl]dec-9-ynal (5, 55 mg, 122.08 µmol) in N,N-dimethylformamide (2.5 mL), were added 3-[4-(4- piperidyl)anilino]piperidine-2,6-dione hydrochloride (35.08 mg, 108.33 µmol), sodium triacetoxyborohydride (110.00 mg, 519.01 µmol) and acetic acid (146.62 ug, 2.44 µmol, 0.14 µL). The resulting mixture was stirred at room temperature for 1 h. The crude mixture was directly loaded onto reverse phase C18 column [Column: ISCO C18 (30 g) column, Mobile phase A: 0.1% HCOOH in water, Mobile phase B: Acetonitrile] and the fractions containing the compound was lyophilized to give the product with 85% purity. This was purified again using mass-based preparative HPLC [Column: X bridge C18 (19 x 150 mm), 5 micron; Mobile phase A: 0.1% HCOOH in water, Mobile phase B: Acetonitrile, Wavelength: 215 nm] and the fractions containing the product was lyophilized to give 3-[4-[1-[10-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1- yl]pyrazolo[1,5-a]pyrimidin-3-yl]dec-9-ynyl]-4-piperidyl]anilino]piperidine-2,6-dione formate (Compound 217, 5 mg, 6.20 µmol, 5% yield) as an off-white solid. LC-MS (ES⁺): m/z 722.4 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆, 353.3 K): δ 10.78 (s, 1H), 8.50 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 7.83 (s, 1H), 7.24-7.18 (m, 1H), 7.11-7.07 (m, 1H), 6.94 (d, J = 6.4 Hz, 3H), 6.64 (d, J = 8.4 Hz, 2H), 6.27 (d, J = 4.0 Hz, 1H), 5.41 (d, J = 7.2 Hz, 1H), 4.26-4.18 (m, 1H), 3.99-3.93 (m, 1H), 3.75-3.66 (m, 1H), 2.92 (d, J = 11.2 Hz, 2H), 2.74-2.64 (m, 2H), 2.41-2.38 (m, 2H), 2.32- 2.30 (m, 4H), 2.17-2.11 (m, 1H), 2.06-1.90 (m, 6H), 1.70-1.67 (m, 2H), 1.60-1.51 (m, 4H), 1.46 (s, 4H), 1.35 (s, 6H) ppm. Example 118 Synthesis of 3-[4-[1-[10-[5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidin-3-yl]decyl]-4-piperidyl]anilino]piperidine-2,6-dione formate (Compound 218)

Step-1: To a solution of 10-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3- yl]dec-9-yn-1-ol (1, 100 mg, 220.98 µmol) in methanol (0.6 mL), was added palladium on carbon (10% dry loading, 5 mg). The contents were stirred under hydrogen pressure at room temperature for 3 h. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 50-60% ethyl acetate in petroleum ether to give 10-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]decan-1-ol (2, 85 mg, 124.73 µmol, 56% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 457.2 [M + H] ⁺. Step-2: To a solution of 10-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3- yl]decan-1-ol (2, 85 mg, 186.17 µmol) in dichloromethane (3 mL) was added Dess-Martin periodinane (86.86 mg, 204.79 µmol). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with diethyl ether (10 mL), the precipitated solid was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the crude product which was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 60-70% ethyl acetate in petroleum ether to give 10-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1- yl]pyrazolo[1,5-a]pyrimidin-3-yl]decanal (3, 50 mg, 79.20 µmol, 43% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 455.2 [M + H] ⁺. Step-3: To a solution of 10-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3- yl]decanal (3, 50 mg, 109.51 µmol) in N,N-dimethylformamide (2.5 mL), were added 3-[4-(4- piperidyl)anilino]piperidine-2,6-dione hydrochloride (4, 31.47 mg, 97.18 µmol), sodium triacetoxyborohydride (98.68 mg, 465.58 µmol) and acetic acid (131.52 ug, 2.19 µmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was treated with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organics were washed with brine solution (5 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by mass-directed preparative HPLC [Column: X bridge C18 (19 x 150 mm), 5 micron; Mobile phase A: 0.1% HCOOH in water, Mobile phase B: Acetonitrile; Wavelength: 215 nm] and the fractions containing the product was lyophilized to give 3-[4-[1-[10-[5-[(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]decyl]-4- piperidyl]anilino]piperidine-2,6-dione formate (Compound 218, 7.5 mg, 9.28 µmol, 8% yield) as an off-white solid. LC-MS (ES⁺): m/z 726.4 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆, 353.2 K): δ 10.75 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.22 (s, 1H), 7.63 (s, 1H), 7.23-7.17 (m, 1H), 7.07-7.02 (m, 1H), 6.97-6.89 (m, 3H), 6.64 (d, J = 8.0 Hz, 2H), 6.25 (d, J = 7.6 Hz, 1H), 5.41 (d, J = 6.0 Hz, 1H), 5.38-5.35 (m, 1H), 4.25-4.19 (m, 1H), 3.93-3.88 (m, 1H), 3.69-3.61 (m, 1H), 2.93 (d, J = 10.4 Hz, 2H), 2.68-2.51 (m, 3H), 2.48-2.41 (m, 4H), 2.39-2.28 (m, 4H), 2.15-2.06 (m, 1H), 2.03-1.89 (m, 4H), 1.72-1.69 (m, 2H), 1.60-1.56 (m, 2H), 1.48-1.43 (m, 4H), 1.30-1.21 (m, 12H) ppm. Example 119 Synthesis of 3-[4-[1-[10-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidin-3-yl]-10-oxo-decyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 219)

To a solution of 10-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3- yl]dec-9-ynal (1, 100 mg, 221.96 µmol) in N,N-dimethylformamide (2.5 mL), were added 3-[4- (4-piperidyl)anilino]piperidine-2,6-dione hydrochloride (2, 63.78 mg, 196.97 µmol), sodium triacetoxyborohydride (200.00 mg, 943.66 µmol) and acetic acid (266.59 ug, 4.44 µmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was treated with water (5 mL) and extracted with ethyl acetate (2x 10 mL). The combined organics were washed with brine solution (5 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by mass-directed preparative HPLC [Column: X SELECT C18 (19 x 150 mm), 5 micron; Mobile phase A: 0.1% HCOOH in water, Mobile phase B: Acetonitrile; Wavelength: 215 nm] and the fractions containing the product was lyophilized to give 3-[4-[1-[10-[5-[(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-10-oxo-decyl]-4- piperidyl]anilino]piperidine-2,6-dione formate (Compound 219, 17 mg, 21.37 µmol, 10% yield) as an off-white solid. LC-MS (ES⁺): m/z 740.3 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.79 (s, 1H), 8.80 (d, J = 7.6 Hz, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.24-7.21 (m, 1H), 7.12-7.02 (m, 1H), 6.94 (d, J = 8.0 Hz, 3H), 6.69 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.4 Hz, 2H), 5.66 (d, J = 7.6 Hz, 1H), 5.04-4.99 (m, 1H), 4.30-4.21 (m, 1H), 4.03-3.98 (m, 2H), 3.67-3.60 (m, 2H), 2.99-2.96 (m, 2H), 2.68-2.50 (m, 2H), 2.46-2.40 (m, 2H), 2.31 (s, 3H), 2.11-1.98 (m, 4H), 1.90-1.85 (m, 2H), 1.69-1.66 (m, 2H), 1.59-1.56 (m, 2H), 1.44 (s, 2H), 1.37-1.34 (m, 2H), 1.25 (s, 5H), 1.19-1.14 (m, 5H) ppm. Example 120 Synthesis of N-[3-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo- ethyl]phenyl]propyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (Compound 220)

