EP4735438A2

EP4735438A2 - Heterobifunctional compounds for the degradation of kras

Info

Publication number: EP4735438A2
Application number: EP24745570.2A
Authority: EP
Inventors: Corey Don Anderson; Xinpeng CHENG; Christopher G. Nasveschuk
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2023-06-30
Filing date: 2024-06-27
Publication date: 2026-05-06
Also published as: AU2024306706A1; WO2025006783A2; WO2025006783A3

Abstract

The invention provides compounds that degrade the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein including mutant forms via the ubiquitination of the KRAS protein and subsequent proteasomal degradation. The compounds are useful for the treatment of various cancers.

Description

HETEROBIFUNCTIONAL COMPOUNDS FOR THE DEGRADATION OF KRAS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63/524,459 filed June 30, 2023, which is incorporated by reference herein for all purposes. FIELD OF THE INVENTION The invention provides compounds that degrade a Kirsten rat sarcoma viral oncogene homolog (KRAS) protein, for example a mutant KRAS protein such as G12D-KRAS or gain- of-function KRAS mutations, for the treatment of abnormal cellular proliferation including cancers and tumors as described in more detail below. BACKGROUND OF THE INVENTION The rat sarcoma (RAS) family of viral oncogene homolog GTPases are involved in cellular signal transduction by acting as molecular switches to mediate cell growth, differentiation, and survival. The RAS family includes three distinct members, i.e. Harvey rat sarcoma viral oncogene homolog (HRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Neuroblastoma rat sarcoma viral oncogene homolog (NRAS). Upon GTP binding, the RAS GTPases engage effector proteins to initiate a variety of downstream signaling including the RAF-MEK-ERK and PI3K-AKT pathways that control mitogenic processes (Cox, A.D. & Der, C.J. Ras history: The saga continues. Small GTPases. 1(1):2- 27(2010 Jul.)). Overexpression or mutation of these genes leads to the accumulation of GTP- bound KRAS and the unrestricted activation of RAF-MEK-ERK and PI3K-AKT signaling pathways and has been implicated in many types of human cancer including colorectal cancer, pancreatic cancer, lung cancer, and non-small cell lung cancer (NSCLC). Single amino acid substitutions caused by missense mutations are associated with 98% of RAS-related cancers and occur at mutational hotspots encoding codons including glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61) (Waters, A.M. & Der, C.J. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb. Perspect. Med.8(9):a031435(2018 Sep)). Mutant KRAS accounts for approximately 84% of all RAS- mutant cancers (Id.). Gain-of-function KRAS mutations are found in approximately 30% of all human cancers (P. Liu et al., “Targeting the untargetable KRAS in cancer therapy”. Acta Pharm. Sinica B 2019; 9(5): 871–879; V. Merz et al., “Targeting KRAS: The Elephant in the Room of Epithelial Cancers”. Front. Oncol.2021, vol. 11, article 638360), including, e.g., pancreatic cancer (>80%), colon cancer (approximately 40-50%), lung cancer (approximately 30-50%), non-small cell lung cancer, myeloid leukemia breast cancer, cervical cancer, endometrial cancer, liver cancer, bladder cancer, and biliary tract malignancies (S. Jančík et al., “Clinical Relevance of KRAS in Human Cancers” J. Biomed. Biotechnol. 2010; 2010: 150960). Activating or gain-of-function mutations interfere with KRAS’s ability to flip between active and inactive states. Patients with KRAS mutations have historically exhibited poor responses to standard of care therapies. Despite the known role of KRAS as an oncogenic hub, the development of KRAS targeting agents has historically been extremely challenging, even earning the nickname, “the undruggable gene” (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol.15:152(2022)). In 2013, the lab of Kevan Shokat at the University of California San Francisco identified an allosteric pocket, termed the switch-II pocket, on KRAS which could by bound by inhibitors (Ostrem, J. et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 503(7477): 548-551). Although this allosteric site is adjacent to the nucleotide binding pocket, it is transiently formed and was not observed in previous crystal structures of the protein. A compound binding in the switch-II pocket alters the relative binding affinity of KRAS to GTP and GDP, favoring the inactive GDP-bound form. Three years later, the first low micromolar compounds against KRAS G12C were disclosed by Wellspring Biosciences (Patricelli, M. et al. Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discovery 6(3):316-29, 2016). In 2018, Wellspring Biosciences published a paper describing improved KRAS binders with a 4- piperazinyl-quinazolinyl-7-phenol pharmacophore (Janes, M. et al. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor, Cell, 172, 578-589). Only recently have KRAS targeting agents been developed and approved by the United States Food and Drug Administration (FDA), albeit for a specific subset of KRAS mutant patients (Huang, L. et al. KRAS mutation: from undruggable to druggable in cancer. Sig Transduct Target Ther. 6(1):386(2021 Nov 15)). Sotorasib (Lumakras®) and adagrasib (Krazati®), indicated for locally advanced or metastatic non-small cell lung cancer are irreversible inhibitors of KRAS G12C that covalently bind the mutant cysteine of KRAS, locking the protein into an inactive state, thereby preventing downstream signaling without affecting the wild-type protein (Lumakras® Package Insert (2022 Dec); Krazati® Package Insert (2021 May)). While novel KRAS G12C inhibitors have achieved beneficial results, acquired treatment resistance is expected to rapidly develop in this patient population, potentially due to a complex combination of multiple mechanisms. Some potential mechanisms of resistance include release of ERK-mediated feedback inhibition, development of secondary KRAS mutations, re-activation of KRAS through activation of receptor tyrosine kinases (RTKs), PI3K activation by the IGFR–IRS1 pathway, and simultaneously converging resistance mechanisms (Id.). The field of targeted protein degradation promoted by small molecules has been intensively studied (Collins, I. et al. Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway. Biochem J.474(7):1127-1147(2017 Mar 15)). Protein degradation plays a role in various cellular functions. For example, the body uses protein degradation to adjust the concentrations of regulatory proteins through degradation into small peptides to maintain health and productivity of the cells. Cereblon is a protein that forms an E3 ubiquitin ligase complex, which ubiquitinates various other proteins. Cereblon is known as the primary target for the anticancer thalidomide analogs. A higher expression of cereblon has been linked to the efficiency of thalidomide analogs in cancer therapy. Modulators for targeted ubiquitination include those described by Arvinas in WO2015160845, WO2016149668, WO2016197032, WO2017011590, WO2017030814, WO2018144649, WO2018226542, and WO2019199816; those described by Dana-Farber Cancer Institute in WO2016105518, WO2017007612, WO2017024317, WO2017024318, WO2017117473, WO2017117474, WO2018148443, WO2018148440, and WO2019165229; those described by Kymera in WO2019/060742, WO2019/140387, and WO2020/01022; and those described by C4 Therapeutics Inc. in WO2017197036, WO2017197046, WO2017197051, WO2017197055, WO2018237026, WO2019099868, WO2019191112, WO2019204353, WO2019236483, WO2020132561, WO2020181232, WO2020210630, WO2021127561, WO2021178920, WO2021255212, WO2021255213, WO2022032026, WO2022032132, WO2022081925, WO2022081928, WO2022235945, WO2022251539, WO2022261250, WO2022251539, WO2023283372, WO2023039208, WO2023055952, WO2023239750, and WO2023244764. Some specific molecules for the degradation of KRAS have also been described (Cheng, J. et al. Discovery of Novel PDEδ Degraders for the Treatment of KRAS Mutant Colorectal Cancer. J Med Chem. 63(14):7892-7905(2020 Jul 23); Zeng, M. et al. Exploring Targeted Degradation Strategy for Oncogenic KRAS^G12C. Cell Chem Biol. 27(1):19- 31.e6(2020 Jan 16); Bond, M.J. et al. Targeted Degradation of Oncogenic KRAS^G12C by VHL- Recruiting PROTACs. ACS Cent Sci.6(8):1367-1375(2020 Aug 26)). Additional examples of KRAS degraders are described in Fell, J.B. et al. Identification of the Clinical Development Candidate MRTX849, a Covalent KRAS^G12C Inhibitor for the Treatment of Cancer, J. Med. Chem.202063 (13), 6679-6693; Fell, J.B. et al., Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS G12C with In Vivo Activity, ACS Med. Chem. Lett. 2018, 9, 12, 1230–1234; Wang, X. et al. “Identification of MRTX1133, a Noncovalent, Potent and Selective KRAS^G12D Inhibitor, J. Med. Chem. 2022, 65, 4, 3123–3133; Canon, J. et al., The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumor immunity, Nature, 2019 Nov;575(7781):217-223; Zhang et al. Chemoselective covalent modification of K-Ras(G12R) with a Small Molecule Electrophile, J. Am. Chem. Soc. 2022, 144, 35, 15916-15921. Patent applications describing KRAS degraders include WO2024119278, WO2024118966, WO2024118960, WO2024055112, WO2024019103, WO2024001839, WO2024054625, WO2024050742, WO2023193085, WO2023205719, WO2023205701, WO2023215802, WO2023215906, WO2023116934, WO2023215801, WO2023280026, WO2023185864, WO2023141570, WO2023138524, WO2022266206, WO2022228576, WO2019195609, CN115785199, CN115260158, CN116332959, and CN116375742. There remains a need for new KRAS modulators to treat disorders mediated by KRAS, for example mutant KRAS, in a host in need thereof. Therefore, it is an object of the present invention to provide new compounds, pharmaceutical compositions, methods of use and manufacture, to treat disorders mediated by KRAS in a host such as a human. SUMMARY OF THE INVENTION Compounds and their uses and manufacture are provided that degrade the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein via the ubiquitin proteasome pathway (UPP). These compounds include a Targeting Ligand that binds to KRAS, an E3 Ligase binding portion (Heterocyclic Moiety^A or Heterocyclic Moiety^B), and a Linker that covalently links the Targeting Ligand to the E3 Ligase binding portion. In certain embodiments a compound of the present invention degrades KRAS with a mutation or combination of mutations, for example a G12D mutation or a mutation selected from G12A, G12C, G12D, G12R, G12V, and G13D, or a combination thereof. In certain embodiments a compound of the present invention is a selective degrader of G12D or G12V containing KRAS mutants. In certain aspects the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic Moiety^A is selected from: and y is 0, 1, 2, 3, or 4; in certain embodiments y is 0; in certain embodiments y is 1; R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R⁶ are combined to form a one or two carbon bridge to form a fused cycle, for example when R¹ and R⁶ are combined to form a one carbon bridge is and a two carbon bridge is ; in certain embodiments R¹ and R⁶ are both hydrogen; 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; in certain embodiments R² is hydrogen or CH3; 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; in certain embodiments each R⁵ is alkyl, haloalkyl, or F; R¹⁶ is selected from: , and R¹², each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R^18B is a , wherein the bicycle is a 9-membered bicycle which is attached to the azaglutarimide moiety through a C-N bond and is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; for example includes but does not include ; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵; in certain embodiments Cycle-A and Cycle-B are both phenyl; 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; in certain embodiments R⁷ and R⁸ are independently selected at each instance form hydrogen and alkyl; 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, and -P(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; KRAS Targeting Ligand^A is selected from: , and ; or KRAS Targeting Ligand^A is selected from: , ; R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R³² is heterocycle optionally substituted with 1, 2, 3, or 4 R⁵¹ groups as allowed by valence; In certain embodiments, R³² is selected from: , , , , and ; In certain embodiments, R³² is selected from , and ; R⁴ is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or bicycle; R⁵¹ is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R^51B is selected from halogen, cyano, haloalkyl, -OR⁷, and -SR⁷. R^51C is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD₃; R^51D and R^51E are hydrogen or together with X^B and the carbon atoms to which they are attached, form a 5-, 6-, or 7-membered ring; z is independently selected at each instance from 0, 1, 2, 3, and 4, as allowed by valence; in certain embodiments z is 0; in certain embodiments z is 1; q is 1, 2, or 3; w is 1, 2, or 3; X^B is selected from -CH₂-, -O-, -NH-, -N(R⁴)-, and -S-; X^C is -CH₂-, -O-, or -S-; R³³ is selected from: , and each ³³ of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; for example when R³³ is the formula includes a compound of Formula ; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; R³⁸ and R³⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, and heterocycle each of which except hydrogen and halogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R⁴¹, R⁴², R⁴³, and R⁴⁴ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; each R⁴⁵, R⁴⁶, and R⁴⁷ 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, and -P(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; p is 3, 4, 5, 6, 7, or 8; R¹³³ and R¹³⁴ are independently selected from hydrogen and C₁-C₃alkyl; or R¹³³ and R¹³⁴, together with the carbon atom to which they are attached form a C₃-C₆ cycloalkyl optionally substituted with 1, 2, 3, or 4 halogen atoms as allowed by valence; R¹³⁵ and R¹³⁶ are independently selected from hydrogen and C₁-C₆ alkyl; or R¹³⁵ and R¹³⁶, together with the nitrogen atom to which they are attached form a heterocycle, optionally substituted with 1, 2, 3, or 4 R¹³⁷ groups wherein R¹³⁷ is independently selected at each instance from C₁-C₆alkyl, C₁-C₆haloalkyl, -OR⁷, -NR⁷R⁸, and halogen. 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 the present invention provides a compound of Formula II, Formula III, or Formula IV: ; ; ; or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic Moiety^B is selected from: and ; Q is CH₂, NR², , O, or S; 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 one 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 one R¹² substituent; KRAS Targeting Ligand^B is selected from: KRAS Targeting Ligand^C is selected from: and ; wherein R^32B is selected from: and ; In certain embodiments, R^32B is selected from, , and ; z is independently selected at each instance from 0, 1, 2, 3, and 4, as allowed by valence; q is 1, 2, or 3; w is 1, 2, or 3; X^D is selected from -CH₂-, -O-, and -S-; R^32C is selected from: and ; R¹⁵¹ is independently selected at each instance from hydrogen, C₂-C₈ alkyl (including for example, C₃-C₈ alkyl and C₄-C₈ alkyl), haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷⁷R⁸⁸, -OR⁷, and -SR⁷; R⁷⁷ and R⁸⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹¹⁴ is independently selected from hydrogen, C₂-C₈ alkyl (including for example, C₃-C₈ alkyl and C₄-C₈ alkyl), haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, -O-C₂-C₈ alkyl (including for example, C₃-C₈ alkyl and C₄-C₈ alkyl), -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; X^E is selected from -O-, and -S-; qq is 2, or 3; R^33D is , or ; each of which R^33D is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, - NR⁷R⁸, -OR⁷, and -SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; for example when R^33D is the formula includes a compound of Formula ; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; R³ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R^3C is independently selected from C₂-C₈ alkyl (including for example, C₃-C₈ alkyl and C₄-C₈ alkyl), haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R^7C is independently selected from hydrogen, C₂-C₈ alkyl (including for example, C₃- C₈ alkyl and C₄-C₈ 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; zz is independently 1, 2, 3, or 4; R^29C is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^45C, R^46C, and R^47C; each R^45C, R^46C, and R^47C is independently selected from hydrogen, C₃-C₈ alkyl (including for example, C₄-C₈ alkyl and C₅-C₈ alkyl), haloalkyl, alkenyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(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; R^29D is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^45D, R^46D, and R^47D; each R^45D, R^46D, and R^47D is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, chloro, bromo, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(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; R^29E is selected from phenyl and heteroaryl each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; and all other variables are as defined herein. KRAS Targeting Ligand^D is selected from: , and ; wherein R^31B is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; and all other variables are as defined herein. Other aspects of the present invention provide a compound of Formula XX , , , and ; wherein In certain embodiments, KRAS Targeting Ligand^A, KRAS Targeting Ligand^B, KRAS Targeting Ligand^C, and KRAS Targeting Ligand^D, are selected from: , , , and In another aspect, the present invention provides a compound of Formula V: or a pharmaceutically acceptable salt thereof; wherein: KRAS Targeting Ligand^E is selected from: , and ; R^33C is , a ^33C nd each of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and - SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; for example when R^33C is the formula includes a compound of Formula ; R^33E is , and ea ^33E ch of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and - SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; and all other variables are as defined herein. In alternative embodiments, R^33C is selected from , , and . In another aspect, the present invention provides a compound of Formula VI: or a pharmaceutically acceptable salt thereof;