Step-1: To a solution of methyl 2-(4-formylphenyl)acetate (1, 1.5 g, 8.42 mmol) in toluene (20 mL), was added 2-(triphenyl-$l^{5}-phosphanylidene)acetonitrile (2, 3.30 g, 10.94 mmol). The resulting mixture was heated at 110 °C for 16 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 25-35% ethyl acetate in petroleum ether to give methyl 2-[4-[(E)-2- cyanovinyl]phenyl]acetate (3, 1.3 g, 5.73 mmol, 68% yield) as an off-white solid. LC-MS (ES-): m/z 199.9 [M - H] -. Step-2: To a solution of methyl 2-[4-[(E)-2-cyanovinyl]phenyl]acetate (3, 1 g, 4.97 mmol) in methanol (40 mL), were added 12N aqueous HCl (2 mL) and palladium on carbon (10% dry loading, 500.00 mg). The contents were stirred under hydrogen atmosphere (75 psi) at room temperature for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure and dried under vacuum to give methyl 2-[4-(3-aminopropyl)phenyl]acetate hydrochloride (4, 900 mg, 3.21 mmol, 65% yield) as an off-white solid. LC-MS (ES⁺): m/z 207.9 [M + H] ⁺. Step-3: To a solution of methyl 2-[4-(3-aminopropyl)phenyl]acetate hydrochloride (4, 233.36 mg, 871.30 µmol) and 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5, 300 mg, 871.30 µmol) in N,N-dimethylformamide (5 mL), were added DIPEA (337.82 mg, 2.61 mmol, 455.28 µL) and PyBOP (544.10 mg, 1.05 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give methyl 2-[4-[3-[[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carbonyl]amino]propyl]phenyl]acetate (6, 400 mg, 654.31 µmol, 75% yield) as an off-white solid. LC-MS (ES⁺): m/z 533.8 [M + H] ⁺. Step-4: To a solution of methyl 2-[4-[3-[[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carbonyl]amino]propyl]phenyl]acetate (6, 70 mg, 131.19 µmol) in methanol (3 mL) and water (3 mL), was added lithium hydroxide monohydrate (27.53 mg, 655.96 µmol). The resulting mixture was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure and the residue was acidified with 1.5N aqueous HCl solution. The precipitated solid was filtered and dried under vacuum to give 2-[4-[3-[[5-[(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carbonyl]amino]propyl]phenyl]acetic acid hydrochloride (7, 55 mg, 89.38 µmol, 68% yield) as an off-white solid. LC-MS (ES⁺): m/z 474.0 [M + H] ⁺. Step-5: To a solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (8, 27.65 mg, 96.24 µmol) and 2- [4-[3-[[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3- carbonyl]amino]propyl]phenyl]acetic acid hydrochloride (7, 50 mg, 96.24 µmol) in N,N- dimethylformamide (2 mL), cooled to 0 °C, were added DIPEA (62.19 mg, 481.19 µmol, 83.81 µL) and PyBOP (60.10 mg, 115.49 µmol). The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was treated with cold water (20 mL) and stirred for 10 min. The precipitated solid was filtered, washed with water and dried under vacuum to give 5-[(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]-N-[3-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]-2-oxo-ethyl]phenyl]propyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 220, 43 mg, 50.26 µmol, 52% yield) as an off-white solid. LC-MS (ES⁺): m/z 788.8 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 1H), 8.80 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.26-7.15 (m, 6H), 7.04-6.99 (m, 3H), 6.88 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.4 Hz, 2H), 5.65 (d, J = 7.2 Hz, 1H), 5.43 (br s, 1H), 4.54-4.49 (m, 1H), 4.26 (br s, 1H), 4.02 (br s, 2H), 3.71-3.64 (m, 3H), 3.04-2.90 (m, 3H), 2.74-2.69 (m, 2H), 2.09-1.83 (m, 4H), 1.76-1.72 (m, 3H), 1.68-1.56 (m, 4H), 1.33-1.24 (m, 5H) ppm. Example 121 Synthesis of N-[3-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]ethyl]phenyl]propyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide formate (Compound 221)

Step-1: To a solution of methyl (R)-2-(4-(3-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamido)propyl)phenyl)acetate (1, 330 mg, 618.48 µmol) in toluene (5 mL) and Tetrahydrofuran (5 mL), cooled to -78 °C, was added diisobutylaluminium hydride (1.0 M in toluene, 3.09 mL). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was cooled to -20 °C and treated with wet silica gel. The reaction mixture was filtered, washed with ethyl acetate and the filtrate was dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 5-[(2R)-2-(2,5- difluorophenyl)pyrrolidin-1-yl]-N-[3-[4-(2-hydroxyethyl)phenyl]propyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (2, 250 mg, 401.44 µmol, 65% yield) as a pale yellow liquid. LC- MS (ES⁺): m/z 506.2 [M + H] ⁺. Step-2: To a solution of 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[3-[4-(2- hydroxyethyl)phenyl]propyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (2, 100 mg, 197.80 µmol) in dichloromethane (5 mL), cooled to 0 °C, was added phosphorus tribromide (80.31 mg, 296.70 µmol, 27.89 µL). The resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the obtained residue was treated with cold water (5 mL). The precipitated solid was filtered and dried under vacuum to give N-[3-[4-(2- bromoethyl)phenyl]propyl]-5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (3, 70 mg, 104.37 µmol, 53% yield) as an off-white solid. LC-MS (ES⁺): m/z 570.2 [M + H] ⁺. Step-3: To a solution of N-[3-[4-(2-bromoethyl)phenyl]propyl]-5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin- 1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (3, 60.56 mg, 106.54 µmol) in acetonitrile (2.0 mL) and N,N-dimethylformamide (0.5 mL), were added 3-[4-(4-piperidyl)anilino]piperidine-2,6- dione hydrochloride (4, 30 mg, 92.64 µmol) and DIPEA (28.12 mg, 217.61 µmol, 37.90 µL). The resulting mixture was heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase C18 column [Column: ISCO C18 (30 g); Mobile phase A: 0.1% HCOOH in water, Mobile phase B: Acetonitrile] and the fractions containing the product was lyophilized to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[3-[4-[2-[4-[4-[(2,6-dioxo- 3-piperidyl)amino]phenyl]-1-piperidyl]ethyl]phenyl]propyl]pyrazolo[1,5-a]pyrimidine-3- carboxamide formate (Compound 221, 20 mg, 23.09 µmol, 25% yield) as an off-white solid. LC- MS (ES⁺): m/z 775.3 [M + H) ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H), 8.79 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 7.25-7.11 (m, 6H), 7.09-6.95 (m, 3H), 6.93 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 8.4 Hz, 2H), 4.29-4.23 (m, 1H), 4.05-3.93 (m, 1H), 3.65-3.61 (m, 2H), 3.17-3.09 (m, 3H), 3.07-2.99 (m, 2H), 2.77-2.60 (m, 3H), 2.56-2.50 (m, 2H), 2.38-2.28 (m, 1H), 2.16-2.01 (m, 4H), 1.91-1.84 (m, 4H), 1.72-1.63 (m, 2H), 1.61-1.51 (m, 5H) ppm. Example 122 Synthesis of ethyl 3-(4-(cyanomethyl)phenyl)acrylate

Step -1: To a solution of 2-(4-bromophenyl)acetonitrile (1, 4.0 g, 20.40 mmol, 2.68 mL) in triethylamine (71.15 g, 703.11 mmol, 98 mL), were added ethyl prop-2-enoate (2, 3.27 g, 32.65 mmol, 3.54 mL), palladium(II) acetate (45.81 mg, 204.04 µmol) and tri(o-tolyl)phosphine (248.41 mg, 816.14 µmol). The resulting mixture was heated at 110 °C for 20 h. The reaction mixture was cooled to room temperature and treated with ice. The crude mixture was acidified with 10% aqueous HCl solution (250 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organics were washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 20-30% ethyl acetate in petroleum ether) to give ethyl (E)-3-[4-(cyanomethyl)phenyl]prop-2-enoate (3, 3.85 g, 17.53 mmol, 86% yield) as a pale yellow solid. LC-MS (ES-): m/z 214.9 [M - H] -. Example 123 N-[2-[4-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-3-oxo- propyl]phenyl]ethyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide (Compound 222)

Compound 222 was prepared substantially following the synthesis of Compound 221, except using ethyl 3-(4-(cyanomethyl)phenyl)acrylate LC-MS (ES⁺): m/z 789.4 [M + H] ⁺. N-[2-[4-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]propyl]phenyl]ethyl]-5- [rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 223)

Compound 223 was prepared substantially following the synthesis of Compound 221. LC-MS (ES⁺): m/z 775.3 [M + H] ⁺. Example 124 Synthesis of N-[3-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]methyl]phenyl]propyl]-5-[rac-(2R)-2-(2,5-difluorophenyl)pyrrolidin-1- yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 224)

Step-1: To a solution of [4-(hydroxymethyl)phenyl]boronic acid (1, 3 g, 19.74 mmol) and tert-butyl N- allylcarbamate (2, 6.21 g, 39.49 mmol) in acetone (30 mL), were added silver(I) acetate (6.59 g, 39.49 mmol) and potassium bifluoride (1.54 g, 19.74 mmol). The contents were degassed in an atmosphere of nitrogen for 5 min. To this mixture, was added palladium(II) acetate (443.24 mg, 1.97 mmol). The contents were heated at 80 °C for 8 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 25-35% ethyl acetate in petroleum ether to give tert-butyl N-[(E)-3-[4- (hydroxymethyl)phenyl]allyl]carbamate (3, 1.9 g, 6.57 mmol, 33% yield) as an off-white solid. LC-MS (ES⁺): m/z 208.1 [M - Isobutene + H] ⁺. Step-2: To a solution of tert-butyl N-[(E)-3-[4-(hydroxymethyl)phenyl]allyl]carbamate (3, 900 mg, 3.42 mmol) in dichloromethane (15 mL), were added tetrabromomethane (1.13 g, 3.42 mmol) and triphenylphosphine (896.43 mg, 3.42 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) with 5-10% ethyl acetate in petroleum ether to give tert-butyl N-[(E)-3-[4- (bromomethyl)phenyl]allyl]carbamate (4, 400 mg, 1.12 mmol, 33% yield) as an off-white solid. LC-MS (ES⁺): m/z 269.9 [M - Isobutene + H] ⁺. Step-3: To a solution of tert-butyl N-[(E)-3-[4-(bromomethyl)phenyl]allyl]carbamate (4, 219.43 mg, 672.64 µmol) and 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione hydrochloride (5, 217.81 mg, 672.64 µmol) in N,N-dimethylformamide (6 mL), was added DIPEA (260.80 mg, 2.02 mmol, 351.49 µL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was treated with water, the precipitated solid was filtered and dried to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 60- 70% ethyl acetate in petroleum ether to give tert-butyl N-[(E)-3-[4-[[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]methyl]phenyl]allyl]carbamate (6, 110 mg, 193.29 µmol, 29% yield) as an off-yellow solid. LC-MS (ES⁺): m/z 533.2 [M + H] ⁺. Step-4: To a solution of tert-butyl N-[(E)-3-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]methyl]phenyl]allyl]carbamate (6, 75 mg, 140.80 µmol) in dioxane (8 mL), was added palladium hydroxide on carbon (30 mg). The contents were stirred under hydrogen pressure (~14 psi) at room temperature for 1 h. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated under reduced pressure to give tert-butyl N-[3-[4-[[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]methyl]phenyl]propyl]carbamate (7, 80 mg, 130.47 µmol, 93% yield) as a green gum. LC-MS (ES⁺): m/z 535.3 [M + H] ⁺. Step-5: To a solution of tert-butyl N-[3-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]methyl]phenyl]propyl]carbamate (7, 80 mg, 149.62 µmol) in dichloromethane (2 mL), cooled to 0 °C, was added HCl in dioxane (4M, 3 mL) drop-wise. The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated, co- distilled with toluene, the residue was triturated with diethyl ether to give 3-[4-[1-[[4-(3- aminopropyl)phenyl]methyl]-4-piperidyl]anilino]piperidine-2,6-dione hydrochloride (8, 70 mg, 117.40 µmol, 78% yield) as a green gum. LC-MS (ES⁺): m/z 435.0 [M + H] ⁺. Step-6: To a solution of 3-[4-[1-[[4-(3-aminopropyl)phenyl]methyl]-4-piperidyl]anilino]piperidine-2,6- dione hydrochloride (8, 55.22 mg, 127.07 µmol) and 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1- yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (9, 35 mg, 101.65 µmol) in N,N- dimethylformamide (2 mL), cooled to 0 °C, were added DIPEA (49.27 mg, 381.19 µmol, 66.40 µL) and PyBOP (79.35 mg, 152.48 µmol). The resulting mixture was stirred at 0 °C for 10 min. The reaction mixture was treated with water (5 mL), the precipitated solid was filtered and dried to give the crude product. The crude product was purified by reverse phase C18 column [ISCO C1830 g column; Mobile phase A: 0.1% HCOOH in water, Mobile phase B: Acetonitrile] and the fractions containing the product was lyophilized to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin- 1-yl]-N-[3-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]methyl]phenyl]propyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 224, 25 mg, 31.87 µmol, 25% yield) as an off-white solid. LC-MS (ES⁺): m/z 761.3 [M + H] ⁺. Example 125 Synthesis of 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[4-[3-[[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]methyl]phenyl]butyl]pyrazolo[1,5-a]pyrimidine-3- carboxamide (Compound 225)

Step-1: To a solution of [3-(hydroxymethyl)phenyl]boronic acid (2, 200 mg, 1.32 mmol) and tert-butyl N- but-3-enylcarbamate (1, 450.75 mg, 2.63 mmol) in acetone (2.0 mL), were added silver acetate (439.37 mg, 2.63 mmol), potassium bifluoride (77.79 mg, 1.32 mmol) and palladium (II) acetate (29.55 mg, 131.62 µmol). The resulting mixture was heated at 60 °C for 8 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was treated with water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organics were washed with brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 40-50% ethyl acetate in petroleum ether to give tert-butyl N-[(E)-4-[3-(hydroxymethyl)phenyl]but-3-enyl]carbamate (3, 260 mg, 917.73 µmol, 70% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 178.2 [M - COOtBu + H] ⁺. Step-2: To a solution of tert-butyl N-[(E)-4-[3-(hydroxymethyl)phenyl]but-3-enyl]carbamate (3, 260 mg, 937.42 µmol) in dichloromethane (5 mL), were added triphenylphosphine (491.74 mg, 1.87 mmol) and tetrabromomethane (621.75 mg, 1.87 mmol, 181.80 µL). The resulting mixture was stirred at room temperature for 7 h. The reaction mixture was treated with water (5 mL) and extracted with dichloromethane (2 x 10 mL). The combined organics were washed with brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 15-20% ethyl acetate in petroleum ether) to give tert-butyl N-[(E)- 4-[3-(bromomethyl)phenyl]but-3-enyl]carbamate (4, 70 mg, 194.29 µmol, 21% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 240.1 [M - COOtBu + H] ⁺. Step-3: To a solution of tert-butyl N-[(E)-4-[3-(bromomethyl)phenyl]but-3-enyl]carbamate (4, 70 mg, 205.73 µmol) and 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione hydrochloride (5, 73.28 mg, 226.30 µmol) in N,N-dimethylformamide (2 mL), was added DIPEA (79.77 mg, 617.19 µmol, 107.50 µL). The resulting mixture was stirred at room temperature for 6 h. The reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organics were washed with brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 15-20 % methanol in ethyl acetate) to give tert-butyl N-[(E)-4-[3-[[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]methyl]phenyl]but-3-enyl]carbamate (6, 70 mg, 121.46 µmol, 59% yield) as an off-white solid. LC-MS (ES⁺): m/z 547.3 [M + H] ⁺. Step-4: To a solution of tert-butyl N-[(E)-4-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]methyl]phenyl]but-3-enyl]carbamate (6, 70 mg, 128.04 µmol) in 1,4-dioxane (1 mL), was added palladium hydroxide on carbon (5 mg). The contents were stirred under hydrogen pressure (~14 psi) at room temperature for 1 h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure and dried under vacuum to give tert-butyl N-[4-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]- 1-piperidyl]methyl]phenyl]butyl]carbamate (7, 70 mg, 95.68 µmol, 75% yield) as a pale yellow gum. LC-MS (ES⁺): m/z 549.3 [M + H] ⁺. Step-5: To a solution of tert-butyl N-[4-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]methyl]phenyl]butyl]carbamate (7, 70 mg, 127.57 µmol) in dichloromethane (2 mL), cooled 0 °C, was added HCl in 1,4-dioxane (4M, 3 mL). The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether (5 mL). The solid was filtered and dried under vacuum to give 3-[4-[1-[[3-(4-aminobutyl)phenyl]methyl]-4-piperidyl]anilino]piperidine- 2,6-dione hydrochloride (8, 60 mg, 105.14 µmol, 82% yield) as an off-white solid. LC-MS (ES⁺): m/z 449.2 [M + H] ⁺. Step-6: To a solution of 3-[4-[1-[[3-(4-aminobutyl)phenyl]methyl]-4-piperidyl]anilino]piperidine-2,6- dione hydrochloride (8, 60 mg, 123.70 µmol) and 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1- yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (9, 42.59 mg, 123.70 µmol) in N,N- dimethylformamide (2 mL), cooled to 0 °C, were added DIPEA (63.95 mg, 494.78 µmol, 86.18 µL) and HATU (56.44 mg, 148.44 µmol). The resulting mixture was stirred at 0 °C for 10 min. The reaction mixture was treated with water (10 mL), the precipitated solid was filtered and dried under vacuum to give the crude product. The crude product was purified by preparative HPLC [Column: X-select C18 (19 x 150 mm), 5 micron; Mobile phase A: 0.1% HCOOH in water, Mobile phase B: Acetonitrile; Wavelength: 215 nm] and the fractions containing the product was lyophilized to give 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[4-[3-[[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]methyl]phenyl]butyl]pyrazolo[1,5-a]pyrimidine-3- carboxamide formate (Compound 225, 14 mg, 16.80 µmol, 14% yield) as an off-white solid. LC- MS (ES⁺): m/z 775.4 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.27-7.20 (m, 3H), 7.15-6.99 (m, 5H), 6.92 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 7.6 Hz, 1H), 6.59 (d, J = 8.0 Hz, 2H), 5.64 (d, J = 7.2 Hz, 1H), 5.42 (d, J = 8.0 Hz, 1H), 4.29-4.21 (m, 1H), 4.03-3.97 (m, 1H), 3.66-3.60 (m, 1H), 3.48-3.32 (m, 2H), 3.20-3.15 (m, 2H), 3.04-2.97 (m, 1H), 2.86 (d, J = 10.0 Hz, 2H), 2.74-2.68 (m, 1H), 2.60-2.50 (m, 2H), 2.34- 2.28 (m, 1H), 2.12-1.93 (m, 8H), 1.60-1.33 (m, 6H), 1.31-1.24 (m, 2H) ppm. Example 126 Synthesis of (5-(methoxymethyl)-2-(trifluoromethyl)phenyl)methanamine