wherein: KRAS Targeting Ligand^F is selected from: , and ; R^29B is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁴⁵, R¹⁴⁶, and R¹⁴⁷; each R¹⁴⁵, R¹⁴⁶, and R¹⁴⁷ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(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; and all other variables are as defined herein. Every combination of variables, substituents, embodiments and the compounds that result from these combinations, is deemed specifically and individually disclosed, as such depiction is for convenience of space only and not intended to describe only a genus or even a subgenus of compounds. A compound of the present invention provided herein or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable composition can be used to treat a disorder which is mediated by KRAS. In some embodiments a method to treat a patient with a disorder mediated by KRAS is provided that includes administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to the patient, typically a human, optionally in a pharmaceutically acceptable composition. A compound of the present invention may be used to treat a KRAS-mediated disorder such as colon cancer; rectal cancer; endometrial cancer; lung cancer, including non-small cell lung cancer; pancreatic cancer; thyroid cancer; astrocytoma; esophageal cancer; cervical cancer; small intestinal cancer; ovarian cancer; gastric cancer; breast cancer; bladder cancer; or kidney cancer. In certain embodiments, a method of treatment is provided comprising administering an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof to a human patient in need thereof, optionally in a pharmaceutically acceptable carrier. For example, in certain embodiments, a compound of the present invention is administered to a human to treat a cancer. In certain embodiments a compound of the present invention is used to treat lung cancer. In certain embodiments, the lung cancer is non-small cell lung cancer. In certain embodiments a compound of the present invention is used to treat colorectal or rectal 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 pancreatic ductal adenocarcinoma (PDAC). In certain embodiments, the compound of the present invention provides one or more, and even may provide multiple advantages over traditional treatment with a KRAS ligand. For example, the KRAS 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 a protein at once rather than a specific catalytic activity or binding event; and/or d) have increased potency compared to inhibitors due to the possibility of the small molecule acting catalytically. In certain aspects, a compound of the present invention is used to treat KRAS mediated cancer, wherein the KRAS has mutated from the wild-type. There are a number of possibilities for KRAS mutations. In certain non-limiting embodiments, the mutation encodes a missense substitution at a codon selected from glycine-12 (G12), glycine-13 (G13), glutamine 61 (Q61), or any combination thereof. In certain nonlimiting embodiments, the mutation encodes a missense substitution selected from K5E, K5N, G12A, G12C, G12D, G12E, G12F, G12I, G12L, G12N, G12R, G12S, G12V, G12W, G12Y, G13A, G13C, G13D, G13E, G13I, G13N, G13R, G13S, G13V, V14I, P34L, P34Q, P34R, I36M, T58I, A59S, A59T, G60R, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, R68S, H95D, H95Q, H95R, Y96C, Y96D, V152G, D153V, F156I, F156L, or a combination thereof. In certain aspects the mutation is G12D. In certain aspects, the cancer has developed one or more KRAS mutations following treatment with at least one KRAS inhibitor including but not limited to covalent inhibitors sotorasib (Lumakras®) and adagrasib (Krazati®). In yet another aspect, the cancer has one or more KRAS missense mutations encoding codon substitutions or optionally non-KRAS mutations that renders the cancer intrinsically resistant to KRAS inhibitor treatment, for example, KRAS with a G12D mutation. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired a resistance to, a KRAS inhibitor such as Sotorasib (AMG- 510; Lumakras®), adagrasib (MRTX849; Krazati®), 12VC1, ARS-1620, ARS-3248, ARS- 853, AZD4785, Bi-2852, BI 1823911, D-1553, GDC-6036, JAB-21822, JDQ443, JNJ- 74699157, KRpep-2d, KS-58, LY3537982, MK-1084, MRTX1133, or SML-8-73-1. In certain embodiments the compound of the present invention is used to treat a mutant KRAS mediated disorder, wherein KRAS has a substitution of at least one of the below listed amino acid sites, or a combination thereof. The substitution may, for example, be G12D and one or more additional mutations selected from the listed exemplary substitutions, or may be a different substitution. Table 1. Exemplary KRAS Substitutions. ¹Specific substitution frequencies at codons G12, G13, and Q61 calculated according to COSMIC database (Cox, A.D. & Der, C.J. Ras history: The saga continues. Small GTPases. 1(1):2-27(2010 Jul)). In certain embodiments the mutant KRAS mediated disorder has two substitutions selected from the table above. In other embodiments the mutant KRAS mediated disorder has three substitutions selected from the table above. In other embodiments the mutant KRAS mediated disorder has four or more substitutions selected from the table above. In certain embodiments the mutant KRAS mediated disorder has an G12D substitution and one additional substitution which may optionally be selected from the table above. In some of these embodiments the mutant KRAS mediated disorder has an G12D mutation and two additional substitutions that may optionally be selected from the table above. In other embodiments the mutant KRAS mediated disorder has a G12D mutation and three additional substitutions selected from the table above. In certain embodiments, the mutant KRAS mediated disorder has any one of the substitutions listed in Table 1 above and one or more additional non-KRAS mutations. In some embodiments, the non-KRAS mutation is selected from a mutation in TP53, STK1, EGFR, or a combination thereof. In certain embodiments the KRAS mediated disorder is mutant KRAS mediated cancer. In certain embodiments a compound of the present invention is used to treat G12D mutant KRAS cancer. In certain embodiments, a compound of the present invention is used to treat G12V mutant KRAS cancer. In certain embodiments, the compound of the present invention provides an improved efficacy and/or safety profile relative to at least one known KRAS inhibitor. For example, the degrader of the present invention has the efficiency of an inhibitor only protein binding moiety combined with the catalytic degradation activity of the cereblon-activated proteasomal degradation. This provides rapid activity against the target overexpressed KRAS by an active moiety that can quickly “return to action” and repeat the catalytic function. In this way, the KRAS is quickly destroyed, in contrast to a covalent inhibitor, like sotorasib (Lumakras®). In certain embodiments, the degrader compound of the present invention has one or more advantages in the treatment of KRAS mediated disorders compared to using an enzyme inhibitor only. In certain embodiments, less of the compounds described herein are needed for the treatment of a KRAS mediated disorder, than by mole of the KRAS Targeting Ligand portion alone. In certain embodiments, KRAS Targeting Ligand is KRAS Targeting Ligand^A, KRAS Targeting Ligand^B, KRAS Targeting Ligand^C, KRAS Targeting Ligand^D. In certain embodiments, the compound of the present invention has less of at least one side-effect in the treatment of a KRAS mediated disorder, than by mole of the KRAS Targeting Ligand portion alone. In certain embodiments, a less frequent dose regimen of a selected compound described herein is needed for the treatment of a KRAS mediated disorder, than the dose by mole of the KRAS Targeting Ligand portion alone. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for treating a disorder mediated by KRAS or for modulating or decreasing the amount of KRAS. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or its pharmaceutical composition, for use in the manufacture of a medicament for treating a disease mediated by KRAS. In certain embodiments, a selected compound as described herein is useful to treat a disorder comprising an abnormal cellular proliferation, such as a tumor or cancer, wherein KRAS is an oncogenic protein or a signaling mediator of the abnormal cellular proliferative pathway and its degradation decreases abnormal cell growth. In certain embodiments, a compound of the present invention, or its pharmaceutically acceptable salt thereof, has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. In certain embodiments, a compound of the present invention, or its pharmaceutically acceptable salt thereof, includes a deuterium atom or multiple deuterium atoms. Other features and advantages of the present application will be apparent from the following detailed description. The present invention thus includes at least the following features: (a) A compound of the present invention, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof; (b) A method for treating a KRAS mediated disorder, such as an abnormal cellular proliferation, including cancer, comprising administering an effective amount of a compound of the present invention, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof; (c) A compound of the present invention, or a pharmaceutically acceptable salt, or isotopic derivative (including a deuterated derivative) thereof for use in the treatment of a disorder that is mediated by KRAS, for example an abnormal cellular proliferation such as a tumor or cancer; (d) Use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment of a patient in need thereof, with a KRAS mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer; (e) Use of a compound of the present invention, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof in the manufacture of a medicament for the treatment of a KRAS mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer; (f) A method for treating a mutant KRAS mediated disorder, such as an abnormal cellular proliferation, including cancer, comprising administering an effective amount of a compound of the present invention, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof; (g) A compound of the present invention, or a pharmaceutically acceptable salt, or isotopic derivative (including a deuterated derivative) thereof for use in the treatment of a disorder that is mediated by mutant KRAS, for example an abnormal cellular proliferation such as a tumor or cancer; (h) Use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment of a patient in need thereof, with a mutant KRAS mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer; (i) Use of a compound of the present invention, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof in the manufacture of a medicament for the treatment of a mutant KRAS mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer; (j) A pharmaceutical composition comprising an effective patient-treating amount of a compound of the present invention, or a pharmaceutically acceptable salt, isotopic derivative thereof; and optionally a pharmaceutically acceptable carrier or diluent; (k) A compound the present invention, as described herein as a mixture of enantiomers or diastereomers (as relevant), including as a racemate; (l) A compound of the present invention, as described herein in enantiomerically or diastereomerically (as relevant) enriched form, including an isolated enantiomer or diastereomer (i.e., about greater than 85, 90, 95, 97, or 99% pure); (m) A process for the preparation of therapeutic products that contain an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, as described herein; (n) A compound of Formula X, as described herein, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof; (o) A compound of Formula XX, as described herein, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof; and (p) A method for treating a KRAS mediated disorder, such as an abnormal cellular proliferation, including cancer, comprising administering an effective amount of a compound of Formula X or XX, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof; DETAILED DESCRIPTION OF THE INVENTION Compounds and their uses and manufacture are provided that degrade the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein via the ubiquitin proteasome pathway (UPP). These compounds include a Targeting Ligand that binds to KRAS, an E3 Ligase binding portion (Heterocyclic Moiety^A or Heterocyclic Moiety^B), and a Linker that covalently links the Targeting Ligand to the E3 Ligase binding portion. In certain embodiments a compound of the present invention degrades KRAS with a mutation or combination of mutations, for example a G12D mutation or a mutation selected from G12A, G12C, G12D, G12R, G12V, and G13D, or a combination thereof. In certain embodiments a compound of the present invention is a selective degrader of G12D or G12V containing KRAS mutants. 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 ordinary skill in the art to which this invention belongs. The compounds of the present invention 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 certain embodiments, 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 certain embodiments, deuterium is 90, 95 or 99% enriched at a desired location. In certain embodiments, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of the present invention. In certain embodiments, 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 KRAS 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. In certain embodiments, a compound of the present invention is isotopically labeled. In certain embodiments, at least one R group is isotopically labeled with 1, 2, or more isotopes as allowed by valence. In certain embodiments, the isotopic label is deuterium. In certain embodiments, at least one deuterium is placed on an atom that has a bond which is broken during metabolism of the compound in vivo, or is one, two or three atoms remote form the metabolized bond (e.g., which may be referred to as an α, β or γ, or primary, secondary or tertiary isotope effect). In other embodiments, the isotopic label is ¹³C. In other embodiments, the isotopic label is ¹⁸F. The compound of the present invention may form a solvate with a solvent (including water). Therefore, in certain non-limiting embodiments, 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, acetone-d₆, DMSO-d₆ (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. Unless denoted otherwise, “alkyl” is typically a C₁-C₈ alkyl. In certain non-limiting embodiments, the alkyl group contains from 1 to 12 carbon atoms, more generally from 1 to 6 carbon atoms or from 1 to 4 carbon atoms. In certain non-limiting embodiments, the alkyl contains from 1 to 8 carbon atoms. In certain embodiments, the alkyl is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, or C₁-C₆. 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. 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. 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. The term “alkoxy” denotes a group of the formula -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. The term “cycloalkoxy” denotes a group of the formula -O-cycloalkyl. Examples of cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy. “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. Unless denoted otherwise, “alkenyl” is typically a C₂-C₈ alkenyl. 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. In certain non-limiting embodiments, the alkenyl contains from 2 to 12 carbon atoms, from 2 to 6 carbon atoms or from 2 to 4 carbon atoms. In certain embodiments, the alkenyl is C₂, C₂-C₃, C₂-C₄, C₂-C₅, or C₂-C₆alkenyl. 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. The term “Alkenyl” also encompasses cycloalkyl or cycloalkyl groups possessing at least one point of unsaturation. “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. Unless denoted otherwise, “alkynyl” is typically a C₂-C₈ alkynyl. 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. In certain non-limiting embodiments, the alkynyl contains from 2 to 12 carbon atoms, more generally from 2 to 6 carbon atoms or from 2 to 4 carbon atoms. In certain embodiments, the alkynyl is C₂, C₂-C₃, C₂-C₄, C₂-C₅, or C₂- C₆alkynyl. 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. The term “Alkynyl” also encompasses cycloalkyl or cycloalkyl groups possessing at least one triple bond. “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. The term “cyano” denotes a -C≡N group. The term “hydroxy” denotes a -OH group. “Halo” and “Halogen” refers independently to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Unless otherwise indicated “halo” or “halogen” typically refers to fluorine (F), chlorine (Cl), and bromine (Br). In certain embodiments “halo” or “halogen” is fluorine (F). “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. Unless denoted otherwise, “haloalkyl” is typically a C₁-C₄ haloalkyl. 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. “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: , or . In certain embodiments, “arylalkyl” is . In certain embodiments, the “arylalkyl” refers to a 2-carbon alkyl group substituted with an aryl group. Non-limiting examples of “arylalkyl” also include: , or . In certain embodiments, 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 certain embodiments, “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 certain embodiments, “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. 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 terms “Heterocyclic Moiety^A” and “Heterocyclic Moiety^B” that are 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. 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-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro- 2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ’-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. 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. 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. 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. Bicyclic ring systems also include spiro-fused bicyclic ring systems. Non-limiting examples of bicycle groups include: , and . 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: , and . “Aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon that is not aromatic. “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 certain embodiments, “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 certain embodiments, the aliphatic group contains from 1 to 12 carbon atoms, more generally from 1 to 6 carbon atoms or from 1 to 4 carbon atoms. In certain embodiments, the aliphatic group contains from 1 to 8 carbon atoms. In certain embodiments, the aliphatic group is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅ or C₁-C₆. 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. 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 certain embodiments, the only heteroatom is nitrogen. In certain embodiments, the only heteroatom is oxygen. In certain embodiments, 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 certain embodiments, “heteroaliphatic” is used to indicate a heteroaliphatic group (cyclic, acyclic, branched or unbranched) having 1-20 carbon atoms. Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, and alkyl-O- haloalkyl. 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 benefit. “Parenteral” administration of a pharmaceutical composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), intrasternal injection, or infusion techniques. 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, 3, 4, 5, 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 excipient. The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use. 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 “pharmaceutically acceptable auxiliary substance” refers to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation. A “patient” or “subject” is a human or non-human animal in need of treatment 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 other embodiments, the patient or subject is a non-human animal in need of such therapy and responsive thereto. 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. COMPOUNDS OF THE PRESENT INVENTION In certain embodiments the compound of the present invention is selected from and or a pharmaceutically acceptable salt thereof. In alternative aspects the compound of the present invention is selected from and or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

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

and or a pharmaceutically acceptable salt thereof. ŉn certain embodiments the compound of the present invention is selected from and or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

and or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from and or a pharmaceutically acceptable salt thereof. ŉn certain embodiments the compound of the present invention is selected from

and ; or a pharmaceutically acceptable salt thereof. In alternative aspects the compound of the present invention is selected from or ; or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

; or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a compound of Formula X: or a pharmaceutically acceptable salt thereof; wherein Linker^B is selected from: X²² is 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; KRAS Targeting Ligand is selected from KRAS Targeting Ligand^A, KRAS Targeting Ligand^B, KRAS Targeting Ligand^C, and KRAS Targeting Ligand^D; and all other variables are defined herein. In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand^A. In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand^B. In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand^C. In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand^D. In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand^E. In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand^F. In certain embodiments X²² is selected from haloalkyl, alkenyl, alkynyl, halogen, heterocycle, - 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. In certain embodiments X²² is selected from haloalkyl, alkenyl, alkynyl, halogen, heterocycle, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -OC(O)R⁹, and -NR⁷C(O)R⁹. In certain embodiments X²² is selected from haloalkyl, alkenyl, alkynyl, halogen, heterocycle, -NH₂, -N(alkyl)H, -OH, -C(O)OH, -C(O)Oalkyl, -NHC(O)Oalkyl, and -NalkylC(O)Oalkyl. In another aspect, the present invention provides a compound of Formula XX and . In certain embodiments the compound of Formula XX is selected from: or a pharmaceutically acceptable salt thereof. In alternative aspects the compound of Formula XX is selected from: and ; or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula XX is selected from: or a pharmaceutically acceptable salt thereof. In alternative aspects the compound of Formula XX is ; or a pharmaceutically acceptable salt thereof. R^33B is , or ; and all other variables are as defined herein. In certain embodiments R^33B is In certain embodiments R^33B is In certain embodiments R^33B is . In certain embodiments R^33B is In certain embodiments R^33B is or . In alternative aspects the compound of Formula XX is selected from:

and ; or a pharmaceutically acceptable salt thereof. A non-limiting example of a compounds of Formula XX is: or a pharmaceutically acceptable salt thereof. Alternative examples of compounds of Formula XX include: and ; or a pharmaceutically acceptable salt thereof. Formulas of the Present Invention A1. In certain embodiments, the invention is a compound of Formula: ; ; ; or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic Moiety^A is selected from: and ; Heterocyclic Moiety^B is selected from:

and ; y is 1, 2, 3, or 4; R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R⁶ are combined to form a one or two carbon bridge to form a fused cycle, 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 , 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; R^18B is a , wherein the bicycle is a 9-membered bicycle which is attached to the azaglutarimide moiety through a C-N bond and is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; Q is CH₂, NR², , O, or S; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one 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 one R¹² substituent; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵; 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, and -P(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 of Formula: 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; 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. KRAS Targeting Ligand^A is selected from: , , , , and KRAS Targeting Ligand^B is selected from: and KRAS Targeting Ligand^C is selected from:

, , , , and ; KRAS Targeting Ligand^D is selected from: , and ; or KRAS Targeting Ligand^A, KRAS Targeting Ligand^B, KRAS Targeting Ligand^C, or KRAS Targeting Ligand^D, is selected from: , , and ; R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R³² is heterocycle optionally substituted with 1, 2, 3, or 4 R⁵¹ groups as allowed by valence; R⁴ is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or bicycle; R⁵¹ is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R^51B is selected from halogen, cyano, haloalkyl, -OR⁷, and -SR⁷. R^51C is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD₃; R^51D and R^51E are hydrogen or together with X^B and the carbon atoms to which they are attached, form a 5-, 6-, or 7-membered ring; z is independently selected at each instance from 1, 2, 3, and 4, as allowed by valence; q is 1, 2, or 3; w is 1, 2, or 3; X^B is selected from -CH₂-, -O-, -NH-, -N(R⁴)-, and -S-; X^C is -CH₂-, -O-, or -S-; R³³ is selected from: and e ³³ ach of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; R³⁸ and R³⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, and heterocycle each of which except hydrogen and halogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R⁴¹, R⁴², R⁴³, and R⁴⁴ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; each R⁴⁵, R⁴⁶, and R⁴⁷ 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, and -P(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; p is 3, 4, 5, 6, 7, or 8; R¹³³ and R¹³⁴ are independently selected from hydrogen and C₁-C₃alkyl; or R¹³³ and R¹³⁴, together with the carbon atom to which they are attached form a C₃-C₆ cycloalkyl optionally substituted with 1, 2, 3, or 4 halogen atoms as allowed by valence; R¹³⁵ and R¹³⁶ are independently selected from hydrogen and C₁-C₆ alkyl; or R¹³⁵ and R¹³⁶, together with the nitrogen atom to which they are attached form a heterocycle, optionally substituted with 1, 2, 3, or 4 R¹³⁷ groups wherein R¹³⁷ is independently selected at each instance from C₁-C₆alkyl, C₁-C₆haloalkyl, -OR⁷, -NR⁷R⁸, and halogen; R^32B is selected from: and ; z is independently selected at each instance from 1, 2, 3, and 4, as allowed by valence; q is 1, 2, or 3; w is 1, 2, or 3; X^D is selected from -CH₂-, -O-, and -S-; R^31B is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷. A2.The compound of embodiment A1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are or . A3.The compound of embodiment A2, wherein Q is NH. A4.The compound of embodiment A2, wherein Q is NCH₃. A5.The compound of embodiment A2, wherein Q is CH₂. A6.The compound of embodiment A2, wherein Q is O. A7.The compound of embodiment A2, wherein Q is S. A8.The compound of embodiment A1, wherein Heterocyclic Moiety^B is . A9.The compound of embodiment A8, wherein R² is H. A10. The compound of embodiment A8, wherein R² is CH₃. A11. The compound of embodiment A1, wherein Heterocyclic Moiety^B is . A12. The compound of any one of embodiments A1-A11, wherein R¹ is hydrogen. A13. The compound of any one of embodiments A1-A11, wherein R¹ is CH₃. A14. The compound of any one of embodiments A1-A11, wherein R¹ and R⁶ combined form a one-carbon bridge. A15. The compound of embodiment A1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B is A16. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. A17. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from , , , , , , and A18. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from

, and . A19. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from and . A20. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. A21. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from , , , , and A22. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from , and . A23. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from , , , , , , and . A24. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from

, and A25. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from and . A26. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. A27. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. A28. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. A29. The compound of embodiment A1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B is A30. The compound of embodiment A29, wherein R¹⁸ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. A31. The compound of embodiment A29, wherein R¹⁸ is which is attached to the azaglutarimide moiety through a C-N bond and optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. A32. The compound of embodiment A29, wherein R¹⁸ is , , or A33. The compound of embodiment A29, wherein R¹⁸ is , or A34. The compound of embodiment A1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B is A35. The compound of embodiment A1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B is . A36. The compound of any one of embodiments A29-A35, wherein R¹ is hydrogen. A37. The compound of any one of embodiments A29-A35, wherein R¹ is CH3. A38. The compound of any one of embodiments A29-A35, wherein R¹ and R⁶ combined form a one-carbon bridge. A39. The compound of embodiment A1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B is A40. The compound of embodiment A1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B is . A41. The compound of any one of embodiments A1-A40, wherein R⁶ is hydrogen. A42. The compound of any one of embodiments A1-A40, wherein R⁶ is methyl. A43. The compound of any one of embodiments A1-A42, wherein each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, and halogen. A44. The compound of any one of embodiments A1-A42, wherein each R⁵ is hydrogen. A45. The compound of any one of embodiments A1-A42, wherein one R⁵ is F. A46. The compound of any one of embodiments A1-A42, wherein R⁵ is -NR⁷R⁸ or - OR⁷. A47. The compound of embodiment A46, wherein R⁷ is hydrogen. A48. The compound of embodiment A46, wherein R⁷ is methyl. A49. The compound of any one of embodiments A46-A48, wherein R⁸ is hydrogen. A50. The compound of any one of embodiments A46-A48, wherein R⁸ is methyl. A51. The compound of any one of embodiments A1-A42, wherein R⁵ is aryl or heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. A52. The compound of any one of embodiments A1-A42, wherein R⁵ is cyano. A53. The compound of any one of embodiments A1-A42, wherein R⁵ is nitro. A54. The compound of any one of embodiments A1-A42, wherein R⁵ -C(O)CH3. A55. The compound of any one of embodiments A1-A54, wherein Linker is of formula: or A56. The compound of embodiment A55, wherein X¹ is bond. A57. The compound of embodiment A55, wherein X¹ is heterocycle. A58. The compound of embodiment A55, wherein X¹ is NR². A59. The compound of embodiment A55, wherein X¹ is C(O). A60. The compound of any one of embodiments A55-A59, wherein X² is bond. A61. The compound of any one of embodiments A55-A59, wherein X² is heterocycle. A62. The compound of any one of embodiments A55-A59, wherein X² is NR². A63. The compound of any one of embodiments A55-A59, wherein X² is C(O). A64. The compound of any one of embodiments A55-A63, wherein R²⁰ is bond. A65. The compound of any one of embodiments A55-A63, wherein R²⁰ is CH₂. A66. The compound of any one of embodiments A55-A63, wherein R²⁰ is heterocycle. A67. The compound of any one of embodiments A55-A63, wherein R²⁰ is aryl. A68. The compound of any one of embodiments A55-A63, wherein R²⁰ is phenyl. A69. The compound of any one of embodiments A55-A63, wherein R²⁰ is bicycle. A70. The compound of any one of embodiments A55-A69, wherein R²¹ is bond. A71. The compound of any one of embodiments A55-A69, wherein R²¹ is CH₂. A72. The compound of any one of embodiments A55-A69, wherein R²¹ is heterocycle. A73. The compound of any one of embodiments A55-A69, wherein R²¹ is aryl. A74. The compound of any one of embodiments A55-A69, wherein R²¹ is phenyl. A75. The compound of any one of embodiments A55-A69, wherein R²¹ is bicycle. A76. The compound of any one of embodiments A1-A54, wherein Linker is of formula: A77. The compound of any one of embodiments A55-A76, wherein R²² is bond. A78. The compound of any one of embodiments A55-A76, wherein R²² is CH₂. A79. The compound of any one of embodiments A55-A76, wherein R²² is heterocycle. A80. The compound of any one of embodiments A55-A76, wherein R²² is aryl. A81. The compound of any one of embodiments A55-A76, wherein R²² is phenyl. A82. The compound of any one of embodiments 55-76, wherein R²² is bicycle. A83. The compound of any one of embodiments A1-A54, wherein Linker is of formula: A84. The compound of any one of embodiments A55-A83, wherein R²³ is bond. A85. The compound of any one of embodiments A55-A83, wherein R²³ is CH₂. A86. The compound of any one of embodiments A55-A83, wherein R²³ is heterocycle. A87. The compound of any one of embodiments A55-A83, wherein R²³ is aryl. A88. The compound of any one of embodiments A55-A83, wherein R²³ is phenyl. A89. The compound of any one of embodiments A55-A83, wherein R²³ is bicycle. A90. The compound of any one of embodiments A1-A54, wherein Linker is of formula: A91. The compound of any one of embodiments A55-A90, wherein R²⁴ is bond. A92. The compound of any one of embodiments A55-A90, wherein R²⁴ is CH₂. A93. The compound of any one of embodiments A55-A90, wherein R²⁴ is heterocycle. A94. The compound of any one of embodiments A55-A90, wherein R²⁴ is aryl. A95. The compound of any one of embodiments A55-A90, wherein R²⁴ is phenyl. A96. The compound of any one of embodiments A55-A90, wherein R²⁴ is bicycle. A97. The compound of any one of embodiments A55-A90, wherein R²⁴ is C(O). A98. The compound of any one of embodiments A1-A97, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. A99. The compound of embodiment A98, wherein the KRAS Targeting Ligand^A is A100. The compound of embodiment A98, wherein the KRAS Targeting Ligand^A is . A101. The compound of embodiment A98, wherein the KRAS Targeting Ligand^A is A102. The compound of embodiment A98, wherein the KRAS Targeting Ligand^A is A103. The compound of embodiment A98, wherein the KRAS Targeting Ligand^A is A104. The compound of embodiment A98, wherein the KRAS Targeting Ligand^A is A105. The compound of embodiment A98, wherein the KRAS Targeting Ligand^A is A106. The compound of embodiment A98, wherein the KRAS Targeting Ligand^A is A107. The compound of embodiment A98, wherein the KRAS Targeting Ligand^A is A108. The compound of any one of embodiments A1-A97, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. A109. The compound of embodiment A108, wherein KRAS Targeting Ligand^B is A110. The compound of embodiment A108, wherein KRAS Targeting Ligand^B is A111. The compound of embodiment A108, wherein KRAS Targeting Ligand^B is A112. The compound of embodiment A108, wherein KRAS Targeting Ligand^B is A113. The compound of embodiment A108, wherein KRAS Targeting Ligand^B is A114. The compound of embodiment A108, wherein KRAS Targeting Ligand^B is A115. The compound of embodiment A108, wherein KRAS Targeting Ligand^B is A116. The compound of any one of embodiments A1-A97, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. A117. The compound of embodiment A116, wherein KRAS Targeting Ligand^D is . A118. The compound of embodiment A116, wherein KRAS Targeting Ligand^D is A119. The compound of embodiment A116, wherein KRAS Targeting Ligand^D is A120. The compound of embodiment A116, wherein KRAS Targeting Ligand^D is A121. The compound of embodiment A116, wherein KRAS Targeting Ligand^D is A122. The compound of embodiment A116, wherein KRAS Targeting Ligand^D is A123. The compound of embodiment A116, wherein KRAS Targeting Ligand^D is A124. The compound of any one of embodiments A1-A123, wherein R³² is a heterocycle optionally substituted with 1, 2, 3, or 4 R⁵¹ groups as allowed by valence. A125. The compound of any one of embodiments A1-A123, wherein R³² is selected from and A126. The compound of any one of embodiments A1-A123, wherein R³² is selected from and . A127. The compound of any one of embodiments A1-A123, wherein R³² is A128. The compound of any one of embodiments A1-A97, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. A129. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A130. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A131. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A132. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A133. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A134. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A135. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A136. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A137. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A138. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A139. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A140. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A141. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A142. The compound of embodiment A128, wherein KRAS Targeting Ligand^C is A143. The compound of any one of embodiments A128-A142, wherein R^32B is selected from and A144. The compound of any one of embodiments A1-A143, wherein R³² or R^32B is A145. The compound of any one of embodiments A1-A143, wherein R³² or R^32B is A146. The compound of any one of embodiments A1-A145, wherein R^51B is selected from halogen, cyano, and -OR⁷. A147. The compound of any one of embodiments A1-A146, wherein R^51C is selected from hydrogen, alkyl, alkynyl, cyano, and CD₃. A148. The compound of any one of embodiments A1-A142, wherein R³² or R^32B is A149. The compound of any one of embodiments A1-A142, wherein R³² or R^32B is A150. The compound of any one of embodiments A1-A142, wherein R³² or R^32B is A151. The compound of any one of embodiments A1-A142, wherein R³² or R^32B is A152. The compound of any one of embodiments A1-A142, wherein R³² or R^32B is A153. The compound of any one of embodiments A1-A142, wherein R³² or R^32B is A154. The compound of any one of embodiments A1-A153, wherein R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷. A155. The compound of any one of embodiments A1-A154, wherein R²⁹ is aryl. A156. The compound of any one of embodiments A1-A154, wherein R²⁹ is heteroaryl. A157. The compound of any one of embodiments A1-A154, wherein R²⁹ is bicycle. A158. The compound of any one of embodiments A1-A153, wherein R²⁹ is A159. The compound of any one of embodiments A1-A158, wherein R⁴⁵ is -OR¹¹. A160. The compound of embodiment A159, wherein R¹¹ is H. A161. The compound of any one of embodiments A1-A158, wherein R⁴⁶ is selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, -OR¹¹, and C(O)R¹⁴. A162. The compound of any one of embodiments A1-A158, wherein R⁴⁶ is selected from alkyl, alkynyl, and halogen. A163. The compound of any one of embodiments A1-A158, wherein R⁴⁶ is ethyl. A164. The compound of any one of embodiments A1-A158, wherein R⁴⁶ is -CCH. A165. The compound of any one of embodiments A1-A158, wherein R⁴⁶ is chloro. A166. The compound of any one of embodiments A1-A158, wherein R⁴⁶ is bromo. A167. The compound of any one of embodiments A1-A166, wherein R⁴⁷ is selected from hydrogen, alkyl, haloalkyl, halogen, and -OR¹¹. A168. The compound of any one of embodiments A1-A166, wherein R⁴⁷ is hydrogen. A169. The compound of any one of embodiments A1-A166, wherein R⁴⁷ is halogen. A170. The compound of any one of embodiments A1-A166, wherein R⁴⁷ is fluoro. A171. The compound of any one of embodiments A1-A166, wherein R⁴⁷ is chloro. A172. The compound of any one of embodiments A1-A171, wherein R³³ is A173. The compound of any one of embodiments A1-A171, wherein R³³ is A174. The compound of any one of embodiments A1-A171, wherein R³³ is A175. The compound of any one of embodiments A172-A174, wherein X is -O-. A176. The compound of any one of embodiments A172-A174, wherein X is -NH-. A177. The compound of any one of embodiments A172-A174, wherein X is -S-. A178. The compound of any one of embodiments A1-A171, wherein R³³ is A179. The compound of any one of embodiments A1-A171, wherein R³³ is A180. The compound of any one of embodiments A1-A171, wherein R³³ is A181. The compound of any one of embodiments A1-A171, wherein R³³ is A182. The compound of any one of embodiments A1-A171, wherein R³³ is A183. The compound of any one of embodiments A1-A171, wherein R³³ is A184. The compound of any one of embodiments A1-A171, wherein R³³ is A185. The compound of any one of embodiments A1-A171, wherein R³³ is A186. The compound of any one of embodiments A1-A171, wherein R³³ is A187. In certain embodiments, the invention is a pharmaceutical composition comprising a compound of any one of embodiments A1-A186, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. A188. The pharmaceutical composition of embodiment A187, in an oral dosage form. A189. The pharmaceutical composition of embodiment A188, wherein the oral dosage form is a solid dosage form. A190. The pharmaceutical composition of embodiment A189, wherein the dosage form is a tablet or capsule. A191. The pharmaceutical composition of embodiment A187, in a liquid dosage form. A192. The pharmaceutical composition of embodiment A191, wherein the liquid dosage form is suitable for parenteral administration. A193. The pharmaceutical composition of embodiment A191, wherein the liquid dosage form is suitable for intravenous administration. A194. The pharmaceutical composition of embodiment A191, wherein the liquid dosage form is suitable for intramuscular administration. A195. In certain embodiments, the invention is a method of treating a KRAS mediated disorder comprising administering an effective amount of a compound of any one of embodiments A1-A194, or a pharmaceutically acceptable salt thereof, to a human patient in need thereof. A196. The method of treatment of embodiment A195, wherein the disorder is a cancer. A197. The method of treatment of embodiment A195 or A196, wherein the cancer is mediated by a mutant form of KRAS. A198. The method of treatment of embodiment A197, wherein the cancer is mediated by KRAS G12D. A199. The method of treatment of embodiment A197, wherein the cancer is mediated by KRAS G12V. A200. The method of treatment of any one of embodiments A195-A199, wherein the compound is administered in combination with an additional anticancer compound. B1.A compound of Formula: ;

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

Heterocyclic Moiety^B is selected from: and ; y is 1, 2, 3, or 4; R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R⁶ are combined to form a one or two carbon bridge to form a fused cycle, 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 , 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; R^18B is a wherein the bicycle is a 9-membered bicycle which is attached to the azaglutarimide moiety through a C-N bond and is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; Q is CH₂, NR², , O, or S; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one 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 one R¹² substituent; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵; 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, and -P(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 of Formula: 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, 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, and heterocycle; 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; KRAS Targeting Ligand^A is selected from: and KRAS Targeting Ligand^B is selected from: and ; KRAS Targeting Ligand^C is selected from:

and ; KRAS Targeting Ligand^D is selected from: , , and ;