Step-1: To a solution of 3-bromo-4-(trifluoromethyl)benzoic acid (1, 2.0 g, 7.43 mmol) in tetrahydrofuran (20 mL), cooled to 0 °C, was added a borane in tetrahydrofuran (2 M, 64.84 mL). The resulting mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was cooled to 0 °C, was added methanol (4 mL) and 1 N HCl (4 mL). The resulting mixture was heated at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water (100 mL / 40 mL) and the organic phase was separated. The aqueous phase was extracted using ethyl acetate (2 x 30 mL), the combined organics were washed with brine solution (40 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 30% ethyl acetate in petroleum ether to give [3-bromo-4-(trifluoromethyl)phenyl]methanol (2, 1.7 g, 6.46 mmol, 87% yield) as a colorless oil.¹H NMR (400 MHz, CDCl₃): δ 7.76 (d, J = 0.4 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.43-7.29 (m, 1H), 4.78 (s, 2H) ppm. Step-2: To a solution of [3-bromo-4-(trifluoromethyl)phenyl]methanol (2, 1.50 g, 5.88 mmol) in N,N- dimethylformamide (10 mL), cooled to 0 °C, was added sodium hydride (60% dispersion in mineral oil, 450.72 mg, 11.76 mmol). The contents were stirred at room temperature for 30 min. To this mixture, was added methyl iodide (2.50 g, 17.64 mmol, 1.10 mL) and the contents were stirred at room temperature for 30 min. The reaction mixture was treated with cold water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-20% of ethyl acetate in petroleum ether to give 2-bromo-4-(methoxymethyl)-1-(trifluoromethyl)benzene (3, 1.0 g, 2.71 mmol, 46% yield) as a colorless oil. The crude product was taken to next step without purification. Step-3: To a solution of 2-bromo-4-(methoxymethyl)-1-(trifluoromethyl)benzene (3, 500 mg, 1.86 mmol) and potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (4, 660.83 mg, 2.79 mmol) in 1,4-dioxane (5 mL) and water (2 mL), was added cesium carbonate (1.82 g, 5.58 mmol). The contents were degassed in an inert atmosphere of nitrogen for 10 min. To this mixture, were added palladium(II) acetate (4.17 mg, 18.58 µmol) and di(1-adamantyl)-n-butylphosphine (33.31 mg, 92.92 µmol). The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was partitioned with ethyl acetate (50 mL) and water (20 mL) and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2 x 25 ml). The combined organics were washed with brine solution and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-30% ethyl acetate in petroleum ether to give tert-butyl N-[[5-(methoxymethyl)-2-(trifluoromethyl)phenyl]methyl]carbamate (5, 100 mg, 313.17 µmol, 17% yield) as a yellow solid.¹H-NMR (300 MHz, DMSO-d₆): δ 7.67 (d, J = 8.1 Hz, 1H), 7.52 (t, J = 4.8 Hz, 1H), 7.45 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 4.50 (s, 2H), 4.32 (d, J = 6.0 Hz, 2H), 3.40 (s, 3H), 1.42 (s, 9H) ppm. Step-4: To a solution of tert-butyl N-[[5-(methoxymethyl)-2-(trifluoromethyl)phenyl]methyl]carbamate (5, 200 mg, 626.33 µmol) in dichloromethane (4 mL), cooled to 0 °C, was added HCl in dioxane (4 M, 2 mL) drop-wise. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to give [5-(methoxymethyl)-2-(trifluoromethyl)phenyl]methanamine hydrochloride (6, 165 mg, 626.02 µmol, 99% yield) as an off-white solid. LC-MS (ES⁺): m/z 220.2 [M + H] ⁺. Example 127 Synthesis of (3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine

Step-1: To a solution of tert-butyl N-[(3S,4R)-4-phenylpyrrolidin-3-yl]carbamate (1, 400 mg, 1.52 mmol) and 1-bromo-2-methoxy-ethane (2, 211.92 mg, 1.52 mmol, 143.19 µL) in N,N-dimethylformamide (5 mL), was added DIPEA (591.16 mg, 4.57 mmol, 796.71 µL). The resulting mixture was heated at 60 °C for 4 h. The reaction mixture was treated with cold water and extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with brine solution (40 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230- 400 mesh) eluted with 0-100% of ethyl acetate in petroleum ether to give tert-butyl N-[(3S,4R)-1- (2-methoxyethyl)-4-phenyl-pyrrolidin-3-yl]carbamate (3, 250 mg, 579.00 µmol, 38% yield) as a brown gum. LC-MS (ES⁺): m/z 321.2 [M + H] ⁺. Step-2: To a solution of tert-butyl N-[(3S,4R)-1-(2-methoxyethyl)-4-phenyl-pyrrolidin-3-yl]carbamate (3, 220 mg, 686.59 µmol) in dichloromethane (5 mL), cooled to 0 °C, was added HCl in dioxane (4 M, 2 mL). The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the crude product was triturated with diethyl ether to give (3S,4R)-1-(2-methoxyethyl)-4-phenyl-pyrrolidin-3-amine hydrochloride (4, 180 mg, 672.97 µmol, 98% yield) as an off-white solid. LC-MS (ES⁺): m/z 221.1 [M + H] ⁺. Example 128 Synthesis of N-((4-hydroxypiperidin-4-yl)methyl)-1-phenyl-5-(3-(2- (trifluoromethyl)benzyl)ureido)-1H-pyrazole-3-carboxamide

Step-1: To a solution of ethyl 5-amino-1-phenyl-pyrazole-3-carboxylate (1, 700 mg, 3.03 mmol) in tetrahydrofuran (10 mL), were added sodium bicarbonate (2.54 g, 30.27 mmol) and 2,2,2- trichloroethyl chloroformate (2, 961.95 mg, 4.54 mmol, 624.65 µL). The contents were stirred at room temperature for 4 h. The reaction mixture was treated with saturated cold water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with brine solution (40 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give ethyl 1-phenyl-5-(2,2,2-trichloroethoxycarbonylamino)pyrazole-3- carboxylate (1.0 g, 2.03 mmol, 67% yield) as a brown solid. LC-MS (ES⁺): m/z 407.8 [M + H] ⁺. To a solution of ethyl 1-phenyl-5-(2,2,2-trichloroethoxycarbonylamino)pyrazole-3-carboxylate (230 mg, 565.60 µmol) in tetrahydrofuran (5 mL), were added [5-(methoxymethyl)-2- (trifluoromethyl)phenyl]methanamine (3, 123.98 mg, 565.60 µmol) and DIPEA (219.30 mg, 1.70 mmol, 295.55 µL). The resulting mixture was heated at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-80% ethyl acetate in petroleum ether to give ethyl 5-(3-(5-(methoxymethyl)-2-(trifluoromethyl)benzyl)ureido)-1-phenyl-1H- pyrazole-3-carboxylate (4, 200 mg, 408.44 µmol, 72% yield) as a yellow solid. LC-MS (ES⁺): m/z 477.2 [M + H] ⁺. Step-2: To a solution of ethyl 5-(3-(5-(methoxymethyl)-2-(trifluoromethyl)benzyl)ureido)-1-phenyl-1H- pyrazole-3-carboxylate (4, 200 mg, 419.77 µmol) in ethanol (2 mL), was added lithium hydroxide monohydrate in water (1 M, 2.18 mL). The resulting mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure, acidified using 2N aqueous HCl until pH 4.0 and extracted using ethyl acetate (2 x 30 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 5-(3-(5-(methoxymethyl)-2- (trifluoromethyl)benzyl)ureido)-1-phenyl-1H-pyrazole-3-carboxylic acid (5, 170 mg, 326.43 µmol, 78% yield) as an off-white solid. LC-MS (ES⁺): m/z 449.0 [M + H] ⁺. Step-3: To a solution of 5-(3-(5-(methoxymethyl)-2-(trifluoromethyl)benzyl)ureido)-1-phenyl-1H- pyrazole-3-carboxylic acid (5, 120.00 mg, 267.62 µmol) and tert-butyl 4-(aminomethyl)-4- hydroxy-piperidine-1-carboxylate (6, 61.63 mg, 267.62 µmol) in N,N-dimethylformamide (2 mL), were added DIPEA (103.76 mg, 802.86 µmol, 139.84 µL) and HATU (152.64 mg, 401.43 µmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was treated with cold water (10 mL) and extracted using ethyl acetate (2 x 30 mL). The combined organics were washed with brine solution (20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-100% ethyl acetate in petroleum ether to give tert-butyl 4-hydroxy-4-((5-(3-(5-(methoxymethyl)-2- (trifluoromethyl)benzyl)ureido)-1-phenyl-1H-pyrazole-3-carboxamido)methyl)piperidine-1- carboxylate (7, 165 mg, 226.34 µmol, 85% yield) as a pale yellow gum. LC-MS (ES-): m/z 659.2 [M - H] -. Step-4: To a solution of tert-butyl 4-hydroxy-4-((5-(3-(5-(methoxymethyl)-2- (trifluoromethyl)benzyl)ureido)-1-phenyl-1H-pyrazole-3-carboxamido)methyl)piperidine-1- carboxylate (7, 165 mg, 249.74 µmol) in dichloromethane (5 mL), cooled to 0 °C, was added HCl in dioxane (4 M, 2 mL) drop-wise. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the crude product was triturated using diethyl ether to give N-((4-hydroxypiperidin-4-yl)methyl)-5-(3-(5-(methoxymethyl)-2- (trifluoromethyl)benzyl)ureido)-1-phenyl-1H-pyrazole-3-carboxamide hydrochloride (8, 150 mg, 245.29 µmol, 98% yield) as an off-white solid. LC-MS (ES⁺): m/z 561.2 [M + H] ⁺. Example 129 5-(3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-3- carboxylic acid

Prepared substantially following the synthesis of ethyl 1-phenyl-5-(3-(2- (trifluoromethyl)benzyl)ureido)-1H-pyrazole-3-carboxylate. LC-MS (ES⁺): 450.2 [M + H] ⁺. 5-(3-(5-(methoxymethyl)-2-(trifluoromethyl)benzyl)ureido)-1-phenyl-1H-pyrazole-3- carboxylic acid

Prepared substantially following the synthesis of ethyl 1-phenyl-5-(3-(2- (trifluoromethyl)benzyl)ureido)-1H-pyrazole-3-carboxylate. LC-MS (ES⁺): m/z 449.0 [M + H] ⁺. N-((4-hydroxypiperidin-4-yl)methyl)-5-(3-(5-(methoxymethyl)-2- (trifluoromethyl)benzyl)ureido)-1-phenyl-1H-pyrazole-3-carboxamide

Prepared substantially following the synthesis of N-((4-hydroxypiperidin-4-yl)methyl)-1-phenyl- 5-(3-(2-(trifluoromethyl)benzyl)ureido)-1H-pyrazole-3-carboxamide. LC-MS (ES⁺): m/z 561.2 [M + H] ⁺.