or KRAS Targeting Ligand^A, KRAS Targeting Ligand^B, KRAS Targeting Ligand^C, or KRAS Targeting Ligand^D, is selected from: , and ; KRAS Targeting Ligand^E is selected from: and KRAS Targeting Ligand^F is selected from: and R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; R^29B is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁴⁵, R¹⁴⁶, and R¹⁴⁷; each R¹⁴⁵, R¹⁴⁶, and R¹⁴⁷ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(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; R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R³² is heterocycle optionally substituted with 1, 2, 3, or 4 R⁵¹ groups as allowed by valence; R⁴ is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or bicycle; R⁵¹ is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R^51B is selected from halogen, cyano, haloalkyl, -OR⁷, and -SR⁷; R^51C is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD₃; R^51D and R^51E are hydrogen or together with X^B and the carbon atoms to which they are attached, form a 5-, 6-, or 7-membered ring; z is independently selected at each instance from 0, 1, 2, 3, and 4, as allowed by valence; X^B is selected from -CH₂-, -O-, -NH-, -N(R⁴)-, and -S-; X^C is -CH₂-, -O-, or -S-; R³³ is selected from: an ³³ d each of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; R^33C is ^33C , and each of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; R³ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R^33E is ^33E , , and each of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and - SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; R^3C is independently selected from C₂-C₈ alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R^7C is independently selected from hydrogen, C₂-C₈ 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; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; R³⁸ and R³⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, and heterocycle each of which except hydrogen and halogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R⁴¹, R⁴², R⁴³, and R⁴⁴ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; each R⁴⁵, R⁴⁶, and R⁴⁷ 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, and -P(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; p is 3, 4, 5, 6, 7, or 8; R¹³³ and R¹³⁴ are independently selected from hydrogen and C₁-C3alkyl; or R¹³³ and R¹³⁴, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted with 1, 2, 3, or 4 halogen atoms as allowed by valence; R¹³⁵ and R¹³⁶ are independently selected from hydrogen and C₁-C₆ alkyl; or R¹³⁵ and R¹³⁶, together with the nitrogen atom to which they are attached form a heterocycle, optionally substituted with 1, 2, 3, or 4 R¹³⁷ groups; R¹³⁷ is independently selected at each instance from C₁-C₆alkyl, C₁-C₆haloalkyl, -OR⁷, -NR⁷R⁸, and halogen; R^32B is selected from: and q is 1, 2, or 3; w is 1, 2, or 3; X^D is selected from -CH₂-, -O-, and -S-; R^32C is selected from: and R¹⁵¹ is independently selected at each instance from hydrogen, C₂-C₈ alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷⁷R⁸⁸, -OR⁷, and -SR⁷; R⁷⁷ and R⁸⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹¹⁴ is independently selected from hydrogen, C₂-C₈ alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, -O-C₂-C₈ alkyl, -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; X^E is selected from -O-, and -S-; qq is 2, or 3; R^33D is , or each of which R^33D is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, - NR⁷R⁸, -OR⁷, and -SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; zz is independently 1, 2, 3, or 4; R^29C is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^45C, R^46C, and R^47C; each R^45C, R^46C, and R^47C is independently selected from hydrogen, C₃-C₈ alkyl, haloalkyl, alkenyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(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; R^29D is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^45D, R^46D, and R^47D; each R^45D, R^46D, and R^47D is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, chloro, bromo, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -O-alkyl, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(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; R^29E is selected from phenyl and heteroaryl each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; and R^31B is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷. B2.The compound of embodiment B1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are or B3.The compound of embodiment B2, wherein Q is NH. B4.The compound of embodiment B2, wherein Q is NCH₃. B5.The compound of embodiment B2, wherein Q is CH₂. B6.The compound of embodiment B2, wherein Q is O. B7.The compound of embodiment B2, wherein Q is S. B8.The compound of embodiment B1, wherein Heterocyclic Moiety^B is . B9.The compound of embodiment B8, wherein R² is H. B10. The compound of embodiment B8, wherein R² is CH3. B11. The compound of embodiment B1, wherein Heterocyclic Moiety^B is B12. The compound of any one of embodiments B1-B11, wherein R¹ is hydrogen. B13. The compound of any one of embodiments B1-B11, wherein R¹ is CH3. B14. The compound of any one of embodiments B1-B11, wherein R¹ and R⁶ combined form a one-carbon bridge. B15. The compound of embodiment B1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are B16. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. B17. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are selected from , , , , , , and B18. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are selected from , and B19. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are selected from , and B20. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. B21. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are selected from , , , , , , , and B22. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are selected from , and B23. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are selected from and . B24. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are selected from , , , , , , , , , , , and B25. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are selected from and . B26. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. B27. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. B28. The compound of any one of embodiments B1-B15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. B29. The compound of embodiment B1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are or B30. The compound of embodiment B29, wherein R¹⁸ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. B31. The compound of embodiment B29, wherein R¹⁸ is which is attached to the azaglutarimide moiety through a C-N bond and optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. B32. The compound of embodiment B29, wherein R¹⁸ and R^18B are , or B33. The compound of embodiment B29, wherein R¹⁸ and R^18B are or B34. The compound of embodiment B1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are B35. The compound of embodiment B1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are B36. The compound of any one of embodiments B34-B35, wherein R¹ is hydrogen. B37. The compound of any one of embodiments B34-B35, wherein R¹ is CH3. B38. The compound of any one of embodiments B34-B35, wherein R¹ and R⁶ combined form a one-carbon bridge. B39. The compound of embodiment B1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are B40. The compound of embodiment B1, wherein Heterocyclic Moiety^B is B41. The compound of any one of embodiments B1-B40, wherein R⁶ is hydrogen. B42. The compound of any one of embodiments B1-B40, wherein R⁶ is methyl. B43. The compound of any one of embodiments B1-B42, wherein each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, and halogen. B44. The compound of any one of embodiments B1-B42, wherein each R⁵ is hydrogen. B45. The compound of any one of embodiments B1-B42, wherein one R⁵ is F. B46. The compound of any one of embodiments B1-B42, wherein R⁵ is -NR⁷R⁸ or - OR⁷. B47. The compound of embodiment B46, wherein R⁷ is hydrogen. B48. The compound of embodiment B46, wherein R⁷ is methyl. B49. The compound of any one of embodiments B46-B48, wherein R⁸ is hydrogen. B50. The compound of any one of embodiments B46-B48, wherein R⁸ is methyl. B51. The compound of any one of embodiments B1-B42, wherein R⁵ is aryl or heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. B52. The compound of any one of embodiments B1-B42, wherein R⁵ is cyano. B53. The compound of any one of embodiments B1-B42, wherein R⁵ is nitro. B54. The compound of any one of embodiments B1-B42, wherein R⁵ -C(O)CH₃. B55. The compound of any one of embodiments B1-B54, wherein Linker is of formula: or B56. The compound of embodiment B55, wherein X¹ is bond. B57. The compound of embodiment B55, wherein X¹ is heterocycle. B58. The compound of embodiment B55, wherein X¹ is NR². B59. The compound of embodiment B55, wherein X¹ is C(O). B60. The compound of any one of embodiments B55-B59, wherein X² is bond. B61. The compound of any one of embodiments B55-B59, wherein X² is heterocycle. B62. The compound of any one of embodiments B55-B59, wherein X² is NR². B63. The compound of any one of embodiments B55-B59, wherein X² is C(O). B64. The compound of any one of embodiments B55-B63, wherein R²⁰ is bond. B65. The compound of any one of embodiments B55-B63, wherein R²⁰ is CH₂. B66. The compound of any one of embodiments B55-B63, wherein R²⁰ is heterocycle. B67. The compound of any one of embodiments B55-B63, wherein R²⁰ is aryl. B68. The compound of any one of embodiments B55-B63, wherein R²⁰ is phenyl. B69. The compound of any one of embodiments B55-B63, wherein R²⁰ is bicycle. B70. The compound of any one of embodiments B55-B69, wherein R²¹ is bond. B71. The compound of any one of embodiments B55-B69, wherein R²¹ is CH₂. B72. The compound of any one of embodiments B55-B69, wherein R²¹ is heterocycle. B73. The compound of any one of embodiments B55-B69, wherein R²¹ is aryl. B74. The compound of any one of embodiments B55-B69, wherein R²¹ is phenyl. B75. The compound of any one of embodiments B55-B69, wherein R²¹ is bicycle. B76. The compound of any one of embodiments B1-B54, wherein Linker is of formula: B77. The compound of any one of embodiments B55-B76, wherein R²² is bond. B78. The compound of any one of embodiments B55-B76, wherein R²² is CH₂. B79. The compound of any one of embodiments B55-B76, wherein R²² is heterocycle. B80. The compound of any one of embodiments B55-B76, wherein R²² is aryl. B81. The compound of any one of embodiments B55-B76, wherein R²² is phenyl. B82. The compound of any one of embodiments B55-B76, wherein R²² is bicycle. B83. The compound of any one of embodiments B1-B54, wherein Linker is of formula: B84. The compound of any one of embodiments B55-B83, wherein R²³ is bond. B85. The compound of any one of embodiments B55-B83, wherein R²³ is CH₂. B86. The compound of any one of embodiments B55-B83, wherein R²³ is heterocycle. B87. The compound of any one of embodiments B55-B83, wherein R²³ is aryl. B88. The compound of any one of embodiments B55-B83, wherein R²³ is phenyl. B89. The compound of any one of embodiments B55-B83, wherein R²³ is bicycle. B90. The compound of any one of embodiments B1-B54, wherein Linker is of formula: B91. The compound of any one of embodiments B55-B90, wherein R²⁴ is bond. B92. The compound of any one of embodiments B55-B90, wherein R²⁴ is CH₂. B93. The compound of any one of embodiments B55-B90, wherein R²⁴ is heterocycle. B94. The compound of any one of embodiments B55-B90, wherein R²⁴ is aryl. B95. The compound of any one of embodiments B55-B90, wherein R²⁴ is phenyl. B96. The compound of any one of embodiments B55-B90, wherein R²⁴ is bicycle. B97. The compound of any one of embodiments B55-B90, wherein R²⁴ is C(O). B98. The compound of any one of embodiments B1-B7, B15-B39, and B41-B97, wherein the compound is of Formula ; or a pharmaceutically acceptable salt thereof. B99. The compound of embodiment B98, wherein the KRAS Targeting Ligand^A is B100. The compound of embodiment B98, wherein the KRAS Targeting Ligand^A is B101. The compound of embodiment B98, wherein the KRAS Targeting Ligand^A is B102. The compound of embodiment B98, wherein the KRAS Targeting Ligand^A is B103. The compound of embodiment B98, wherein the KRAS Targeting Ligand^A is B104. The compound of embodiment B98, wherein the KRAS Targeting Ligand^A is B105. The compound of embodiment B98, wherein the KRAS Targeting Ligand^A is B106. The compound of embodiment B98, wherein the KRAS Targeting Ligand^A is B107. The compound of any one of embodiments B1-B97, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. B108. The compound of embodiment B107, wherein KRAS Targeting Ligand^B is B109. The compound of embodiment B107, wherein KRAS Targeting Ligand^B is B110. The compound of embodiment B107, wherein KRAS Targeting Ligand^B is B111. The compound of embodiment B107, wherein KRAS Targeting Ligand^B is B112. The compound of embodiment B107, wherein KRAS Targeting Ligand^B is B113. The compound of embodiment B107, wherein KRAS Targeting Ligand^B is B114. The compound of embodiment B107, wherein KRAS Targeting Ligand^B is B115. The compound of any one of embodiments B1-B97, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. B116. The compound of embodiment B115, wherein KRAS Targeting Ligand^D is B117. The compound of embodiment B115, wherein KRAS Targeting Ligand^D is B118. The compound of embodiment B115, wherein KRAS Targeting Ligand^D is B119. The compound of embodiment B115, wherein KRAS Targeting Ligand^D is B120. The compound of embodiment B115, wherein KRAS Targeting Ligand^D is B121. The compound of embodiment B115, wherein KRAS Targeting Ligand^D is B122. The compound of embodiment B115, wherein KRAS Targeting Ligand^D is B123. The compound of any one of embodiments B1-B97, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. B124. The compound of embodiment B123, wherein KRAS Targeting Ligand^E is B125. The compound of embodiment B123, wherein KRAS Targeting Ligand^E is selected from , and B126. The compound of any one of embodiments B1-B97, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. B127. The compound of any one of embodiments B1-B126, wherein R³² is a heterocycle optionally substituted with 1, 2, 3, or 4 R⁵¹ groups as allowed by valence. B128. The compound of any one of embodiments B1-B126, wherein R³² is selected from B129. The compound of any one of embodiments B1-B126, wherein R³² is selected from and B130. The compound of any one of embodiments B1-B126, wherein R³² is B131. The compound of any one of embodiments B1-B97, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. B132. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B133. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B134. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B135. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B136. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B137. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B138. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B139. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B140. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B141. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B142. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B143. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B144. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B145. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is , , or B146. The compound of any one of embodiments B131-B145, wherein R^32B is selected from and B147. The compound of any one of embodiments B1-B146, wherein R³² and R^32B are B148. The compound of any one of embodiments B1-B146, wherein R³² and R^32B are B149. The compound of any one of embodiments B1-B148, wherein R^51B is selected from halogen, cyano, and -OR⁷. B150. The compound of any one of embodiments B1-B149, wherein R^51C is selected from hydrogen, alkyl, alkynyl, cyano, and CD3. B151. The compound of any one of embodiments B1-B146, wherein R³² and R^32B are B152. The compound of any one of embodiments B1-B146, wherein R³² and R^32B are B153. The compound of any one of embodiments B1-B146, wherein R³² and R^32B are B154. The compound of any one of embodiments B1-B146, wherein R³² and R^32B are B155. The compound of any one of embodiments B1-B146, wherein R³² and R^32B are B156. The compound of any one of embodiments B1-B146, wherein R³² and R^32B are B157. The compound of embodiment B131, wherein KRAS Targeting Ligand^C is B158. The compound of any one of embodiments B1-B125, B127-B144 and B146- B157, wherein R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷. B159. The compound of any one of embodiments B1-B125, B127-B144 and B146- B158, wherein R²⁹ is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷. B160. The compound of any one of embodiments B1-B125, B127-B144 and B146- B158, wherein R²⁹ is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷. B161. The compound of any one of embodiments B1-B125, B127-B144 and B146- B158, wherein R²⁹ is bicycle optionally substituted with 1, 2, or 3 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷. B162. The compound of any one of embodiments B1-B125, B127-B144 and B146- B158, wherein R²⁹ is B163. The compound of any one of embodiments B158-B162, wherein R⁴⁵ is -OR¹¹. B164. The compound of embodiment B163, wherein R¹¹ is H. B165. The compound of any one of embodiments B158-B164, wherein R⁴⁶ is selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, -OR¹¹, and C(O)R¹⁴. B166. The compound of any one of embodiments B158-B164, wherein R⁴⁶ is selected from alkyl, alkynyl, and halogen. B167. The compound of any one of embodiments B158-B164, wherein R⁴⁶ is ethyl. B168. The compound of any one of embodiments B158-B164, wherein R⁴⁶ is -CCH. B169. The compound of any one of embodiments B158-B164, wherein R⁴⁶ is chloro. B170. The compound of any one of embodiments B158-B164, wherein R⁴⁶ is bromo. B171. The compound of any one of embodiments B158-B170, wherein R⁴⁷ is selected from hydrogen, alkyl, haloalkyl, halogen, and -OR¹¹. B172. The compound of any one of embodiments B158-B170, wherein R⁴⁷ is hydrogen. B173. The compound of any one of embodiments B158-B170, wherein R⁴⁷ is halogen. B174. The compound of any one of embodiments B158-B170, wherein R⁴⁷ is fluoro. B175. The compound of any one of embodiments B158-B170, wherein R⁴⁷ is chloro. B176. The compound of any one of embodiments B1-B122, B126-B143, and B145- B175, wherein R³³ is . B177. The compound of any one of embodiments B1-B175, wherein R³³, R^33C and R^33D are B178. The compound of any one of embodiments B1-B122 and B126-B175, wherein R³³ and R^33D are B179. The compound of any one of embodiments B1-B175, wherein R³³, R^33C and R^33D are B180. The compound of any one of embodiments B1-B175, wherein R³³, R^33C and R^33D are B181. The compound of any one of embodiments B176-B180, wherein X is -O-. B182. The compound of any one of embodiments B176-B180, wherein X is -NH-. B183. The compound of any one of embodiments B176-B180, wherein X is -S-. B184. The compound of embodiments B1-B122, B126-B143, and B145-B175, wherein R³³ is B185. The compound of embodiment B176, wherein R³³ is B186. The compound of embodiment B176, wherein R³³ is B187. The compound of embodiment B176, wherein R³³ is B188. The compound of embodiment B178, wherein R³³ and R^33D are . B189. The compound of embodiment B180, wherein R³³, R^33C and R^33D are B190. The compound of embodiment B176, wherein R³³ is B191. The compound of embodiment B176, wherein R³³ is B192. A compound selected from:

or a pharmaceutically acceptable salt thereof. B193. A pharmaceutical composition comprising a compound of any one of embodiments B1-B192, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. B194. The pharmaceutical composition of embodiment B193, in an oral dosage form. B195. The pharmaceutical composition of embodiment B194, wherein the oral dosage form is a solid dosage form. B196. The pharmaceutical composition of embodiment B195, wherein the dosage form is a tablet or capsule. B197. The pharmaceutical composition of embodiment B193, in a liquid dosage form. B198. The pharmaceutical composition of embodiment B197, wherein the liquid dosage form is suitable for parenteral administration. B199. The pharmaceutical composition of embodiment B197, wherein the liquid dosage form is suitable for intravenous administration. B200. The pharmaceutical composition of embodiment B197, wherein the liquid dosage form is suitable for intramuscular administration. B201. A method of treating a KRAS mediated disorder comprising administering an effective amount of a compound of any one of embodiments B1-B192, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to a human patient in need thereof. B202. The method of treatment of embodiment B201, wherein the disorder is a cancer. B203. The method of treatment of embodiment B201 or B202, wherein the cancer is mediated by a mutant form of KRAS. B204. The method of treatment of embodiment B203, wherein the cancer is mediated by KRAS G12D. B205. The method of treatment of embodiment B203, wherein the cancer is mediated by KRAS G12V. B206. The method of treatment of any one of embodiments B201-B205, wherein the compound is administered in combination with an additional anticancer compound. B207. Use of a compound of any one of embodiments B1-B192, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a KRAS mediated disorder. B208. Use of a compound of any one of embodiments B1-B192, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the treatment of a KRAS mediated disorder. B209. The use of embodiment B207 or B208, wherein the disorder is a cancer. B210. The use of embodiment B209, wherein the cancer is mediated by a mutant form of KRAS. B211. The use of embodiment B209, wherein the cancer is mediated by KRAS G12D. B212. The use of embodiment B209, wherein the cancer is mediated by KRAS G12V. C1.A compound of Formula: ; or ; or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic Moiety^A is selected from: and Heterocyclic Moiety^B is selected from: and y is 1, 2, 3, or 4; R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R⁶ are combined to form a one or two carbon bridge to form a fused cycle, 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 , 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; R^18B is a wherein the bicycle is a 9-membered bicycle which is attached to the azaglutarimide moiety through a C-N bond and is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; Q is CH₂, NR², O, or S; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one 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 one R¹² substituent; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵; 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, and -P(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 of Formula: 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, 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, and heterocycle; 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; KRAS Targeting Ligand^A is selected from: and B KRAS Targeting Ligand is selected from: and KRAS Targeting Ligand^C is selected from:

and KRAS Targeting Ligand^D is selected from: , , and ;

or KRAS Targeting Ligand^A, KRAS Targeting Ligand^B, KRAS Targeting Ligand^C, or KRAS Targeting Ligand^D, is selected from: , and ; KRAS Targeting Ligand^E is selected from: , , , and ; KRAS Targeting Ligand^F is selected from: , and R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; R^29B is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁴⁵, R¹⁴⁶, and R¹⁴⁷; each R¹⁴⁵, R¹⁴⁶, and R¹⁴⁷ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(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; R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R³² is heterocycle optionally substituted with 1, 2, 3, or 4 R⁵¹ groups as allowed by valence; R⁴ is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or bicycle; R⁵¹ is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R^51B is selected from halogen, cyano, haloalkyl, -OR⁷, and -SR⁷; R^51C is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD₃; R^51D and R^51E are hydrogen or together with X^B and the carbon atoms to which they are attached, form a 5-, 6-, or 7-membered ring; z is independently selected at each instance from 0, 1, 2, 3, and 4, as allowed by valence; X^B is selected from -CH₂-, -O-, -NH-, -N(R⁴)-, and -S-; X^C is -CH₂-, -O-, or -S-; R³³ is selected from: an ³³ d each of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; R^33C is ^33C and each of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; R³ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R^33E is , ^33E and each of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and - SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; R^3C is independently selected from hydrogen, C₂-C₈ alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R^7C is independently selected from hydrogen, C₂-C₈ 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; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; R³⁸ and R³⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, and heterocycle each of which except hydrogen and halogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R⁴¹, R⁴², R⁴³, and R⁴⁴ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; each R⁴⁵, R⁴⁶, and R⁴⁷ 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, and -P(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; p is 3, 4, 5, 6, 7, or 8; R¹³³ and R¹³⁴ are independently selected from hydrogen and C1-C3alkyl; or R¹³³ and R¹³⁴, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted with 1, 2, 3, or 4 halogen atoms as allowed by valence; R¹³⁵ and R¹³⁶ are independently selected from hydrogen and C₁-C₆ alkyl; or R¹³⁵ and R¹³⁶, together with the nitrogen atom to which they are attached form a heterocycle, optionally substituted with 1, 2, 3, or 4 R¹³⁷ groups; R¹³⁷ is independently selected at each instance from C₁-C₆alkyl, C₁-C₆haloalkyl, -OR⁷, -NR⁷R⁸, and halogen; R^32B is selected from: , , , and q is 1, 2, or 3; w is 1, 2, or 3; X^D is selected from -CH₂-, -O-, and -S-; R^32C is selected from: , , , , , and R¹⁵¹ is independently selected at each instance from hydrogen, C₂-C₈ alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷⁷R⁸⁸, -OR⁷, and -SR⁷; R⁷⁷ and R⁸⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹¹⁴ is independently selected from hydrogen, C₂-C₈ alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, -O-C₂-C₈ alkyl, -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; X^E is selected from -O-, and -S-; qq is 2, or 3; R^33D is , or each of which R^33D is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, - NR⁷R⁸, -OR⁷, and -SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; zz is independently 1, 2, 3, or 4; R^29C is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^45C, R^46C, and R^47C; each R^45C, R^46C, and R^47C is independently selected from hydrogen, C₃-C₈ alkyl, haloalkyl, alkenyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(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; R^29D is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^45D, R^46D, and R^47D; each R^45D, R^46D, and R^47D is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, chloro, bromo, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -O-alkyl, Attorney Docket No.: P23-255L-WO-PCT -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(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; R^29E is selected from phenyl and heteroaryl each of which is optionally substituted with 5 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; and R^31B is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷. C2.The compound of embodiment C1, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are 10 o . C3.The compound of embodiment C2, wherein S. C4.The compound of embodiment C1, wherein is . C5. any one of embodiments C1-C4, wherein R¹ is hydrogen. 15 C6.The compound of any one of embodiments C1-C5, wherein R¹⁶ and R¹⁷ are selected from . lected from -150-

C8.The compound of embodiment Cl, wherein Heterocyclic Moiety^A and Heterocyclic

Moiety^B are

C9.The compound of embodiment C8, wherein R¹⁸ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^s.

C10. The compound of embodiment C8, wherein R¹⁸ and R⁵ are

Cl l. The compound of embodiment Cl , wherein Heterocyclic .A and

Heterocyclic Moiety⁸ are

C12. The compound of any one of embodiments Cl -Cl 1, w'herein R⁶ is hydrogen.

C13. The compound of any one of embodiments Cl -Cl 2, wherein each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, and halogen.

C14. The compound of any one of embodiments Cl -Cl 3, wherein Linker is of formula:

C15. The compound of any one of embodiments Cl -Cl 4, wherein X¹ is bond, heterocycle, or -NR²-.