N-((4-hydroxypiperidin-4-yl)methyl)-5-(3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin- 3-yl)ureido)-1-phenyl-1H-pyrazole-3-carboxamide

Prepared substantially following the synthesis of N-((4-hydroxypiperidin-4-yl)methyl)-1-phenyl- 5-(3-(2-(trifluoromethyl)benzyl)ureido)-1H-pyrazole-3-carboxamide. LC-MS (ES⁺): m/z 562.3 [M + H] ⁺. Example 130 Synthesis of N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]octyl]-1-phenyl-5- [[2-(trifluoromethyl)phenyl]methylcarbamoylamino]pyrazole-3-carboxamide (Compound 226)

To a solution of 1-phenyl-5-(3-(2-(trifluoromethyl)benzyl)ureido)-1H-pyrazole-3-carboxylic acid (1, 40.00 mg, 98.93 µmol) and 3-[4-[1-(8-aminooctyl)-4-piperidyl]anilino]piperidine-2,6-dione (2, 41.01 mg, 98.93 µmol) in N,N-dimethylformamide (1 mL), were added HATU (56.42 mg, 148.39 µmol) and DIPEA (38.36 mg, 296.78 µmol, 51.69 µL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was treated cold water (20 mL), precipitated solid was filtered washed with water and dried under vacuum to give the crude product. The crude product was purified by reverse phase [ISCO 150 g C18 column; Mobile phase A: 0.1% HCOOH in water, Mobile phase B: Acetonitrile; Wavelength: 215 nm] and the fractions containing the compound was lyophilized to give N-(8-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)octyl)- 1-phenyl-5-(3-(2-(trifluoromethyl)benzyl)ureido)-1H-pyrazole-3-carboxamide formate (Compound 226, 12 mg, 14.12 µmol, 14% yield) as an off-white solid. LC-MS (ES⁺): m/z 801.1 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H), 8.69 (s, 1H), 8.33 (s, 2H), 8.16 (t, J = 6.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.71-7.41 (m, 7H), 7.23 (t, J = 6.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.72 (s, 1H), 6.60 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.8 Hz, 1H), 4.43 (d, J = 5.6 Hz, 2H), 4.31-4.23 (m, 1H), 3.27-3.18 (m, 3H), 2.94 (d, J = 11.6 Hz, 2H), 2.74-2.67 (m, 1H), 2.52-2.50 (m, 1H), 2.34-2.26 (m, 2H), 2.13-2.05 (m, 1H), 1.97-1.90 (m, 3H), 1.68-1.43 (m, 7H), 1.28 (s, 7H) ppm. Example 131 N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]octyl]-5-[[5-(methoxymethyl)- 2-(trifluoromethyl)phenyl]methylcarbamoylamino]-1-phenyl-pyrazole-3-carboxamide (Compound 227)

Compound 227 was prepared substantially following the synthesis of Compound 226. LC-MS (ES⁺): m/z 845.4 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H), 8.73 (s, 1H), 8.15 (t, J = 6.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.60-7.49 (m, 5H), 7.45 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 6.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.72 (s, 1H), 6.60 (d, J = 8.8 Hz, 2H), 5.64 (d, J = 7.6 Hz, 1H), 4.48 (s, 2H), 4.44 (d, J = 5.2 Hz, 2H), 4.28-4.21 (m, 1H), 3.26-3.16 (m, 2H), 2.91 (d, J = 11.2 Hz, 2H), 2.69-2.61 (m, 3H), 2.35-2.33 (m, 2H), 2.26-2.22 (m, 1H), 1.92- 1.87 (m, 2H), 1.77 (s, 6H), 1.63-1.54 (m, 2H), 1.56-1.42 (m, 6H), 1.24 (s, 8H) ppm. N-[8-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]octyl]-1-phenyl-5-[[rac- (3S,4R)-1-(2-methoxyethyl)-4-phenyl-pyrrolidin-3-yl]carbamoylamino]pyrazole-3- carboxamide (Compound 228)

Compound 228 was prepared substantially following the synthesis of Compound 226. LC-MS (ES⁺): m/z 846.5 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.79 (s, 1H), 10.43 (s, 1H), 9.35 (s, 1H), 8.56 (s, 1H), 8.16 (t, J = 6.0 Hz, 1H), 7.55-7.49 (m, 5H), 7.41-7.30 (m, 5H), 6.95 (d, J = 8.4 Hz, 2H), 6.63 (s, 3H), 5.75 (br s, 1H), 4.56-4.48 (m, 1H), 4.34-4.25 (m, 1H), 3.86 (br s, 1H), 3.65 (t, J = 4.8 Hz, 3H), 3.54 (d, J = 11.2 Hz, 4H), 3.37-3.18 (m, 4H), 3.06-2.96 (m, 4H), 2.74-2.67 (m, 1H), 2.53-2.50 (m, 1H), 2.12-2.03 (m, 1H), 1.91-1.80 (m, 5H), 1.67 (br s, 2H), 1.51-1.48 (m, 5H), 1.30 (s, 9H) ppm.

Example 132 Synthesis of N-[[1-[12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-12-oxo- dodecanoyl]-4-hydroxy-4-piperidyl]methyl]-1-phenyl-5-[[2- (trifluoromethyl)phenyl]methylcarbamoylamino]pyrazole-3-carboxamide trifluoroacetate (Compound 229)

To a solution of N-((4-hydroxypiperidin-4-yl)methyl)-1-phenyl-5-(3-(2- (trifluoromethyl)benzyl)ureido)-1H-pyrazole-3-carboxamide (1, 50.00 mg, 96.80 µmol) and 12- [4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-12-oxo-dodecanoic acid (2, 48.37 mg, 96.80 µmol) in N,N-dimethylformamide (1 mL), were added HATU (55.21 mg, 145.20 µmol) and DIPEA (37.53 mg, 290.41 µmol, 50.58 µL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was treated cold water (20 mL), precipitated solid was filtered, washed with water and dried under vacuum to give the crude product. The crude product was purified by mass-directed preparative HPLC [Column: Sunfire C18 OBD (19 x 100 mm), 5 micron Mobile phase A: 0.1% TFA in water, Mobile phase B: Acetonitrile, Wavelength: 215 nm] to give N-((1-(12-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-12-oxododecanoyl)-4- hydroxypiperidin-4-yl)methyl)-1-phenyl-5-(3-(2-(trifluoromethyl)benzyl)ureido)-1H-pyrazole-3- carboxamide trifluoroacetate (Compound 229, 10.5 mg, 9.24 µmol, 10% yield) as a grey solid. LC-MS (ES⁺): m/z 998.5 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H), 8.61 (s, 1H), 7.89 (t, J = 6.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.59-7.51 (m, 5H), 7.49- 7.41 (m, 2H), 7.13 (t, J = 6.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.77 (s, 1H), 6.62 (d, J = 8.8 Hz, 2H), 4.43 (d, J = 5.2 Hz, 1H), 4.29 (d, J = 4.8 Hz, 2H), 4.26 (d, J = 4.4 Hz, 1H), 3.99-3.96 (m, 2H), 3.30-3.21 (m, 2H), 3.04-2.94 (m, 2H), 2.74-2.61 (m, 1H), 2.60-2.52 (m, 2H), 2.34-2.24 (m, 4H), 2.13-2.02 (m, 1H), 1.89-1.83 (m, 1H), 1.72-1.69 (m, 3H), 1.49-1.41 (m, 11H), 1.24 (br s, 13H) ppm. Example 133 N-[[1-[12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-12-oxo-dodecanoyl]-4- hydroxy-4-piperidyl]methyl]-1-phenyl-5-[[rac-(3S,4R)-1-(2-methoxyethyl)-4-phenyl- pyrrolidin-3-yl]carbamoylamino]pyrazole-3-carboxamide (Compound 230)

Compound 230 was prepared substantially following the synthesis of Compound 229. LC-MS (ES⁺): m/z 1043.6 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H), 8.32 (br s, 1H), 8.21 (s, 1H), 7.85 (t, J = 6.4 Hz, 1H), 7.59-7.49 (m, 5H), 7.32-7.20 (m, 5H), 7.20-7.11 (m, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 6.61 (d, J = 8.4 Hz, 2H), 5.68 (d, J = 7.2 Hz, 1H), 4.78 (br s, 1H), 4.45 (d, J = 5.2 Hz, 1H), 4.33-4.22 (m, 1H), 4.15-4.05 (m, 1H), 4.03-3.94 (m, 2H), 3.56-3.51 (m, 2H), 3.49-3.41 (m, 4H), 3.44-3.41 (m, 2H), 3.30-3.24 (m, 3H), 3.14-3.01 (m, 2H), 2.85-2.80 (m, 2H), 2.62-2.51 (m, 8H), 2.39-2.33 (m, 1H), 2.32-2.24 (m, 4H), 2.12-2.05 (m, 1H), 1.89-1.81 (m, 1H), 1.72-1.62 (m, 2H), 1.49-1.40 (m, 8H), 1.36-1.31 (m, 1H), 1.24 (s, 11H) ppm. N-[[1-[12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-12-oxo-dodecanoyl]-4- hydroxy-4-piperidyl]methyl]-5-[[5-(methoxymethyl)-2- (trifluoromethyl)phenyl]methylcarbamoylamino]-1-phenyl-pyrazole-3-carboxamide (Compound 231)

Compound 231 was prepared substantially following the synthesis of Compound 229. LC-MS (ES⁺): m/z 1042.4 [M + H] ⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H), 8.63 (s, 1H), 7.89 (t, J = 6.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.59-7.51 (m, 5H), 7.51 (s, 1H), 7.49-7.41 (m, 1H), 7.16 (t, J = 5.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.76 (s, 1H), 6.61 (d, J = 8.8 Hz, 2H), 5.68 (d, J = 7.2 Hz, 1H), 4.79 (s, 1H), 4.53-4.42 (m, 5H), 4.41-4.32 (m, 1H), 4.03-3.92 (m, 2H), 3.59-3.54 (m, 1H), 3.34-3.27 (m, 3H), 3.07-2.98 (m, 2H), 2.74-2.61 (m, 1H), 2.60-2.50 (m, 2H), 2.34-2.24 (m, 5H), 2.13-2.06 (m, 1H), 1.89-1.81 (m, 1H), 1.74-1.62 (m, 2H), 1.49-1.41 (m, 11H), 1.24 (s, 10H) ppm. Example 134 NTRK HiBiT Method Materials DMEM with high glucose, HEPES, and no-phenol red and fetal bovine serum (FBS) were purchased from Gibco (Grand Island, NY, USA). Nano-Glo® HiBiT Lytic Assay System was purchased from Promega (Madison, WI USA). NTRK-HiBiT cell lines were generated in house. Cell culture flasks and 384-well microplates were acquired from VWR (Radnor, PA, USA). NTRK Degradation Assay NTRK degradation was assessed using the HiBiT assay, a high-throughput approach for measuring protein degradation using Nano-Glo® HiBiT technology (Promega, Madison, WI, USA). Briefly, the genetic sequence of an 11-amino acid peptide tag was inserted into C-terminus of the TRKA kinase domain, corresponding to residues 441-796 TRKA, and expressed ectopically through lentiviral transduction of the parental HEK293T cell line. Three additional 293 T cell lines containing mutations in the TRK kinase domain (F589L, G595R, and G667C) with a C-terminal HiBiT fusion were also constructed in a similar manner to the wild-type TRKA kinase domain cell line. To determine the effect of degraders on protein levels, cells were plated in 384-well plates and treated with compounds of interest in duplicate for six hours using an 11 -point half-log dilution series with the highest concentration set 10 mM. Cells were grown in no-phenol red DMEM with 10% FBS and plated at 2500 cells per well for the HiBiT assay. Cell lysis and addition of the LgBiT complementary protein plus a luciferase substrate were then performed, generating a luminescence signal proportional to the amount of the HiBiT-tagged protein. The luminescence signal was measured using an Envision Multimode plate reader (Perkin Elmer, Santa Clara, CA, USA). The half-maximal degradation concentration (DC50), inflection point of the logistic curve where the second derivative is 0 (IP), and % remaining protein (Emax) were then derived from the dose-response curves using a four parametric logistic fit that minimized the root mean squared error between observed and calculated values.

Representative Compounds of the Present Invention

Table 1

Example 135 NTRK Degradation Western Blot Assay Western blot was used to determine the NTRK degradation. AP1060 (DSMZ, AC 593) cells harboring the ETV6-NTRK3 fusion were cultured with IMDM + 20% heat-inactivated FBS + 10% cultured media from 5637 cells (ATCC, HTB-9), which are grown in RPMI + 20% heat- inactivated FBS. AP1060 cells were plated in a 6-well dish at 500,000 cells/well and allowed to adhere for 16 hours. Cells were treated with a compound serially diluted in DMSO for 24 hours, at which point the cells were rinsed with PBS and flash frozen. Cell pellets were lysed in lysis buffer (RIPA (Thermo, Ref 89901), 1x Halt Protease and Phosphatase inhibitor cocktail (Thermo, Pro#1361281), benzonase (Sigma, E1014-5JU)) for 10 minutes on ice. Insoluble proteins were cleared form the lysates by centrifugation (21.2 x g, 10 minutes). Protein concentrations were measured using the BCA Protein Assay Kit (Thermo, 23228). Protein standard curve, prepared with BSA, and samples protein concentrations were read using the Envision Multilabel Reader (PerkinElmer). Lysate concentrations were normalized with lysis buffer and Laemmli 6X, SDS-Sample Buffer, Reducing (Boston BioProducts, Inc. Part #BP-111R- 50ml). Normalized samples and Chameleon^® Duo Pre-stained Protein Ladder (LI-COR, 928- 60000) were loaded onto 4–15% Criterion™ Tris-HCl Protein Gel (Bio-Rad, #3450028). Gels ran at 120 V for 1.5 hours. Protein transfer was completed with the Trans-Blot Turbo Transfer System (Bio-Rad, 1704150EDU) at 25 V for 7 minutes using the Trans-Blot Turbo RTA Midi 0.2 µm Nitrocellulose Transfer Kit (Bio-Rad, catalog #1704271) following manufacturer recommendations. Membranes were blocked while rocking for one hour in Intercept^® Blocking Buffer (TBS) (LI-COR, catalog # 927-50000). Primary antibodies pan-TRK (1:1000; Cell Signaling, 92991) and Vinculin (1:10,000; EMD, 05-386) were diluted in Intercept^® T20 (TBS) Protein-Free Antibody Diluent (LI-COR, catalog #927-85001) and incubated while rocking at 4°C overnight. Membranes were washed 3 times for 5 minutes in TBS-T while rocking. Secondary antibodies IR Dye 800 CW goat anti-rabbit (1:5000; LiCor, 926-32211/C91030-13) and IR Dye 680 RD goat anti-mouse (1:5000; LiCor, 926-68072/C90910-21) were diluted in Intercept^® T20 (TBS) Protein-Free Antibody Diluent (LI-COR, catalog # 927-85001) and incubated on membranes for 1 hour while rocking at room temperature. Membranes were washed as previously described and imaged on the Odyssey CLx. The resulting data are shown in Figure 2. Example 136 CellTiter-Glo Growth Inhibition Assay AP1060 (DSMZ, AC 593) cells harboring the ETV6-NTRK3 fusion were cultured with IMDM + 20% heat-inactivated FBS + 10% cultured media from 5637 cells (ATCC, HTB-9), which are grown in RPMI + 20% heat-inactivated FBS. KM12 cells carrying the TPM3-TRKA fusion were grown in RPMI + 20% heat-inactivated FBS. AP1060 and KM12 cell viability was determined based on quantification of ATP using CellTiter-Glo^® 2.0 luminescent Assay kit (Promega, Madison, WI, USA), which signals the presence of metabolically-active cells. Test compound was added to 384-well plates at a top concentration of 10 μΜ with 14 points, half log titration in duplicates. AP1060 cells were seeded into the 384-well plates (Corning, Corning, NY, USA) in complete medium at a cell density of 10,000 cells per well, and KM12 cells were seeded at 1,500 cells/well. Cells treated in the absence of the test compound were the negative control, normalized to 100% viability, and cells treated in the absence of CellTiter-Glo^® 2.0 were the positive control, normalized to 0% viability. AP1060 and KM12 cells were incubated at 37°C with 5% CO2 for 96 hr. CellTiter-Glo reagent was then added to the cells and incubated at room temperature for 1 hour before Luminescence was acquired on EnVision™ Multilabel Reader (PerkinElmer, Santa Clara, CA, USA).The resulting data are shown in Table 2 below. Table 2. GI₅₀ for representative compounds

Example 137 In vivo Evaluation of Efficacy and PD in Female BALB/c Nude Mice Bearing KM12 Xenografts The in vivo efficacy and pharmacodynamics (PD) of selected compounds were evaluated in the KM12 xenograft model. BALB/c nude female mice bearing KM12 xenografts were treated once or twice daily via intravenous injection or oral gavage with vehicle or a range of doses for Compound 145, Compound 98, and Compound 149. Compared with vehicle group, all treatment groups showed significant tumor growth inhibition. All doses were well tolerated BALB/c nude mice bearing established Yamato-SS xenografts were orally administered vehicle, larotrectinib (200mg/kg QD), entrectinib (60mg/kg BID), Compound 145 (200 mg/kg QD, 100 mg/kg BID,200 mg/kg BID, 5 mg/kg i.v., QD), Compound 98 (200 mg/kg QD, 100 mg/kg BID,200 mg/kg BID, 4 mg/kg i.v., QD), and Compound 149 (200mg/kg QD, 41.5 mg/kg i.v., QD). Efficacy data are expressed as mean tumor volumes ± SEM. TGI was calculated using the formula TGI=[1-(T_i/T₀)/(V_i/V₀)]*100 where T_i was treatment group mean tumor volume at day 21, T₀ was treatment group mice mean tumor volume on day of treatment start, V_i was vehicle mean tumor volume at day 21, and V₀ was mean tumor volume on day of treatment start. Body weight data is expressed as percent of pre-dosing body weight measured on Day 0 ± SEM. The results are shown in Table 3, and FIG.3 and FIG.4. Table 3. Tumor growth inhibition analysis (T/C and TGI)