C16. The compound of any one of embodiments C1-C15, wherein R²³ is bond, heterocycle, or -NR²-.

C17. The compound of any one of embodiments Cl -Cl 6, wherein R²⁰ is alkyl, heterocycle, aryl, heteroaryl or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R⁴⁰.

CIS. The compound of any one of embodiments Cl -Cl 7, wherein R²ⁱ is bond, -O-, -NR²-, -S-, alkyl, heterocycle, aryl, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R⁴⁰.

C19. The compound of any one of embodiments Cl -Cl 8, wherein R²² is alkyl, heterocycle, aryl, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R⁴⁰. C20. I'he compound of any one of embodiments C1 -C19, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof, wherein KRAS Targeting Ligand⁸ is

C21. The compound of any one of embodiments C1 -C19, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof; wherein KRAS Targeting Ligand^D is

C22. The compound of any one of embodiments C1 -C19, wherein the compound is of Formula KRAS

Lin Heterocyclic Targeting ker Moiety⁸ Ligand⁸ or a pharmaceutically acceptable salt thereof; wherein KRAS Targeting

C23. The compound of any one of embodiments Cl -Cl 9, w'herein the compound is

5 of Formula

KRAS Heterocycl argeting Li ic T nker Moiety⁸ Ligand⁸ or a pharmaceutically acceptable salt thereof.

C24. The compound of any one of embodiments C1-C23, wherein R³² is

10 C25. The compound of any one of embodiments Cl -Cl 9, wherein the compound is of Formula

KRAS

Linker Heterocyclic Targeting Moiety⁸ Ligand⁸ or a pharmaceutically acceptable salt thereof; wherein KRAS Targeting

R31 p^32B p32B R³ ' p^3z'.C

R³¹

N N N N Nr N

_R33 R33 N R33

R^28D N _R298 N R²⁸

15 F F , or s F

C26. The compound of embodiment C25, wh 52B |_{g se}J_ect_e j fj-_om

-154-

C27. The compound of any one of embodiments C1-C26, wherein R²⁹ i

C28. The compound of embodiment Cl, wherein the compound is selected from the compounds of Table 16B or a pharmaceutically acceptable salt thereof.

C29. A compound of Table 16A or a pharmaceutically acceptable salt thereof.

C30. A pharmaceutical composition comprising a compound of any one of embodiments C1-C29, oorr aa pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

C31. The pharmaceutical composition of embodiment C30 for the treatment of a KRAS mediated cancer.

C32. A method of treating a KRAS mediated cancer comprising administering an effective amount of a compound of any one of embodiments C1-C29 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to a human patient in need thereof.

C33, Use of a compound of any one of embodiments C1-C29 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in tire treatment of a KRAS mediated cancer.

C34. Use of a compound of any one of embodiments C1-C29 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament to treat a KRAS mediated cancer. ADDITIONAL EMBODIMENTS OF THE CURRENT INVENTION

KRAS Targeting Ligand is selected from KRAS Targeting Ligand^A, KRAS Targeting Ligand®, KRAS Targeting Ligand^C, and KRAS Targeting Ligand^D.

KRAS Targeting Ligand^G is selected from KRAS Targeting Ligand^B, KRAS Targeting Ligand^C, KRAS Targeting Ligand^D, KRAS Targeting Ligand^E Fnd KRAS Targeting Ligand^F.

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

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

In certain embodiments, the compound of the present in vention is of Formula: or a pharmaceutically acceptable salt thereof.

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

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

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

or a pharmaceutically acceptable salt thereof.

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

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

In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof,

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

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

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

or a pharmaceutically acceptable salt thereof.

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

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

or a pharmaceutically acceptable salt thereof.

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

In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand^A. In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand^B. In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand^C. In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand^D. In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand^E. In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand^F.

Embodiments of R¹ and R⁶

In certain embodiments R¹ is hydrogen.

In certain embodiments R.¹ is alkyl.

In certain embodiments R¹ is halogen. In certain embodiments, R.¹ is halogen, wherein the halogen is F. In certain embodiments, R¹ is halogen, wherein the halogen is C1. 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 R⁶ is alkyl.

In certain embodiments R° is haloalkyl.

In certain embodiments R¹ and R⁶ are combined to form a single carbon bridge.

In certain embodiments R‘ and R⁶ are both hydrogen.

Embodiments of R²

In certain embodiments R² is hydrogen.

In certain embodiments R² is alkyl.

In certain embodiments R² is haloalkyl.

In certain embodiments R² is alkenyl.

In certain embodiments R² is alkynyl. 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 phenyl. In certain embodiments, R² is phenyl 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 R^!0,

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 R¹, R², and R⁶ are each hydrogen.

Embodiments of R⁵

In certain embodiments R⁵ is hydrogen.

In certain embodiments each R⁵ is selected from alkyl, haloalkyl, and halogen.

In certain embodiments R⁵ is alkyl.

In certain embodiments R^; is haloalkyl.

In certain embodiments R³ 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 C1. In certain embodiments, R⁵ is halogen, wherein the halogen is Br. In certain embodiments, R^s is halogen, wherein the halogen is I.

In certain embodiments R⁵ is heteroaryl. In certain embodiments, R⁵ is aryl. In certain embodiments, R³ is heterocycle.

In certain embodiments R³ is cyano.

In certain embodiments R⁵ is -NR⁷R⁸. In certain embodiments, R³ is -NR⁷C(O)R⁹, In certain embodiments, R⁵ is -NR⁷C(S)R⁹. In certain embodiments, R³ is -NR⁷C(O)R⁹. In certain embodiments, R⁵ is -NR⁷S(O)₂R⁹.

In certain embodiments R⁵ is -OR⁷"

In certain embodiments R³ is -SR⁷. In certain embodiments, R⁵ is -S(O)₂R⁹.

In certain embodiments R³ is -C(O)R⁹. Embodiments of R⁷ and R⁸

Tn certain embodiments R⁷ is hydrogen.

In certain embodiments R⁷ is alkyl.

In certain embodiments R⁷ is methyl.

In certain embodiments R⁷ is haloalkyi.

In certain embodiments R⁷ is CFJ.

In certain embodiments R^? is aryl. In certain embodiments R⁷ is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In certain embodiments R⁷ is heteroaryl. In certain embodiments R⁷ is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In certain embodiments R⁷ is heterocycle. In certain embodiments R⁷ is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In certain embodiments R⁷ is C(O)R¹⁴.

In certain embodiments R⁷ is C(O) alkyl.

In certain embodiments R⁸ is hydrogen.

In certain embodiments R⁸ is alkyl.

In certain embodiments R⁸ is methyl.

In certain embodiments R⁸ is haloalkyi.

In certain embodiments R⁸ is CF₃.

In certain embodiments R⁷ and R⁸ are both hydrogen.

Embodiments of R³

In certain embodiments R⁹ is hydrogen.

In certain embodiments R⁹ is alkyl.

In certain embodiments R⁹ is methyl.

In certain embodiments R⁹ is ethyl.

In certain embodiments R⁹ is haloalkyi.

In certain embodiments R³ is CF₃.

In certain embodiments R⁹ is aryl. In certain embodiments R⁹ is and optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

In certain embodiments R⁹ is heteroaryl. In certain embodiments R^s is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. In certain embodiments R⁹ is heterocycle. In certain embodiments R⁹ is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰.

Tn certain embodiments R⁹ is -NR⁷R⁸.

In certain embodiments R⁹ is -NH₂.

In certain embodiments R⁹ is -N(CH₃)H.

In certain embodiments R⁹ is -N(CH₃)₂.

In certain embodiments R⁹ is -OR⁷.

In certain embodiments R⁹ is -OH.

In certain embodiments R⁹ is -SR⁷.

In certain embodiments R⁹ is -SH.

Embodiments of R¹⁰

In certain embodiments Rⁱ⁰ is hydrogen.

In certain embodiments R¹⁰ is alkyl.

In certain embodiments R¹⁰ is methyl.

In certain embodiments R¹⁰ is ethyl.

In certain embodiments R¹⁰ is haloalkyl.

In certain embodiments R¹⁰ is CF₃.

In certain embodiments R¹⁰ is aryl. In certain embodiments R¹⁰ is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹³.

In certain embodiments R¹⁰ is heteroaryl. In certain embodiments R¹⁰ is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵.

In certain embodiments R¹⁰ is heterocycle. In certain embodiments R¹⁰ is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵.

In certain embodiments R¹⁰ is -NR¹¹R¹³.

In certain embodiments R¹⁰ is -NH₂.

In certain embodiments R¹⁰ is -N(CH₃)H.

In certain embodiments R¹⁰ is -N(CH₃)₂.

In certain embodiments R^1C is -OR¹¹.

In certain embodiments R¹⁰ is -OH.

In certain embodiments R¹⁰ is -SR¹¹.

In certain embodiments R¹⁰ is -SH.

In certain embodiments R¹⁰ is alkenyl.

In certain embodiments R¹⁰ is alkynyl. In certain embodiments R¹⁰ is cyano.

In certain embodiments R¹⁰ is nitro.

Tn certain embodiments R¹⁰ is -C(O)R¹⁴.

In certain embodiments R¹⁰ is -C(O)alkyl.

In certain embodiments R¹⁰ is -C(O)N(alkyl)₂.

In certain embodiments R¹⁰ is -C(O)N(II)(a1kyl).

In certain embodiments R¹⁰ is -C(S) R¹⁴.

In certain embodiments R¹⁰ is -C(S)alkyl

In certain embodiments R¹⁰ is -C(S)N(alkyl)₂.

In certain embodiments R¹⁰ is -C(S)N(H)(alkyl).

In certain embodiments R¹⁰ is -S(O)R³⁴.

In certain embodiments R¹⁰ is -S(O)₂R¹⁴.

In certain embodiments R¹⁰ is -P(O)(R¹⁴)₂.

Embodiments of R¹¹ and R¹³

In certain embodiments R¹¹ is hydrogen.

In certain embodiments R¹¹ is alkyl.

In certain embodiments R¹¹ is methyl.

In certain embodiments R¹¹ is haloalkyl.

In certain embodiments R¹¹ is CF₃.

In certain embodiments R¹¹ is aryl. In certain embodiments R¹³ is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵.

In certain embodiments R¹¹ is heteroaryl. In certain embodiments R¹¹ is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵.

In certain embodiments R¹¹ is heterocycle. In certain embodiments Rⁿ is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵.

In certain embodiments R¹¹ is C(O)R¹⁴.

In certain embodiments R¹¹ is C(O)alkyl.

In certain embodiments R¹³ is hydrogen.

In certain embodiments R¹³ is alkyl. in certain embodiments R¹³ is methyl.

In certain embodiments R¹³ is haloalkyl.

In certain embodiments R¹³ is C_F3. Embodiments of R¹⁴

In certain embodiments R¹⁴ is hydrogen.

Tn certain embodiments R¹⁴ is alkyl.

In certain embodiments R¹⁴ is methyl.

In certain embodiments R¹⁴ is ethyl.

In certain embodiments R¹⁴ is haioaikyl.

In certain embodiments R¹⁴ is CF₃.

In certain embodiments R¹⁴ is aryl. In certain embodiments R¹⁴ is and optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵.

In certain embodiments R¹⁴ is heteroaryl. In certain embodiments R¹⁴ is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵.

In certain embodiments R¹⁴ is heterocycle. In certain embodiments R¹⁴ is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵.

In certain embodiments R¹⁴ is -NH₂.

In certain embodiments R¹⁴ is -N(H)(alkyl).

In certain embodiments R¹⁴ is -N(alkyl)₂.

In certain embodiments R¹⁴ is -OH.

In certain embodiments R¹⁴ is alkoxy.

Embodiments of R¹⁵

In certain embodiments R¹³ is hydrogen.

In certain embodiments each R¹⁵ is selected from alkyl, haioaikyl, and halogen.

In certain embodiments R¹⁵ is alkyl.

In certain embodiments R¹⁵ is haioaikyl.

In certain embodiments R¹⁵ is alkenyl.

In certain embodiments R¹⁵ is alkynyl.

In certain embodiments R¹⁵ is halogen.

In certain embodiments R¹⁵ is aryl.

In certain embodiments R¹⁵ is heteroaryl. hr certain embodiments R¹⁵ is heterocycle.

In certain embodiments R¹⁵ is cyano.

In certain embodiments R¹⁵ is nitro.

In certain embodiments R¹⁵ is amino. In certain embodiments R¹⁵ is hydroxyl.

In certain embodiments R¹⁵ is alkoxy.

Tn certain embodiments R¹⁵ is -N(H)(alkyl).

In certain embodiments R¹⁵ is -N(alkyl)₂.

Embodiments of Cyde-A and Cycle-B

In certain embodiments Cycle-A is phenyl optionally substituted with 1 or 2 substituents independently selected from R⁵.

In certain embodiments Cycle-A is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from R^s.

In certain embodiments Cycle-A is a 5- to 8-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from R^s.

In certain embodiments Cycle-A is a 5- to 8-membered cycloalkyl optionally substituted with 1 or 2 substituents independently selected from R⁵.

In certain embodiments Cycle-A is a 5- to 8-membered cycloalkenyl optionally substituted with 1 or 2 substituents independently selected from R⁵.

In certain embodiments Cycle-A is phenyl.

In certain embodiments Cycle-A is a 5- or 6-membered heteroaryl.

In certain embodiments Cycle-A is a 5- to 8-membered heterocycle.

In certain embodiments Cycle-A is a 5- to 8-membered cycloalkyl.

In certain embodiments Cycle-A is a 5- to 8-membered cycloalkenyl.

In certain embodiments Cycle~B is phenyl optionally substituted with 1 or 2 substituents independently selected from R⁵.

In certain embodiments Cycle-B is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from R^s.

In certain embodiments Cycle-B is a 5- to 8-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from R⁵.

In certain embodiments Cycle-B Is a 5- to 8-membered cycloalkyl optionally substituted with 1 or 2 substituents independently selected from R⁵.

In certain embodiments Cycle-B is a 5- to 8-membered cycloalkenyl optionally substituted with 1 or 2 substituents independently selected from R⁵.

In certain embodiments Cycle-B is phenyl.

In certain embodiments Cycle-B is a 5- or 6~membered heteroaryi.

In certain embodiments Cycle-B is a 5- to 8-membered heterocycle. In certain embodiments Cycle-B is a 5- to 8-membered cycloalkyl.

In certain embodiments Cycle-B is a 5- to 8-membered cycloalkenyl.

In certain embodiments Cycle-A is phenyl optionally substituted with 1 or 2 substituents independently selected from R^s and Cycle-B is phenyl.

In certain embodiments Cycle-B is phenyl optionally substituted with 1 or 2 substituents independently selected from R⁵ and Cycle-A is phenyl.

In certain embodiments Cycle-A and Cycle-B are both phenyl.

Embodiments of Spirocycle

In certain embodiments spirocycle is a cycloalkyl optionally substituted with 1, 2, 3, or

4 substituents independently selected from R⁵ and substituted with one R¹² substituent.

In certain embodiments cycloalkene is a cycloalkyl optionally substituted with 1, 2₅ 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent.

In certain embodiments heterocycle is a cycloalkyl optionally substituted with 1, 2, 3. or 4 substituents independently selected from R³ and substituted with one R¹² substituent.

In certain embodiments spirocycle is piperidine optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent.

In certain embodiments spirocycle is a pyrrolidine optionally substituted with 1, 2, 3, or 4 substituents independently selected from R³ and substituted with one R¹² substituent.

Embodiments of R¹⁶, R¹⁷, and R¹⁸

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

In certain embodiments R¹⁶ is R¹².

In certain embodiments R¹⁶ 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 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 w'ith 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 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 R¹⁸ is which is optionally substituted with 1, 2, 3. or 4 substituents independently selected from R⁵.

In certain embodiments R¹⁶ and R¹⁷ are selected from

In certain embodiments R¹⁸ is selected from In certain embodiments R¹⁸ is selected from

In certain embodiments is selected from

, and

In certain embodiments is selected from

In certain embodiments is selected from In certain embodiments or is selected from , wherein each Y is independently selected from N, CH, or CR⁵, wherein 0, 1, or 2 (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 or is selected from , wherein each Y is independently selected from N, CH, or CR⁵, wherein 0, 1, or 2, (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.

Non-limiting examples of include the following: Additional examples of include the following: to certain embodiments is selected from :

and

Non-limiting examples of R¹⁶, R¹⁷, and R¹⁸ include: and

Embodiments of X²²

In certain embodiments X²² is hydrogen.

In certain embodiments X²² is alkyl.

In certain embodiments X²² is haloalkyl.

In certain embodiments X²² is alkenyl.

In certain embodiments X²² is alkynyl.

In certain embodiments X²² is halogen.

In certain embodiments X²² is aryl.

In certain embodiments X²² is heteroaryl.

In certain embodiments X²² is heterocycle.

In certain embodiments X²² is cyano. In certain embodiments X²² is nitro.

In certain embodiments X²² is -NR⁷R⁸.

In certain embodiments X²² is -OR⁷.

In certain embodiments X²² is -SR⁷.

In certain embodiments X²² is -C(O)R⁹.

In certain embodiments X²² is -C(S)R⁹.

In certain embodiments X²² is -S(O)R⁹.

In certain embodiments X²² is -S(O)₂R⁹.

In certain embodiments X²² is -OC(O)R⁹.

In certain embodiments X²² is -OC(S)R⁹.

In certain embodiments X²² is -OS(O)R⁹.

In certain embodiments X²² is -OS(O)₂R⁹.

In certain embodiments X²² is -SC(O)R⁹.

In certain embodiments X²² is -OS(O)₂R⁹.

In certain embodiments X²² is -NR⁷C(O)R⁹.

In certain embodiments X²² is -NR⁷C(S)R⁹.

In certain embodiments X²² is -NR⁷S(O)R⁹.

In certain embodiments X²² is -NR⁷S(O)zR⁹.

In certain embodiments X²² is -P(O)(R⁹)₂.

In certain embodiments X²² is -SP(O)(R⁹)₂.

In certain embodiments X²² is -NR⁷P(O)(R⁹)₂.

In certain embodiments X²² is -OP(O)(R⁹)₂.

Embodiments of Heterocyclic Moiety^A and Heterocyclic Moiety^B

In certain embodiments, the Heterocyclic Moiety^A and Heterocyclic Moiety^B is of Formula:

In certain embodiments, the Heterocyclic Moiety^A and Heterocyclic Moiety^B is of

Formula: In certain embodiments, the Heterocyclic Moiety^A and Heterocyclic Moiety^B is of Formula:

In certain embodiments, the Heterocyclic Moiety^B is of Formula :

In certain embodiments, the Heterocyclic Moiety^B is of Formula:

In certain embodiments, the Heterocyclic Moiety^B is of Formula: In certain embodiments, the Heterocyclic Moiety^B is of Formula:

In certain embodiments, the Heterocyclic Moiety^B is of Formula:

In certain embodiments, the Heterocyclic Moiety^A and Heterocyclic Moiety^B is of Formula

In certain embodiments, the Heterocyclic Moiety^B is of Formula:

In certain embodiments, the Heterocyclic Moiety^B is of Formula :

In certain embodiments the Heterocyclic Moiety^A and Heterocyclic Moiety^B is of Formula

In certain embodiments the Heterocyclic Moiety^A and Heterocyclic Moiety^B is of Formula In certain embodiments the Heterocyclic Moiety^A and Heterocyclic Moiety^B is of Formula

In certain embodiments, the Heterocyclic Moiety^A and Heterocyclic Moiety^B is of Formula In certain embodiments, the Heterocyclic Moiety^A and Heterocyclic Moiety^B is of Formula: .