Example 138 Pharmacodynamics and Pharmacokinetics of Compound 145, Compound 98, and Compound 149 in the KM12 Xenograft Model – End of Efficacy Tumors To demonstrate the ability of Compound 145, Compound 98, and Compound 149to degrade NTRK in vivo, mice bearing KM12 tumor xenografts were treated once or twice daily via intravenous injection or oral gavage with vehicle or a range of doses for 14 days (FIG.3 and FIG. 4). On the last dose (D14) mice were sacrificed and tumors were collected 6hr and 24hrs post last dose. As shown in Figure 5, at doses 200 mg/kg p.o. QD, 100 mg/kg p.o. BID, and 200mg/kg p.o. BID, Compound 145was able to degrade greater than 90% NTRK at both 6hrs and 24hrs. As shown in Figure 6, at doses 200 mg/kg p.o. QD, Compound 98 was able to degrade greater than 80% NTRK at both 6hrs and 24hrs. At doses 100 mg/kg p.o. BID, and 200mg/kg p.o. BID, Compound 98 was able to degrade greater than 90% NTRK at both 6hrs and 24hrs. As shown in Figure 7, at doses 200 mg/kg p.o. QD, and 41.5 mg/kg i.v. QD, Compound 149 was able to degrade greater than 80% NTRK at 6hrs. At 5 mg/kg i.v. QD, Compound 145was able to degrade greater than 90% NTRK at 6hrs, and 70% NTRK at 24hrs. At 4 mg/kg i.v. QD, Compound 98 was able to degrade greater than 79% NTRK at 6hrs, and 80% NTRK at 24hrs. Example 139 Pharmacodynamics of Compound 149 in the KM12 Xenograft Model – Acute PK/PD NTRK degradation by Compound 149 was evaluated in female BALB/c nude mice bearing KM12 xenografts. As shown in Figure 8, Compound 149 dosed at 10 mg/kg p.o., QD was able to degrade NTRK greater than 40% at 2h, 30% at 6h, 25% at 16h, and 3% at 24h. Compound 149 dosed at 10 mg/kg p.o., BID was able to degrade NTRK greater than 25% at 16h, and 5% at 24h. As shown in Figure 9, Compound 149 dosed at 100 mg/kg p.o., QD was able to degrade NTRK greater than 40% at 2h, 75% at 6h, 85% at 16h, and 65% at 24h. Compound 149 dosed at 100 mg/kg p.o., BID was able to degrade NTRK greater than 85% at 24h. All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for the purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teaching of this invention that certain changes and modification may be made thereto without departing from the spirit or scope of the invention as defined in the appended claims.

Claims

CLAIMS We claim: 1. A compound of Formula:

or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic Moiety is selected from:

Heterocyclic Moiety^B is selected from:

Q is CH₂, NR², O, or S; X³, X⁴, X⁵,and X⁶ are independently selected from N, CH, and CR⁵, wherein one of X³, X⁴, X⁵, and X⁶ is a carbon atom that is attached to Linker; R¹, R³, R⁴, and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R³ and R⁴ together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group; or R¹ and R⁶ are combined together to form a 1 or 2-carbon bridge; or R¹ and R³ are combined together to form a 3-6 membered fused ring; each R² is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R⁹, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)₂R⁹, -SC(O)R⁹, -OS(O)₂R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, -NR⁷P(O)(R⁹)₂, and -OP(O)(R⁹)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R¹⁶ is selected from:

and R¹², each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R¹⁷ is selected from:

and

and

each of which is attached to the azaglutarimide moiety through a C-N bond and each of which R¹⁸ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with 1 R¹²; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with 1 R¹²; R¹² is the attachment point to Linker; R⁷ and R⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R⁸, -OR⁷, and -SR⁷ each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, -OC(O)R¹⁴, -OC(S)R¹⁴, -OS(O)R¹⁴, -OS(O)₂R¹⁴, -NR¹¹C(O)R¹⁴, -NR¹¹C(S)R¹⁴, -NR¹¹S(O)R¹⁴, -NR¹¹S(O)₂R¹⁴, -P(O)(R¹⁴)₂, -NR¹¹P(O)(R¹⁴)₂, and -OP(O)(R¹⁴)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; R¹¹ and R¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂; Linker is a bivalent chemical group; NTRK Targeting Ligand is selected from:

NTRK Targeting Ligand^B is selected from:

X¹⁶ is selected from

and bond; each x is independently 0, 1, 2, 3, or 4; X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, and X¹⁵ are independently selected from N, CH, and CR³² wherein no more than 3 of X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, and X¹⁵ are selected to be N; R²⁷ is selected from

, and

each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R³⁰; each R²⁹, R³⁰, R³¹, R³², and R³³ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)₂R⁹, -SC(O)R⁹, -OS(O)₂R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, -NR⁷P(O)(R⁹)₂, and -OP(O)(R⁹)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R³⁴ is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -C(O)R⁹, and -C(S)R⁹, each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R³⁵ is selected from hydrogen alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -P(O)(R⁹)₂, and -alkyl-O-alkyl; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰.

2. The compound of claim 1 of Formula:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein the Heterocyclic Moiety is

.

4. The compound of claim 2, wherein the Heterocyclic Moiety is

and R⁵ is hydrogen.

5. The compound of claim 1 of Formula:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5, wherein Heterocyclic Moiety^B is

.

7. The compound of claim 6, wherein Q is NH.

8. The compound of claim 6, wherein Q is NCH₃.

9. The compound of claim 6, wherein Q is CH₂.

10. The compound of claim 5, wherein Heterocyclic Moiety^B is

.

11. The compound of claim 5, wherein Heterocyclic Moiety^B is

.

12. The compound of any one of claims 5-11, wherein R¹⁶ is

optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵.

13. The compound of any one of claims 5-11, wherein R¹⁶ is

14. The compound of any one of claims 5-11, wherein R¹⁶ is

15. The compound of any one of claims 5-11, wherein R¹⁶ is

16. The compound of any one of claims 5-11, wherein R¹⁶ is

17. The compound of any one of claims 5-11, wherein R¹⁶ is R¹².

18. The compound of claim 5, wherein Heterocyclic Moiety^B is

.

19. The compound of claim 18, wherein R¹⁷ is

20. The compound of claim 18, wherein R¹⁷ is

21. The compound of claim 18, wherein R¹⁷ is

22. The compound of claim 18, wherein R¹⁷ is

23. The compound of claim 18, wherein R¹⁷ is

24. The compound of claim 19, wherein aryl is phenyl.

25. The compound of claim 5, wherein Heterocyclic Moiety^B is

.

26. The compound of claim 25, wherein R¹⁸ is

27. The compound of claim 25, wherein R¹⁸ is

28. The compound of claim 5, wherein Heterocyclic Moiety^B is

.

29. The compound of claim 28, wherein cycle is phenyl.

30. The compound of claim 5, wherein Heterocyclic Moiety^B is

.

31. The compound of claim 5, wherein Heterocyclic Moiety^B is

.

32. The compound of claim 5, wherein Heterocyclic Moiety^B is

.

33. The compound of claim 31 or 32, wherein X⁶ is a carbon atom that is attached to Linker.

34. The compound of claim 31 or 32, wherein X⁵ is a carbon atom that is attached to Linker.

35. The compound of claim 31 or 32, wherein X⁴ is a carbon atom that is attached to Linker.

36. The compound of claim 31 or 32, wherein X³ is a carbon atom that is attached to Linker.

37. The compound of claim 5, wherein Heterocyclic Moiety^B is

.

38. The compound of any one of claims 1-37, wherein R³ is hydrogen.

39. The compound of any one of claims 1-38, wherein R⁴ is hydrogen.

40. The compound of any one of claims 1-39, wherein R⁶ is hydrogen.

41. A compound of Formula:

or a pharmaceutically acceptable salt thereof; wherein: w is 0, 1, 2, or 3; each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)₂R⁹, -SC(O)R⁹, -OS(O)₂R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, -NR⁷P(O)(R⁹)₂, -OP(O)(R⁹)₂, and oxo; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R⁷ and R⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R⁸, -OR⁷, and -SR⁷ each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, -OC(O)R¹⁴, -OC(S)R¹⁴, -OS(O)R¹⁴, -OS(O)₂R¹⁴, -NR¹¹C(O)R¹⁴, -NR¹¹C(S)R¹⁴, -NR¹¹S(O)R¹⁴, -NR¹¹S(O)₂R¹⁴, -P(O)(R¹⁴)₂, -NR¹¹P(O)(R¹⁴)₂, and -OP(O)(R¹⁴)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; R¹¹ and R¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂; Linker is a bivalent chemical group;

NTRK Targeting Ligand is selected from:

X¹⁶ is selected from

, , , ,

, , , , , ,

, , and bond; each x is independently 0, 1, 2, 3, or 4; X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, and X¹⁵ are independently selected from N, CH, and CR³² wherein no more than 3 of X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, and X¹⁵ are selected to be N; R²⁷ is selected from

and

, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²⁹; R²⁸ is selected from each of which is optionally

substituted with 1, 2, 3, or 4 substituents independently selected from R³⁰; each R²⁹, R³⁰, R³¹, R³², and R³³ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)₂R⁹, -SC(O)R⁹, -OS(O)₂R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, -NR⁷P(O)(R⁹)₂, and -OP(O)(R⁹)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R³⁴ is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -C(O)R⁹, and -C(S)R⁹, each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R³⁵ is selected from hydrogen alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -P(O)(R⁹)₂, and -alkyl-O-alkyl; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰.

42. The compound of any one of claims 1-41 wherein Linker is selected from

; wherein: X¹ and X² are independently at each occurrence selected from bond, heterocycle, NR², C(R²)₂, O, C(O), and S; R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO₂-, -S(O)-, -C(S)-, -C(O)NR²-, -NR²C(O)-, -O-, -S-, -NR²-, -C(R⁴⁰R⁴⁰)-, -P(O)(OR²⁶)O-, -P(O)(OR²⁶)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁰; R²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and R⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), - N(alkyl)₂, -NHSO₂(alkyl), -N(alkyl)SO₂alkyl, -NHSO₂(aryl, heteroaryl or heterocycle), - N(alkyl)SO₂(aryl, heteroaryl or heterocycle), -NHSO₂alkenyl, -N(alkyl)SO₂alkenyl, - NHSO₂alkynyl, -N(alkyl)SO₂alkynyl, haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl.

43. The compound of claim 42, wherein Linker is selected from:

44. The compound of claim 42, wherein Linker is selected from:

45. The compound of claim 42, wherein Linker is selected from:

46. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand is selected from:

.

47. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand is selected from:

.

48. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is selected from:

.

49. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is selected from:

.

50. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is selected from:

.

51. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand is selected from:

.

52. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is selected from:

.

53. The compound of any one of claims 1-52, wherein X¹⁶ is

54. The compound of any one of claims 1-52, wherein X¹⁶ is

55. The compound of any one of claims 1-52, wherein X¹⁶ is

56. The compound of any one of claims 1-52, wherein X¹⁶ is

.

57. The compound of any one of claims 1-52, wherein X¹⁶ is

.

58. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is

.

59. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is

60. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is

.

61. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand or NTRK Targeting Ligand^B is

.

62. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand is

.

63. The compound of any one of claims 1-45, wherein the NTRK Targeting Ligand is

.

64. The compound of any one of claims 1-63, wherein Linker is of formula:

.

65. The compound of claim 64, wherein X¹ is bond.

66. The compound of claim 64, wherein X¹ is heterocycle.

67. The compound of claim 64, wherein X¹ is NR².

68. The compound of claim 64, wherein X¹ is C(O).

69. The compound of any one of claims 64-68, wherein X² is bond.

70. The compound of any one of claims 64-68, wherein X² is heterocycle.

71. The compound of any one of claims 64-68, wherein X² is NR².

72. The compound of any one of claims 64-68, wherein X² is C(O).

73. The compound of any one of claims 64-72, wherein R²⁰ is bond.

74. The compound of any one of claims 64-72, wherein R²⁰ is CH₂.

75. The compound of any one of claims 64-72, wherein R²⁰ is heterocycle.

76. The compound of any one of claims 64-72, wherein R²⁰ is aryl.

77. The compound of any one of claims 64-72, wherein R²⁰ is phenyl.

78. The compound of any one of claims 64-72, wherein R²⁰ is bicycle.

79. The compound of any one of claims 64-78, wherein R²¹ is bond.

80. The compound of any one of claims 64-78, wherein R²¹ is CH₂.

81. The compound of any one of claims 64-78, wherein R²¹ is heterocycle.

82. The compound of any one of claims 64-78, wherein R²¹ is aryl.

83. The compound of any one of claims 64-78, wherein R²¹ is phenyl.

84. The compound of any one of claims 64-78, wherein R²¹ is bicycle.

85. The compound of any one of claims 1-63, wherein Linker is of formula:

86. The compound of any one of claims 64-85, wherein R²² is CH₂.

87. The compound of any one of claims 64-85, wherein R²² is heterocycle.

88. The compound of any one of claims 64-85, wherein R²² is aryl.

89. The compound of any one of claims 64-85, wherein R²² is phenyl.

90. The compound of any one of claims 64-85, wherein R²² is bicycle.

91. The compound of any one of claims 1-63, wherein Linker is of formula:

92. The compound of any one of claims 64-91, wherein R²³ is CH₂.

93. The compound of any one of claims 64-91, wherein R²³ is heterocycle.

94. The compound of any one of claims 64-91, wherein R²³ is aryl.

95. The compound of any one of claims 64-91, wherein R²³ is phenyl.

96. The compound of any one of claims 64-91, wherein R²³ is bicycle.

97. The compound of any one of claims 1-63, wherein Linker is of formula:

98. The compound of any one of claims 64-97, wherein R²⁴ is bond.

99. The compound of any one of claims 64-97, wherein R²⁴ is CH₂.

100. The compound of any one of claims 64-97, wherein R²⁴ is heterocycle.

101. The compound of any one of claims 64-97, wherein R²⁴ is aryl.

102. The compound of any one of claims 64-97, wherein R²⁴ is phenyl.

103. The compound of any one of claims 64-97, wherein R²⁴ is bicycle.

104. The compound of any one of claims 64-97, wherein R²⁴ is C(O).

105. A compound from Table 1.

106. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

107. The compound of claim 106 of structure:

or a pharmaceutically acceptable salt thereof.

108. The compound of claim 106 of structure:

or a pharmaceutically acceptable salt thereof.

109. The compound of claim 106 of structure:

or a pharmaceutically acceptable salt thereof.

110. The compound of claim 106 of structure:

or a pharmaceutically acceptable salt thereof.

111. The compound of claim 106 of structure:

or a pharmaceutically acceptable salt thereof.

112. A compound of structure:

or a pharmaceutically acceptable salt thereof; wherein: each R² is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R⁹, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R⁷ and R⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R⁸, -OR⁷, and -SR⁷ each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, -OC(O)R¹⁴, -OC(S)R¹⁴, -OS(O)R¹⁴, -OS(O)₂R¹⁴, -NR¹¹C(O)R¹⁴, -NR¹¹C(S)R¹⁴, -NR¹¹S(O)R¹⁴, -NR¹¹S(O)₂R¹⁴, -P(O)(R¹⁴)₂, -NR¹¹P(O)(R¹⁴)₂, and -OP(O)(R¹⁴)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; R¹¹ and R¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂; X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, and X¹⁵ are independently selected from N, CH, and CR³² wherein no more than 3 of X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, and X¹⁵ are selected to be N; each R³⁰, R³¹, R³², and R³³ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)₂R⁹, -SC(O)R⁹, -OS(O)₂R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, -NR⁷P(O)(R⁹)₂, and -OP(O)(R⁹)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R³⁴ is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -C(O)R⁹, and -C(S)R⁹, each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R³⁵ is selected from hydrogen alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -P(O)(R⁹)₂, and -alkyl-O-alkyl; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰.

113. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-112 and a pharmaceutically acceptable excipient.

114. A method of treating a disorder mediated by NTRK comprising administering an effective amount of a compound of any one of claims 1-112 or a pharmaceutical composition of claim 113.

115. The method of claim 114, wherein the disorder is a cancer.

116. The method of claim 115, wherein the cancer is driven in part by an NTRK mutation.

117. The method of claim 115, wherein the mutant NTRK is mutant NTRK1.

118. The method of claim 116 or 117, wherein the NTRK mutation comprises a F589L mutation.

119. The method of any one of claims 116-118, wherein the NTRK mutation comprises a G595R mutation.

120. The method of any one of claims 116-119, wherein the NTRK mutation comprises a G667C mutation.

121. The method of claim 115, wherein the mutant NTRK is mutant NTRK3.

122. The method of claim 121, wherein the NTRK mutation comprises a F617L mutation.

123. The method of any one of claims 121-122, wherein the NTRK mutation comprises a G623R mutation.

124. The method of any one of claims 121-123, wherein the NTRK mutation comprises a G696A mutation.

125. Use of a compound of any one of claims 1-112 or a pharmaceutical composition of claim 113 in the treatment of a disorder mediated by NTRK.

126. Use of a compound of any one of claims 1-112 or a pharmaceutical composition of claim 113 in the manufacture of a medicament for the treatment of a disorder mediated by NTRK.

127. The use of claim 125 or 126, wherein the disorder is a cancer.

128. The use of claim 127, wherein the cancer is driven in part by an NTRK mutation.

129. The use of claim 128, wherein the mutant NTRK is mutant NTRK1.

130. The use of claim 128 or 129, wherein the NTRK mutation comprises a F589L mutation.

131. The use of any one of claims 128-130, wherein the NTRK mutation comprises a G595R mutation.

132. The use of any one of claims 128-131, wherein the NTRK mutation comprises a G667C mutation.

133. The use of claim 128, wherein the mutant NTRK is mutant NTRK3.

134. The use of claim 133, wherein the NTRK mutation comprises a F617L mutation.

135. The use of claim 133 or 134, wherein the NTRK mutation comprises a G623R mutation.

136. The use of any one of claims 133-135, wherein the NTRK mutation comprises a G696A mutation.

137. A pharmaceutical composition for use in the treatment of a disorder mediated by NTRK comprising administering an effective amount of a compound of any one of claims 1-112 or a pharmaceutical composition of claim 113.

138. The pharmaceutical composition of claim 137, wherein the disorder is a cancer.

139. The pharmaceutical composition of claim 137, wherein the cancer is driven in part by an NTRK mutation.

140. The pharmaceutical composition of claim 137, wherein the mutant NTRK is mutant NTRK1.

141. The pharmaceutical composition of claim 139 or 140, wherein the NTRK mutation comprises a F589L mutation.

142. The pharmaceutical composition of any one of claims 139-141, wherein the NTRK mutation comprises a G595R mutation.

143. The pharmaceutical composition of any one of claims 139-142, wherein the NTRK mutation comprises a G667C mutation.

144. The pharmaceutical composition of claim 137, wherein the mutant NTRK is mutant NTRK3.

145. The pharmaceutical composition of claim 144, wherein the NTRK mutation comprises a F617L mutation.

146. The pharmaceutical composition of any one of claims 144-145, wherein the NTRK mutation comprises a G623R mutation.

147. The pharmaceutical composition of any one of claims 144-146, wherein the NTRK mutation comprises a G696A mutation.