In certain embodiments, the Heterocyclic Moieiy^A and Heterocyclic Moiety^B is of Formula:

In certain embodiments, the Heterocyclic Moiety⁸ is of Formula: In certain embodiments, the Heterocyclic Moiety^B is of Formula:

In certain embodiments, the Heterocyclic Moiety^B is of Formula:

In certain embodiments, the Heterocyclic Moiety^B is of Formula :

In certain embodiments, the Heterocyclic Mc-iety^A and Heterocyclic Moiety^B is of Formula:

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

In certain embodiments the Heterocyclic Moiety⁸ is selected from:

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

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

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

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

In certain embodiments the Heterocyclic Moiety^A is selected from:

In certain embodiments the Heterocyclic Moiety^A and Heterocyclic Moiety^B is selected from: In certain embodiments the Heterocyclic Moiety^A and Heterocyclic Moiety^B is selected from: Embodiments of KRAS Targeting Ligand

In certain embodiments, KRAS Targeting Ligand is selected from:

In certain embodiments, KRAS Targeting Ligand is selected from: , ,

In certain embodiments, KRAS Targeting Ligand is selected from: In certain embodiments, KRAS Targeting Ligand is selected from:

In certain embodiments, KRAS Targeting Ligand is selected from:

In certain embodiments, KRAS Targeting Ligand is selected from: In certain embodiments. KRAS Targeting Ligand is selected from: In certain embodiments, KRAS Targeting Ligand is selected from:

In certain embodiments. KRAS Targeting Ligand is selected from:

In certain embodiments, R³¹ is R^31B.

In certain embodiments KRAS Targeting Ligand^E is

In certainn embodiments KRAS Targeting Ligand^E is In certain embodiments KRAS Targeting Ligand^E is

In certain embodiments KRAS Targeting Ligand^E is

In an alternative embodiment KRAS Targeting Ligand^E is

In an alternative embodiment KRAS Targeting Ligand^E is In an alternative embodiment KRAS Targeting Ligand^E is

In certain embodiments KRAS Targeting Ligand^F is

In an alternative embodiment KRAS Targeting Ligand^F Is

In certain embodiments KRAS Targeting Ligand^F is

In certain embodiments KRAS Targeting Llgand^F is In certain embodiments KRAS Targeting Ligand^F is

In an alternative embodiment KRAS Targeting Ligand^F is

Embodiments of R²⁹, R^29B, R^29C, and R^29I)

In certain embodiments, R²⁹ is selected from the group consisting of:

In certain embodiments, R^29B is selected from the group consisting of:

In certain embodiments, R^29D is selected from the group consisting of:

Embodiments of R³²

In certain embodiments, R³² is selected from:

Embodiments of R³³, R^33B, R^33C, R^33D, and R^33E

Non-limiting examples of R³³ include

In certain embodiments, R^33B is selected from: and

In certain embodiments, R^33B is selected from:

Nonlimiting examples of R^33B include:

and

In certain embodiments, R^33C is

In certain embodiments, R^33D is

In certain embodiments, R^33E is

In certain embodiments, R^33E is Exemplary Compounds of the Present Invention to certain embodiments, compounds of Formula I or their pharmaceutically acceptable sails thereof are provided as described below:

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

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

and or a pharmaceutically acceptable salt thereof.

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

5

or a pharmaceutically acceptable salt thereof. hi certain embodiments, the compound of the present invention is selected from

or a pharmaceutically acceptable salt thereof. hr certain embodiments, the compound of the present invention is selected from

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

Chirality Embodiments

The compounds of the present invention may have multiple stereoeenters (e.g., chiral carbon atoms) including for example one or more stereocenters in the E3 ligase binding moiety

(for example ), one or more stereocenters in the linker, and/or at least one stereoeenter in the KRAS binding ligand moiety of the molecule. In certain embodiments, the KRAS-degrading compound of the present invention is provided without regard to stereochemistry. In other embodiments, the KRAS-degrading compound may have one or more chiral carbons presented in an enantiomerically enriched (i.e., greater than about 50%, 60%, 70%, 80% or 90% pure) or even substantially pure form (greater than about 95%, 98% or 99% pure) of R and S stereochemistry. In certain aspects, the KRAS-degrading compound has two enantiomerically enriched and/or substantially pure stereocenters.

In certain embodiments one stereocenter is in the R configuration and any others present are either enantiomerically enriched or substantially pure. In certain embodiments one stereoeenter is in the S configuration and any others present are either enantiomerically enriched or substantially pure.

In certain embodiments one stereoeenter is in the R configuration and any others present are without regard to stereochemistry, enantiomerically enriched or substantially pure. In certain embodiments one stereocenter is in the S configuration and any others present are without regard to stereochemistry, enantiomerically enriched or substantially pure.

In certain embodiments there is one stereoeenter in the E3 ligase binding moiety and it is enantiomerically enriched or substantially pure in the R-configuration, as indicated below. In another embodiment there is one stereocenter in the E3 ligase binding moiety and it enantiomericaHy enriched or substantially pure in the S-configuration, as indicated below.

In certain embodiments

In certain embodiments there is one stereocenter in the linker portion and it is a mixture of R- and S-configuration. In another embodiment there is one stereocenter in the linker portion and it is enantiomericaHy enriched or substantially pure R-configuration. In another embodiment there is one stereocenter in the linker portion and it is enantiomericaHy enriched or substantially pure S-configuration.

In certain embodiments the linker contains one or more moieties with a chiral center.

Non-limiting examples include heterocycle with an enantiomericaHy enriched or substantially pure stereocenter for example piperidine with a substituent meta- or ortho to the nitrogen or linking in the meta- or ortho- configuration; piperazine with a substituent or linking In the meta- or ortho- configuration; pyrrolidinone with or without a substituent; and pyrrolidine with or without a substituent.

Additional non-limiting examples of linker moieties with at least one chiral center include an alkyl with an enantiomericaHy enriched or substantially pure stereocenter; an alkene with an enantiomericaHy enriched or substantially pure stereocenter; an alkyne with an enantiomericaHy enriched or substantially pure stereocenter; a haloalkyl with an enantiomericaHy enriched or substantially pure sstteerreeoocceenntteerr:; an alkoxy with an enantiomericaHy enriched or substantially pure stereocenter; an aliphatic group with an enantiomericaHy enriched or substantially pure stereocenter; a heteroaliphatic group with an enantiomericaHy enriched or substantially pure stereocenter; and a cycloalkyl with an enantiomericaHy enriched or substantially pure stereocenter

In certain embodiments the linker includes In certain embodiments the linker includes or

In certain embodiments the linker includes or

In certain embodiments the linker includes

In certain embodiments the linker includes In certain embodiments the linker includes

In certain embodiments the linker includes

Embodiments of alkyl

In certain embodiments “alkyl” is a C₁-C₁₀alkyl, C₁-C₉alkyl, C₁-C₈alkyl, C₁-C₇alkyL C₁-C₆alkyl, C₁-C₅alkyl, C₁-C₄alkyl, C₁-C₃alkyl, or C₁-C₂alkyl.

In certain embodiments “alkyl” has one carbon.

Tn certain embodiments “alkyl” has two carbons.

In certain embodiments “alkyl” has three carbons.

In certain embodiments “alkyl” has four carbons.

In certain embodiments “alkyl” has five carbons.

In certain embodiments “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: .s'ec-butyi, 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.

Embodiments of cycloalkyl

In certain embodiments “cycloalkyl” is a C₃-C₈cycloalkyl, C₃-C₇cycloalkyl, C₃- C₆cycloalkyl, C₃-C₅cycloalkyl, C₃-C₄cycloalkyl, C₄-C₈cycloalkyl, C₅-C₈cycloalkyl, or C₆- C₈cycloalkyl.

In certain embodiments “cycloalkyl” has three carbons.

In certain embodiments “cycloalkyl” has four carbons.

In certain embodiments “cycloalkyl” has five carbons. In certain embodiments “cycloalkyl” has six carbons.

In certain embodiments “cycloalkyl” has seven carbons.

In certain embodiments “cycloalky!” has eight carbons.

In certain embodiments “cycloalkyl” has nine carbons.

In certain embodiments “cycloalkyl” has ten carbons.

Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyk cyclooctyl, and cyclodecyl.

Embodiments of haloalkyl

In certain embodiments “haloalkyl” is a C₁-C₁₀haloalkyl, C₁-C₉haloalkyl, C₁- C₈haloalkyl, C₁-C₇haloalkyl, C₁-C₆haloalkyl, C₁-C₅haloalkyl, C₁-C₄haloalkyl, C₁-C₃haloalkyl, and C₁-C₂haloalkyl.

In certain embodiments “haloalkyl” has one carbon.

In certain embodiments “haloalkyl” has one carbon and one halogen.

In certain embodiments “haloalkyl” has one carbon and two halogens.

In certain embodiments “haloalkyl” has one carbon and three halogens.

In certain embodiments “haloalkyl" has two carbons.

In certain embodiments “haloalkyl” has three carbons.

In certain embodiments “haloalkyl” has four carbons.

In certain embodiments “haloalkyl” has five carbons.

In certain embodiments “haloalkyl” has six carbons.

Non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include: Embodiments of heterocycle to certain embodiments “heterocycle” refers to a cyclic ring wife one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In certain embodiments “heterocycle” refers to a cyclic ring with two nitrogens and 3,

4, 5, 6, 7, or 8 carbon atoms.

In certain embodiments “heterocycle” refers to a cyclic ring with one oxygen and 3, 4,

5, 6, 7, or 8 carbon atoms.

In certain embodiments “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 hnidazolidine.

Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3- dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxafeiolane.

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 ooff “heterocycle” iinncclluuddee indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzoforan wherein the point of attachment for each group is on the heterocycle ring.

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:

Additional non-limiting examples of “heterocycle” include:

Embodiments of heteroaryl

In certain embodiments “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 certain embodiments “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: and

In certain embodiments “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, benzofiiran, 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: , and

In certain embodiments “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:

Embodiments of and

In certain embodiments aryl is phenyl.

In certain embodiments aryl is napthyl.

Embodiments of bicycle

The term “bicycle” refers to a ring system wherein two rings share at least one atom in common. These rings can be spirocyciic or 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 di fferent rings. Non-limiting examples of bivalent bicycle groups include:

Additional non-limiting examples of bivalent bicycle include: Embodiments of optional substituents to certain embodiments wherein a variable can be optionally substituted it is not substituted,

In certain embodiments wherein a variable can be optionally substituted it is substituted with 1 substituent.

In certain embodiments wherein a variable can be optionally substituted it is substituted with 2 substituents.

In certain embodiments wherein a variable can be optionally substituted it is substituted with 3 substituents.

In certain embodiments wherein a variable can be optionally substituted it is substituted with 4 substituents.

Embodiments of Aliphatic and Heteroaliphatic

In certain embodiments “aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. In these embodiments aliphatic is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In certain embodiments, '’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 certain embodiments, 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 certain embodiments, the aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, tire aliphatic group is C1-C2, C1-C3, C1-C4, C1-C5 or Ci-Ce. 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-C5 aliphatic as used herein indicates a straight or branched alkyd, 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 certain embodiments, the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety.

In certain embodiments "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 certain embodiments, the only heteroatom is nitrogen. In certain embodiments, the only heteroatom is oxygen. In certain embodiments, the only heteroatom is sulfur. In certain embodiments “heteroaliphatic” is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In certain embodiments, "heteroaiiphatic" is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, un substituted, branched or unbranched) having 1-20 carbon atoms. In certain embodiments, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Nonlimiting examples of heteroaiiphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

IV. LINKERS

A Linker is included in the compounds of the present invention. Linker is a. chemically stable bivalent group that attaches an E3 Ligase binding portion to a KRAS Targeting Ligand. According to the invention, any desired linker, as described herein, can be used as long as the resulting compound has a stable shelf life, for example at least 1 month, 2 months, 3 months, 6 months or 1 year as part of a pharmaceutically acceptable dosage form, and itself is pharmaceutically acceptable.

Linker as described herein can be used in either direction, i.e., either the left end is linked to the E3 Ligase binding portion and the right end to the KRAS Targeting Ligand, or the left end is linked to the KRAS Targeting Ligand and the right end is linked to the E3 Ligase binding portion.

In certain embodiments Linker is a bond.

In certain embodiments, the Linker has a chain of 2 to 14, 15, 16, 17, 18 or 20 or more carbon atoms of which one or more carbons can be replaced by a heteroatom such as O, N, S, or P.

In certain embodiments the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, I I, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous atoms in the chain. For example, the chain may include 1 or more ethylene glycol units that can be contiguous, partially contiguous or non-contiguous (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units).

In certain embodiments the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous chains which can have branches which can be independently alkyl, aiyl, heteroaryl, alkenyl, or alkynyl, aliphatic, heteroaliphatic, cycloalkyl or heterocycle substituents. 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. 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, heterocycle, cycloalkyl, etc., as desired to achieve the appropriate drag properties.

In certain embodiments, Linker is selected from:

In certain aspects, Linker is selected from the group consisting of a moiety of Formula LI, Formula LII, Formula LID, Formula LIV, Formula. LV, Formula LVI, Formula LVII Formula LVIII, Formula IX and Formula LX: wherein all variables are as defined herein. hr certain embodiments, Linker is selected from:

In certain aspects, Linker is selected from the group consisting of a moiety of Formula LDI, Formula LDII, Formula LDIII, Formula LDIV, Formula LDV, Formula LDVI, and Formula LDVII: wherein all variables are described herein.

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.

In certain embodiments Linker is selected from:

In certain embodiments Linker is selected from: In certain embodiments Linker is selected from:

In certain embodiments Linker is selected from:

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 moiety is an optionally substituted (poly)ethylene glycol having at least L 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, the Linker is flanked, substituted, or interspersed with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group.

In certain embodiments, the Linker may be asymmetric or symmetrical.

In certain embodiments, Linker can be a nonlinear chain, and can be, or include, aliphatic or aromatic or heteroaromatic cyclic moieties.

In any of the embodiments of the compounds described herein, the Linker group may be any suitable moiety as described herein.

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

In certain embodiments Linker or a portion thereof is selected from:

V. METHODS OF TREATMENT

A compound of the present invention or a pharmaceutically acceptable salt thereof can be used in an effective amount to treat a KRAS mediated disorder in a patient, in need thereof.

Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for treating cancer in a patient in need thereof; wherein there is a need of KRAS inhibition for foe treatment of cancer.

Tn certain aspects, a compound of the present invention is used to treat a KRAS mediated cancer, wherein the KRAS has mutated from the wild-type. There are a number of possibilities for KRAS mutations. In some embodiments, the KRAS mutation is a missense mutation encoding a substituted codons. In certain nonlimiting embodiments, the substitution is selected from K5E, K.5N, G12A, G12C, GI2D, G12E, G12F, G12I, G12L, G12N, G12R, G12S, G12V, G12W, G12Y, G13A, G13C, G13D, G13E, G13I, G13N, G13R, G13S, G13V, V14I, P34L, P34Q, P34R, I36M, T58I, A59S, A59T, G60R, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, R68S, H95D, H9SQ, H95R, Y96C, Y96D, V152G, D153V, F156I, F156L, or a combination thereof. In certain embodiments the mutation is a G12D mutation.

In certain aspects, the cancer has developed one or more KRAS mutations following treatment with at least one KRAS inhibitor for example, a covalent inhibitor (such as sotorasib or adagrasib). In yet another aspect, the cancer has one or more KRAS mutations or non- KRAS mutations that renders the cancer intrinsically resistant to KRAS inhibitor treatment, for example, a G12V mutation.

In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired a resistance to, a KRAS inhibitor such as sotorasib or adagrasib.

In certain embodiments the compound of the present invention is used to treat a mutant KRAS mediated disorder, wherein KRAS has a mutation encoding a missense substitution at one of the listed codon sites in Table 1. The mutation may, for example, be selected from one of the listed exemplary mutations, or may be a different mutation.

In certain embodiments the mutant KRAS mediated disorder has two substitutions selected from the table above. In other embodiments the mutant KRAS mediated disorder has three substitutions selected from the table above. In other embodiments the mutant KRAS mediated disorder has four or more mutations, which may optionally be selected from the table above.

In certain embodiments the mutant KRAS mediated disorder has a G12D substitution and one additional substitution which may optionally be selected from the table above. In some of these embodiments the mutant KRAS mediated disorder has a G12D substitution and two additional substitutions that may optionally be selected from the table above.

In certain embodiments the mutant KRAS mediated disorder has a G12V substitution and one additional substitution which may optionally be selected from the table above. In some of these embodiments the mutant KRAS mediated disorder has a G12V substitution and two additional substitutions that may optionally be selected from the table above.

Tn certain embodiments a compound of the present invention is more active against a disorder driven by a mutated KRAS than wild-type KRAS.

In certain embodiments the KRAS mediated disorder is mutant KRZ\S mediated cancer. In certain embodiments the KRAS mediated cancer has a substitution selected from K5E, K5N, G12A, G12C, G12D, G12E, G12F, G12I, G12L, G12N, G12R, G12S, G12V, G12W, G12Y, G13A, G13C, G13D, G13E, G13I, G13N, G13R, G13S, GL3V, V14L P34L, P34Q, P34R, I36M, T58I, A59S, A59T, G60R, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, R68S, H95D, H95Q, H95R, Y96C, Y96D, VI 52G, DI 53V, F156I, F156L, or a combination thereof

In certain embodiments a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12D substitution.

In certain embodiments, a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12V substitution.

In certain embodiments, a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12C substitution.

In certain embodiments, a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12R substitution.

In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to at least one KRAS inhibitor, for example a cancer that is resistant to a KRAS inhibitor such as sotorasib and/or adagrasib. In certain embodiments, a compound of the present invention is used to treat a cancer that has acquired resistance to a first generation KRAS inhibitor, for example a cancer that has acquired resistance to a KRAS inhibitor such as sotorasib and/or adagrasib.

Tn certain embodiments, the method comprises administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination or alternation with another bioactive agent or combination of agents, to a patient in need thereof.

In other embodiments, the patient is administered an additional therapeutic agent. In other embodiments, the compound as described herein, and the additional therapeutic agent are administered simultaneously or sequentially.

In certain embodiments, the patient is a human. As degraders of mutant K RAS, the compounds and compositions of this application are particularly useful for treating or lessening tire severity of a disease, condition, or disorder where mutant KRAS is implicated in the disease, condition, or disorder.

In certain aspects, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where mutant KRAS is implicated in the disease state.

Another aspect of the present invention provides a method of treating a proliferative disease. The method comprises administering an effective amount of a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof and optionally a pharmaceutically acceptable carrier to a patient in need thereof. In some embodiments, the disease is mediated by KRAS. In other embodiments, KRAS plays a role in tire initiation or development of the disease.

In certain embodiments, the disease or disorder is cancer or a proliferation disease.

In certain embodiments, the KRAS mediated disorder is an abnormal cell proliferation, including, but not limited to, a solid or hematological cancer.

Solid tumors that can be treated with, the compounds described herein include, but are not limited to lung cancers, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), breast cancers including inflammatory breast cancer, ER-positive breast cancer including tamoxifen resistant ER-positive breast cancer, and triple negative breast cancer, colon cancers, midline carcinomas, liver cancers, renal cancers, prostate cancers including castrate resistant prostate cancer (CRPC), brain cancers including gliomas, glioblastomas, neuroblastoma, and medulloblastoma including MYC-amplified medulloblastoma, colorectal cancers, Wilm's tumor, Ewing’s sarcoma, rhabdomyosarcomas, ependymomas, head and neck cancers, melanomas, squamous cell carcinomas, ovarian cancers, pancreatic cancers including pancreatic ductal adenocarcinomas (PDAC) and pancreatic neuroendocrine tumors (PanNET), osteosarcomas, giant cell tumors of bone, thyroid cancers, bladder cancers, urothelial cancers, vulval cancers, cervical cancers, endometrial cancers, mesotheliomas, esophageal cancers, salivary gland cancers, gastric cancer, nasopharyngeal cancers, buccal cancers, cancers of the mouth, GIST (gastrointestinal stromal tumors), NUT-midline carcinomas, testicular cancers, squamous ceil carcinomas, hepatocellular carcinomas (HCC), MYCN driven solid tumors, and NUT midline carcinomas (NMC). In certain embodiments, the disease or disorder is multiple myeloma.

In certain embodiments, the hematological cancer is acute myelogenous leukemia. (AML), acute lymphoblastic leukemia (ALL), lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), hairy-cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryobiastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, mixed lineage leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, B cell acute lymphoblastic leukemia, diffuse large B cell lymphoma, Myc and B~CelI Leukemia (BCL)2 and/or BCL6 rearrangements/overexpression [double- and tripie-hit lymphoma], myelodysplastic/myeloproliferative neoplasm, mantle cell lymphoma including bortezomib resistant mantle cell lymphoma.

In certain embodiments, the disease or disorder is sarcoma of the bones, muscles, tendons, cartilage, nerves, fat, or blood vessels. In certain embodiments, the disease or disorder is soft tissue sarcoma, bone sarcoma, or osteosarcoma. In certain embodiments, the disease or disorder is angiosarcoma, fibrosarcoma, Hposarcoma, leiomyosarcoma, Kaposi’s sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, meningiosarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma.

In certahi embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used as a medicament in therapeutic treatment of a patient suffering from cancer, in particular non-small-cell lung cancer, with KRAS activating mutations as determined by next-generation sequencing (NGS), comprising determining the KRAS activating mutations status hi said patient and then administering the compound of the present invention, or a pharmaceutically acceptable salt thereof, to said patient.

In certain embodiments, said method is used to treat a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immunologically-mediated diseases. In certain embodiments, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyiarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, and other arthritic conditions, neuroinflammation, allergy, pain, neuropathic pain, fever, pulmonary disorders, lung inflammation, adult respiratory distress chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, autoimmune disease, graft vs, host reaction and allograft rejections, cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bone cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and/or basal cell cancers, prostate cancer, renal ceil carcinoma, and other known cancers that affect epithelial cells throughout the body, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (API.), angiogenesis including neoplasia, metastasis, central nervous system disorders, central nervous system disorders having an inflammatory or apoptotic component, peripheral neuropathy, or B-Cell Lymphoma.

This application further embraces the treatment of cell proliferative disorders such as hyperplasias, dysplasias and pre-cancerous lesions. Dysplasia is the earliest form of pre- cancerous lesion recognizable in a biopsy by a pathologist. The compounds may be administered for the purpose of treating said hyperplasias, dysplasias or pre-cancerous lesions. Examples of pre-cancerous lesions may occur in skin, esophageal tissue, breast and cervical intra-epithelial tissue.

KRAS and KRAS -mutant associated disorders

Mutation of KRAS leads to the accumulation of GTP-bound KRAS and the unrestricted activation of MAP kinase, PBK-AKT-mTOR, and the tumor invasion and metastasis-inducing protein 1 (TIAM1-RAC) and RAS-related protein (RAL) signaling pathways, and has been implicated in many types of human cancer. KRAS is the most commonly mutated gene in human cancers, present in approximately 14% of all human cancers and contributing to over 200,000 new cancer patients per year in the United States (Parikh et al. Dragging KRAS: current perspectives and state-of-art review. Journal of Hematology & Oncology. 15:152(2022)). Mutations of KRAS cause unrestricted activation of the RAF-MEK- ERK and PI3K-AKT pathways.

KRAS

The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene (Entrez 3845) encodes the KRAS protein that is a member of the RAS/MAPK pathway signaling pathway . The KRAS gene is a member of the Has family of oncogenes, which also includes two other genes: HRAS and NRAS. The KRAS protein is a membrane-associated GTPase that converts GTP into GDP. The KRAS protein acts like a molecular switch that is turned on and off by the GTP and GDP molecules, respectively, to control cellular differentiation, growth, and survival. The KRAS protein is turned on (activated) by binding to a molecule of GTP whereby the activated KRAS protein transmits cellular signaling. The KRAS protein is turned off (inactivated) when it converts the GTP to GDP. When the KRAS protein is bound to GDP, it does not transmit cellular signaling.

The amino acid positions G12, G13, and Q61 are commonly substituted for different residues by missense mutations, and account for the overwhelming majority of KRAS mutations in cancer. Alternative splicing of KR.4S encodes isoforms KRAS4A and KRAS4B, and despite their raw similarity, these isoforms have divergent functions when expressed in non-native tissue types. This heterogeneity is likely due to sequence differences between isoforms in the C-terminal hyper-variable regions. For clinical and research purposes, KRAS refers to the KRAS4B isoform which is the gene product most frequently expressed in human cells (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol. 15:152(2022)). Dysregulated isoform expression and missense mutations at the sequences encoding the hotspot codons G12, G13, and Q61 are thought to be core drivers of cancer.

KRAS Pan

Targeting KRAS mutations with drugs has been considered extremely challenging for many years, even earning the nickname, ‘the undniggable gene” (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol. 15:152(2022)). Mutant KRAS is found in 32% of lung cancers, 40% of colorectal cancers, and between >90% of pancreatic cancer cases (Table 2). hi fact, KRAS is mutated in 1 in 7 (-14%) of all human cancers (Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 23(6):703-713(2017 Jun)). An estimated 240,000 new patients per year each harbor a KRAS mutation. The implications of different KRAS mutations for prognosis vary between cancer types, but individual KRAS mutations are demonstrated to associate with poorer outcomes in certain cancers, for example, colorectal cancer, non-small cell lung cancer (NSCLC), and others.

Table 2', KRAS mutation incidence in different KRAS-associated disorders.

KRAS G12D

G12 is the most frequently altered codon found in cancer, accounting for 80% of all KRAS mutations and is found in 12% of all patients (Zehir, A. et al, Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 23(6):703-713(2017 Jun)). An estimated 71,200 new patients per year in the United States each harbor a KRAS G12D mutation. The KRAS G12D mutation is the most common KRAS mutation found in pancreatic adenocarcinoma (Table 2).

KRAS GUV

An estimated 55,100 new patients per year in the United States each harbor a KRAS

G12V mutation. The KRAS G12V mutation is the second most common KRAS mutation found in pancreatic adenocarcinoma (Table 2).

Pancreatic Cancer

KRAS mutation is an early and initiating event of pancreatic cancer. KRAS mutation occurs in 90% of all pancreatic adenocarcinoma patients (Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 23(6):703-713(2017 Jun)). Pancreatic cancer is the deadliest cancer in the United States, as the 5-year survival rate of pancreatic cancer is 8% (Siegel, R.L. et al. Cancer statistics. CA Cancer J Clin. 66:7-30(2016)).

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death among cancer patients in the United States and is one of the major causes of morbidity and mortality worldwide (Siegel, R.L. et al. Cancer statistics. CA Cancer J Clin. 66:7-30(2016)). Standard of care for PDAC is surgery followed by adjuvant therapy; however, only 15-20% of patients are even eligible for surgery (Waters, A,M. & Der, CJ. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb. Perspect. Med. 8(9):a031435(2018 Sep)). Therapeutic approaches have been largely unsuccessful in PDAC (Id.). KRAS mutation is a hallmark of PDAC, occurring in greater than 90% of all PDAC patients (Zd) (Table 2). This is supported by in vitro data demonstrating the central role of KRAS in proliferation of PDAC cancer cell models. For example, knockdown of KRAS by RNA. interference (RNAi) demonstrates reduced cellular proliferation and induction of apoptosis in several independent human PDAC model cancer cell lines, supporting the central role of KRAS in the development of this cancer (Collisson, E.A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 17(4):500-503(2011 Apr)). Complete ablation of endogenous KRAS in PDAC model cells by CRISPR/Cas- mediated genome editing significantly reduced in vitro proliferation and in vivo tumorigenic growth, further supporting the potential for KRAS targeting agents for the treatment of PDAC ((Muzumdar, M.D. et al. Survival of pancreatic cancer cells lacking KRAS function. Nat. Commun. 8(1): 1090(2017)). PDAC development is a step-wise progression lasting an estimated 12 years (lacobuzio-Donahue, C.A. et al. Genetic basis of pancreas cancer development and progression: Insights from wholc-exome and whole-genome sequencing. Clin Cancer Res. 18:4257-4265(2012)), characterized by histologically defined lesions showing increasingly disrupted cellular morphology, nuclear atypia, and dysplastic growth (Cox, A.D. & Der, CJ. Ras history: The saga continues. Small GTPases. 1 (l):2~27(2010 Jul)). Activating KRAS mutations are an early, initiating event that induces the transformation of normal pancreatic duct epithelium into pancreatic intraepithelial neoplasms (PanlNs). Although infrequent in other forms of cancer, G12R mutations comprise 16% of all KRAS mutations hi PDAC (Waters, A.M. & Der, CJ. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med. 8(9):a031435(2018 Sep)).

In certain aspects an effective amount of a compound of the present invention is used to treat pancreatic cancer.

Colorectal Cancer

Colorectal cancer is one of the most common cancers worldwide (Porru, M. et al. Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. J Exp Clin Cancer Res. 37(l):57(2018 Mar 13). Most colorectal cancers are adenocarcinomas. KRAS is mutated in between 27.9-43.7% of all colorectal adenocarcinoma (Table 2). The current standard of care in colorectal cancer is a combination of different chemotherapeutic drags, comprising either protracted infusion of 5-fluorouraciI (5-FU) modulated by leucovorin in combination with irinotecan (FOLFIRI) or with oxaliplatin (FOLFOX), capecitabine and oxaliplatin combination (XELOX), or 5-FU, leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI) (Id).

In certain aspects an effective amount of a compound of the present invention is used to treat colorectal cancer.

Lung Cuneer

Lung cancer is the most common form of cancer and responsible for the most cancer- related deaths worldwide (Westcott, P.M.K. & To, M.D. 1'he genetics and biology of KRAS in lung cancer. Chin J Cancer. 32(2):63-70(2013 Feb)). Smoking is the most common risk factor for lung cancer, with an estimated 80% of all lung cancer patients having previously smoked (Id.). KRAS is more frequently mutated in smokers compared to non-smokers, with G12C the most common KRAS mutation hi smokers (44%), followed by G12V (19%) (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol. 15:152(2022)). In contrast, KRAS G12D is the most frequent KRAS mutation (56%) in non- smokers (Id.).

In some embodiments, the lung cancer comprises non-small cell lung cancer (NSCLC). The makeup of KRAS mutation in lung cancer is heterogeneous compared to other KRAS- associated disorders. KRAS is mutated in 23% of all NSCLC (Table 2). The KRAS G12C mutation is the major KRAS mutation in NSCLC, comprising approximately 41% of all KRAS mutations in this population (Table 2) (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol 15:152(2022)). KRAS mutations mostly occur in lung adenocarcinomas, the most common histological subclass of NSCLC. The KRAS G12C mutation is the major KRAS mutation in lung adenocarcinoma, comprising approximately 43% of all KRAS mutations in this population (Waters, A.M. & Der, C.J. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med. 8(9):a031435(2018 Sep)). The frequency of KRAS mutation is lower in squamous cell carcinoma (another subclass of NSCLC), comprising 5% of all cases (Table 2) (Id.). In some embodiments, the NSCLC comprises lung adenocarcinoma or squamous cell carcinoma.

In certain aspects an effective amount of a compound of the present invention is used to treat lung cancer. VI. COMBINATION THERAPY

A compound described herein or a pharmaceutically acceptable salt thereof can be used in an effective amount alone or in combination with another bioactive agent or second therapeutic agent to treat a human patient with a KRAS mediated disorder.

The term “bioactive agent” is used to describe an agent, other than the selected compound according to the present invention, which can be used in combination or alternation with a compound of the present invention to achieve a desired result of therapy. Tn certain embodiments, the compound of the present invention and the bioaetive agent are administered in a manner that they are active in vivo during overlapping time periods, for example, have time-period overlapping Cmax, Truax, AUC or another pharmacokinetic parameter. In another embodiment, the compound of the present invention and the bioactive agent are administered to a patient in need thereof that do not have overlapping pharmacokinetic parameter, however, one has a therapeutic impact on the therapeutic efficacy of the other.

MAPK Inhibitors

In certain embodiments, the bioactive agent is an inhibitor of a protein involved in signaling through the mitogen-associated protein kinase (MAPK) pathway. Proteins involved in MAPK signaling include but are not limited to EGFR, SOS (including but not limited to SOS1), RAS (including but not limited to KRAS, NRAS, and HRAS), SHP2, RAF (including but not limited to BRAF), MEK (including but not limited to MEK1 and MEK2) and ERK.

EGFR

In certain embodiments, the bioactive agent is an epidermal growth factor receptor (EGFR) inhibitor, including, for example gefitinib (Iressa), erlotinib (Tarceva), lapatinib (Tykerb), osimertinib (Tagrisso), neratinib (Nerlynx), vandetanib (Caprelsa), dacomitinib (Vizimpro), rociletinib (Xegafri), afatinib (Glotriff, Giotriff, Afanix). lazertinib, or nazartib. Additional examples of EGFR inhibitors include rociletinib (CO- 1686), olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775, icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF- 06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-0I9), transtinib, WZ-3146, WZ8040, CNX-2006, dacomitinib (PF-00299804; Pfizer), brigatinib (Alunbrig), lorlatinib, and PF- 06747775 (PF7775). In certain embodiments, the bioactive agent is a first-generation EGFR inhibitor such as erlotinib, gefitinib, or iapatinib. In certain embodiments, the bioactive agent is a second- generation EGFR inhibitor such as afatinib and/or dacomitinib. In certain embodiments, the bioactive agent is a third-generation EGFR inhibitor such as osimertinib.

In certain embodiments a compound of the present invention is administered to a patient in need thereof in combination with an anti-EGFR antibody, for example, cetuximab, panitumab, or necitumab.

In certain embodiments a compound of the present invention is administered to a patient in need thereof in combination with cetuximab.

In certain embodiments a compound of the present invention is administered to a patient in need thereof in combination with panitumab.

In certain embodiments a compound of the present invention is administered to a patient in need thereof in combination with necitumab.

SOS

In certain embodiments, the bioactive agent is a son of sevenless (SOS) inhibitor, hi certain embodiments, the bioactive agent is a SOS1 inhibitor, including but not limited to BI- 1701963, RGT-018, MRTX-0902, BAY-293, BI-3406, SOS1-1N-9,

RAS

In certain embodiments, the bioactive agent is a rat sarcoma virus (RAS) protein inhibitor. Examples of RAS inhibitors include but are not limited to rigosertib, RMC-6236, Reolysin and siG12D LODER. In certain embodiments, the bioactive agent is an additional KRAS inhibitor. Nonlimiting examples of KRAS inhibitors include sotorasib, adagradib, JDQ443, D-1553, mRNA-5671, JAB-21822, 1BI351, GFH925, LY3537982, ELI-002, ASP3082, RMC-6291, ERAS-3490, IMM-1-104, and GDC-6036. hi certain embodiments, the bioactive agent is an NRAS inhibitor. In certain embodiments, the bioactive agent is an HRAS inhibitor.

SHP2

In certain embodiments, the bioactive agent is a Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) inhibitor. Examples of SHP2 inhibitors include but are not limited to BBP-398, SHP099, PF-07284892 (ARRY-558), RG6433, JAB-3068, JAB-3312, ERAS-601, HBI-2376, SH3809, ET0038, BP1-442096, 1740155, RMC-4630, RMC-4550, and

RLY-1971. Additional SHP-2 inhibitors can be found in U.S. Patent No. 11,634,417.

RAF

In certain embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, Vemurafinib (N-[3-[[5-(4~Chlorophenyl)-lH-pyrrolo[2,3-b]pyridin- 3-yl]carbonyl]~2,4-difluorophenyl]-1 -propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro- 3-(trifluoromethyl)phenyr]carbamoyiamino]phenoxy]-N-methylpyridine-2-carboxamide;4~ methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo- 3,4-dihydroquinazolin-6-ylamino)phenyi)berizamide), NVP-BHG712 (4-methyl~3~(l -methyl- 6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N~(3- (tritluoromethyl)phenyl)benzamide), RAF-265 ( 1 -methyl-5- [2 -[5 -(trifluoromethyl)- 1 H- imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2- Bromoaldisine (2-Bromo-6,7-dihydro-lH,5H-pyrrolo[2,3-c]azepine-4,8~dione), Raf Kinase Inhibitor IV (2-ehloro-5-(2-phenyl-5-(pyridin-4-yI)-1H-hnidazoI-4-yI)phenoI), Sorafenib N- Oxide (4-|4-[[[[4-Chloro-3(trifluoroMethyI)phenyI]aMino]carbonyl]aMino]phenoxy]-N- Methyl-2pyridinecarboxaMide 1-Oxide), PLX-4720, vemurafenib, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (Encorafenib).

In certain embodiments, the bioactive agent is a dual RAF/MEK inhibitor such as Avutometinib (ROS 126766, CHS 126766, VS-6766, CKI-27, R-7304, RG-7304).

MEK

In certain embodiments, the bioactive agent is a mitogen-activated protein kinase kinase (MEK, MAP2K, MAPKK) inhibitor. MEK inhibitors are well known, and include, for example, trametinib/ GSKI 120212 (N-(3 -{ 3 -Cyclopropyl~5~[(2-fluoro-4~iodophenyl)amino]~ 6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyTimidin-1(2H- yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2- hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)~3~((2-fluoro~4- iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol), refametinib/BAY869766/RDEAl 19 (N-(3,4-difluoro-2-(2- fluoro-4-iodophenylamino)-6-methoxyphenyl)~1~(2,3-dihydroxypropyl)eyclopropane-1- sulfonamide), PD-0325901 (N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4- iodophenyl)aminoj- benzamide), TAK733 ((R)-3-(2,3-Dihydroxypropyl)-6-iluoro-5-(2-fluoro- 4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione),

MEK162/ARRY438162 (5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N~(2- hydroxyethoxy)- 1 -methyl- 1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-FIuoro-2-

(methyIsulfamoyiamino)-4-pyridyl]methyl]-4-metliyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655/CH4987655 (3,4-difiuoro-2-((2-tluoro-4-iodophenyI)amino)-N-(2- hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyI)benzamide), or AZD8330 (2-((2-fluoro-4- iodophenyl)amino)-N-(2 hydroxyethoxy)- 1,5-dimethy]-6-oxo-1,6-dihydropyridine-3- carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088.

ERK

In certain embodiments, the bioactive agent is an extracellular signal-regulated kinase (ERK) inhibitor, including ERKl and ERK2 inhibitors. Nonlimiting examples of ERK inhibitors include Ulixertinib (BVD-523, VRT752271), VX-lle (4-(2-((2-chloro-4- fluorophenyl)aniino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H - pyrrole-2-carboxamide), AZD0364, MK-8353 (SCH900353), LY3214996, CC-9003, BIX- 02189, SCH772984, ASN007, MRTX-1257, ERK5-IN-2, AZD0364 (ATG-017), and FR180204.

Immunotherapeuties

In certain aspects of this embodiment, the bioactive agent is an immune modulator, including but not limited to a checkpoint inhibitor, including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecule, peptide, nucleotide, or other inhibitor. In certain aspects, the immune modulator is an antibody, such as a monoclonal antibody.

PD-1 inhibitors that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibit immune suppression include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and Medlmmune), PF- 06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Tncyte Corporation), TSR-042 (Tesaro), and the PD-L1/VISTA inhibitor CA-170 (Curls Inc.). PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression, include for example, atezolizumab (Tecentriq), durvalurnab (AstraZeneca and Medlmmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immune suppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and Medlmmune), AGEN1884 and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS- 986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), 1MP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenies). An example of a TIM-3 inhibitor is TSR-022 (T'esaro).

In certain embodiments, the PD-L1 inhibitor is a small molecule PD-L1 inhibitor including but not limited to INCB99280, BMS-202, BMS-1001, BMS-1166, CA-170, TPP-1, ALJNP-12, and DPPA-1.

In certain embodiments the checkpoint inhibitor is selected from nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®; and pidilizumab/CT-011, MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559, a PDL2/lg fusion protein such as AMP 224 or an inhibitor of B7-H3 (e.g., MGA271 ), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD 160, CGEN- 15049, CHK 1 , CHK.2, A2aR, B-7 family ligands, or a combination thereof.

In another embodiment, one of the active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the female reproductive system such as breast, ovarian, endometrial, or uterine cancer, in combination or alternation with an effective amount of an estrogen inhibitor including, but not limited to, a SERM (selective estrogen receptor modulator), a SERB (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist. Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen- like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth. In contrast, fulvestrant, a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors.

Non-limiting examples of anti-estrogen compounds are provided in WO201419176 assigned to Astra Zeneca, WO2013090921, WO 2014203129, WO2014203132, and US2013/0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703, 810, as well as US20150005286, WO2014205136, and WO2014205138. Additional non-limiting examples of anti-estrogen compounds include: SERMS such as anordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxlfene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvcstratnt; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, fonnestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, eyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone.

Other estrogenic ligands that can be used according to the present invention are described in U.S. Patent Nos. 4,41 §,068; 5,478,847; 5,393,763; and 5,457,1 17, WO201 1/156518, US Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853,423; 8,703,810; US 2015/0005286; and WO 2014/205138, US2016/0175289, US2015/0258080, WO2014191726, WO2012084711; WO2002013802; WO2002004418; WO2002003992; WO2002003991; WO2002003990; WO2002003989; WO2002003988; WO2002003986; WO2002003977; WO2002003976; WO2002003975; WO2006078834; US 6821989; US 2002/0128276; US 6777424; US 2002/0016340; US 6326392; US 6756401 ; US 2002/0013327; US 6512002; US 6632834; US 2001/0056099; US 6583170; US 6479535; WO1999024027; US 6005102; EP 0802184; US 5998402; US 5780497, US 5880137, WO2012048058 and WO2007087684.

In another embodiment, active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor including, but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In certahi embodiments, the prostate or testicular cancer is androgen-resistant.

Non-limiting examples of anti-androgen compounds are provided in WO 2011/156518 and US Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of antiandrogen compounds include: enzalutamide, apalutamide, eyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazoie, topilutamide, abiraterone acetate, and cimetidine.

In certain embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include but are not limited to Crizotinib, Alectinib, ceritinib, TAE684 (NVP- TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.

In certain embodiments, the bioactive agent is an HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab. In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab, tositumomab, and ocrelizumab.

In certain embodiments, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

In certain embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-ChIorophenyl)-4,4-dimethylcydohex-1- en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4~[[(tetrahydro-2H-pyTan-4- yl)methyl]amino|phenyl|sulfonyl]-2-[(1H- pyrroIo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT- 737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4- [[(2R)-4-(dimethylamino)- 1 -phenylsulfanylbutan-2-yl] amino]-3- nitrophenyljsulfonyibenzamide) (navitoclax), ABT-263 ((R)-4-(4-((4'-chloro~4,4-dimethyl-3,4,5,6~tetrahydro-[1, 1',biphenyl]-2-yl)methyl)piperazin-1- yl)-N-((4-((4-morpholino- 1 -(phenyhhio)butan-2-yl)amino)- 3((tritluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX 15-070 (obatoclax mesylate, (2Z)-

2-[(5Z)-5-[(3,5- dimethyl-1H-pyrrol~2~yl)methylidene]-4-methoxypyrroL2-ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9- dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pogosin, ethyl 2-amino-6-bromo-4-(1- cyano-2-ethoxy-2-oxoethyl)-4H-chromene~3~carboxylate, Nilotinib-d3, TW-37 (N-[4-[[2-(1 , 1- Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4~trihydroxy-5-[[2-(1- methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, or G3139 (Obhmersen).

In certain embodiments, the bioactive agent is a kinase inhibitor. In certain embodiments, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.

Examples of PI.3 kinase inhibitors include, but are not limited to, Wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib , Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2-(2- Isopropyl-5-methyl-l,2,4-triazol-3-yl)-5,6-dihydroimidaz;o[l,2-d][l,4]benzoxazepin-9- yl]pyrazol-l~yl]-2-methylpropanamide), MLN-1117 ((2R)-1-Phenoxy~2~butanyl hydrogen (S)- methylphosphonate; or Methyl(oxo) {[(2R)-l-phenoxy-2-butanyI]oxy}phosphonium)), BYL- 719 ((2S)-Nl-[4-Methyl-5-[2-(2,2,2-trifluoro-l,l-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-l,2- pyrrolidinedicarboxamide), GGSSKK22112266445588 (2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4- pyridazmyl)-6~quinolinyl]-3~pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7~ Methyl-2-(morpholin-4-yl)-9-(l-phenylammoethyl)-pyrido[l,2-a]-pyrimidin-4-one), GSK2636771 (2-Methyl-1-(2-methyl-3-(trifluoromethyl)berizyl)-6-morpholino-1H- benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2- inorpholino~4~oxo-4H-pyrido[1,2-a]pyrimidin~9~yl)ethyl)amino)benzoic acid), TGR- 1202/RP5264, GS-9820 ((S)- 1-(4-((2-(2-aminopyTimidin-5~yl)-7-methyl-4-mohydroxypropan- 1 -one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin- 4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5- dimethoxypheny])ainino)quinoxaIin~2-yl)sulfamoyl)phenyl)-3-methoxy~4 methylbenzamide), RAY80-6946 (2-amino~N~(7~methoxy-8-(3-moipholinopropoxy)~2,3-dihydroimidazo[l,2- cjquinaz), AS 252424 (5-[l-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene|- thiazolidine-2, 4-dione), CZ 24832 (5-(2-amino-8-fluoro-[l,2,4]triazolo[1,5~a]pyridin-6-yl)-N- ten-butylpyridine-S-sulfonamide), Buparlisib (5-[2,6-Di(4~morpholinyl)-4- pyrimidinyl]-4~ (tritluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-lndazol-4-yl)-6-[[4-(methylsulfonyl)-1- piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2- aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6 yl)methyl)piperazin-1- yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14- (carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4- oxo-8-phenyl-4H-chromen~2-yl)morpholino-4-ium)-2-oxa-7,10, 13,16-tetraazaoctadecan-18- oate), PF-05212384 (N-[4-[[4-(Dimethylamino)-l- piperidmyl]carbonyl]phenyl]-N'-[4~(4,6-di- 4-morpholinyl-1,3,5-triazin-2-yl)phenyl]nrea) (gedatolisib), LY3023414, BEZ235 (2-Methyl-2- {4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-lH-imidazo[4,5-c]quinolin-1- yl]phenyl}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5- dimethoxyphenylamino)quinoxaIin-2-yl)sulfamoyl)phenyl)-3-methoxy~4-methylbenzamide), and GSK1059615 (5-[[4-(4-Pyridinyl)-6-qumolinyl]methylenej-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,l laS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9- (methoxymethyl)-9a,l la~dimethyl-1,4,7-troioxo-2,3,3a,9,10,11-hexahydroindeno [4,5h]isochromen- 10-yl] acetate (also known as sonolisib)), LY294002, AZD8186, PF- 4989216, pilaralisib, GNE-317, Pl-3065, Pl-103, NL7441 (KU-57788), MS 173, VS-5584 (SB2343), CZC24832, TGI 00-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS- 605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CHS 132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PLK-293, PJK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422).

Examples of BTK inhibitors include ibrutinib (also known as PCI-32765)(Imbruvica™)(1- [(3R)-3"-[4~amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]p>Timidin-1-yl]piperidin-l-yl]prop~2- en-1-one), dianilmopyrimidine-based inhibitors such as AVL-101 and AVL-291/292 (N-(3- ((5-tluoro-2-((4-(2-metiioxyetiioxy)phenyl)amino)pyrinudin-4-yl)amino)pheByl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011/0117073, incorporated herein in its entirety), Dasatinib ([N-(2-ch]oro-6-methyIphenyl)-2-(6~(4~(2-hydroxyethyl)piperazin-l-yl)~2~ methylpyTimidin-4~ylaniino)thiazole-5-carboxamide], LFM-A13 (alpha-cyano-beta-hydroxy- beta-methyl-N-(2,5-ibromophenyl) propenamide), GDC -0834 ([R-N-(3-(6-(4-(l,4-dimethyl-3- oxopiperazin-2-yl)pheny1amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yi)-2-niethylpheny1)- 4,5,6,7-tetrahydrobenzo[b]thiophene-2~carboxamide], CGI-560 4-(tert-butyl)-N-(3-(8-

(phenyiamino)imidazo[ 1 ,2-a]pyrazm~6-yl)phenyl)benzamide, CGT-1746 (4-(tert-butyl)-N-(2- methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin- 2-yl)phenyl)benzamide), CNX-774 (4-(4~((4~((3-acrylamidophenyl)amino)-5-fluoropyrimidin- 2-yl)amtao)phenoxy)-N~methylpieolinamide), CTA056 (7-benzyl-l-(3~(piperidin-l-yl)propyl)~ 2-(4-(pyridin-4-yl)phenyl)-lH-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6- ((4-(l,4-dimethyl-3-oxopiperazm-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2- yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N- (3-(6-((4-(l,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl)-4, 5, 6,7-tetrahydrobenzo[b]thiophene-2 -carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-112,3~ triazol-2-yl)phenyl)amino)-2-(((lR,2S)~2-aniinocydohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 ( 1 -( 1 -acryloylindolin-6-yl)-9-( 1 -methyl- 1H-pyrazol-4- yl)benzo[h][l,6]naphthyridin-2(lH)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2- hydroxymethy1-3-{l-methyl-5-[5-(4-metbyl-piperazin-1-yl)~pyridin-2-ylamino]~6-oxo-l,6- dihydro-pyridin-3~yl}-phenyl)-2H-isoquinolin-1-one), and other molecules capable of inhibiting BTK activity⁷, for example those BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology & Oncology, 2013, 6:59, tlie entirety of which is incorporated herein by reference.

Syk inhibitors include, but are not limited to, Cerdulatinib (4-(cyclopropylamino)-2-((4- (4-(ethylsulfonyl)piperazin- 1 -yl)phenyl)amino)pyrhnidine-5-carboxamide), entospletinib (6- (1H-indazol-6-yl)-N-(4-morpholinophenyl)hnidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6- ({5-Fluaro-2-[(3,4,5~tfmethoxyphenyl)amino]~4~pyrimidinyl}amino)-2,2-dimethyl-3~oxo-2,3- dihydro-4H-pyrido[3,2~b][l,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5 -fluoro-2-((3.4,5 -trimethoxyphenyl)amino)pyTimidin-4-yl)amino)- 2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][l,4]oxazin~4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-Dimethoxyphenyl)~imidazo[1,2~c]pyrimidin-5-ylamino)-nicotinamide HC1), RO9021 (6-[(lR,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)- pyridazme-3 -carboxylic acid amide), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]- N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)~3~aminotetrahydro-2H-pyran-4~yl)ammo)~4~(p~tolyiamino)pyTimidine~ 5 -carboxamide), PP2 ( 1 -(tert-butyl)-3 -(4-chlorophenyl)- 1H-pyrazolo [3 /4~d]pynmidin~4~ amine), PRT-060318 (2-((( 1 R,2S)-2-aminocyclohexyd)ammo)-4-(m-tolylamino)pyriniidine-5- carboxamide), PRT-062607 (4-((3-(2H-l,2,3-triazol-2-yI)phenyl)amino)-2-(((lR,2S)-2- aminocyciohexyl)amir!o)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5- fluoropyrimidine-2,4-diyl)bis(azanediyl))dipheno!), R348 (3-Ethyl-4-rnethylpyridine), R406 (6-((5-fluoro-2-((3,4,5-tiiniethoxyphenyl)amino)pyrimidin-4-y1)amino)-2,2-dimethyl-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-Hydroxyresveratol), YM193306 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614- 3643 incorporated in its entirety herein), Compound D (see Singh et al. Discovery' and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614- 3643 incorporated in its entirety herein), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614- 3643 incorporated in its entirety herein), luteolin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), apigenin (see Singh et al. Discovery and Development of Spieen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), fisetin (see Singh et aL Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), myricetin (see Singh et al. Discovery' and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein).

In certain embodiments, the bioactive agent is a c-MET inhibitor, for example, crizotinib (Xalkori, Crizonix), tepotinib (XL880, EXEL-2880, GSK1363089, GSK089), or tivantinib (ARQ197).

In certain embodiments, the bioactive agent is an AKT inhibitor, including, but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosinc, a FLT-3 inhibitor, including, but not limited to, P406, Dovltinib, Quizartinib (AC₂20), Amuvatinib (MP-470), Tandutinib (MLNS 18), ENMD-2076, and KW-2449, or a combination thereof.

In certain embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus.

In certain embodiments, the bioactive agent is an HSP inhibitor. HSP inhibitors include but are not limited to Geldanamycin or ]7“N~AliyIamino-17"demethoxygeldanamycin (17AAG), and Radicicol.

Additional bioactive compounds include, lor example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON O91O.Na, AZD 6244 (ARRY- 142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VKRAS inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a focal adhesion kinase inhibitor, a Map kinase kinase (MEK) inhibitor, a VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, of atumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdRl KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS- 100380, sunitinib, 5 -fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5 ' -deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4"[2-(2-amino-4,7~dihydro-4-oxo~ lH-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremilene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)"indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, lonafamib, BMS-214662, tipifamib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, earboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, tluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuproHde, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamyein, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposlde, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycta, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastai, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin- 12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezhnib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4~hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)- rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, 1.-779,450, PEG-fllgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L- asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin- 11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestroi, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tosltumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, aann NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof. In certain embodiments the compound is administered in combination with ifosfamide.

In certain embodiments, the bioactive agent is selected from, but are not limited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), trastuzumab-DMl, Pertuzumab (PeijetaTM), Lapatinib (Tykerb®), Gefitinib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin (Panretin®), Tretinoin (Vesanoid®), Carfilizomib (KyprolisTM), Pralatrexate (Folotyn®), Bevacizumab (A vastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), and Cabozantinib (CometriqTM).

In certain aspects, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic, an additional therapeutic agent, or an immunosuppressive agent. Suitable chemotherapeutic bioactive agents include, but are not limited to, a radioactive molecule, a toxin, also referred to as cytotoxin or cytotoxic agent, which includes any agent that is detrimental to the viability of cells, and liposomes or other vesicles containing chemotherapeutic compounds. General anticancer pharmaceutical agents include: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin or Cenibidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L~ asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP- 16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™).

Examples of additional suitable chemotherapeutic agents include, but are not limited to 1 -dehydrotestosterone, 5 -fluorouracil deearbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylating agent, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum (II) (DDE) cisplatin), diamino dichloro platinum, an thracy cline, an antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens, Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerly actinomycin), daunirubicin HCL, daunorucbicin citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coll L-asparaginase, emetine, epoetin-a, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, etoposide citrororum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, tlutamide, folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea, idarubicin HCL, ifosfamide, interferon a-2b, irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotene, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL, plimycin, politeprosan 20 with carmustine implant, porfimer sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostirn, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

In some embodiments, the compound of the present invention is administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5 -fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamlne, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocannycin (including the synthetic analogues, KW-2189 and CB1-TM1 ); eleutherobin; pancratistatin; a sarcodictyln; spongistatin; nitrogen mustards such as chlorambucil, cblomaphazine, cholophospbamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofostamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omega!! (see, e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo- 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholinodoxorubicin, cyanomorpholino- doxorubicin, 2-pynoiino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5~fluorouracil (5- FIJ); folic acid analogues such as denopterin, methotrexate, pteropterin, timetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenatnel; pirarubicin; losoxantrone; podophyllinic acid; 2~ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; spirogermaciurn; tenuazonic acid; triaziquone; 2,2', 2 "-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®, cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL), and TAXOTERE® doxetaxei (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® gemcitabine; 6~thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE.® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-1 1 ); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the compound of the present invention. Suitable dosing regimens of combination chemotherapies are known in the ar. For example combination dosing regimes are described in Saltz et al., Proc. Am. Soe. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209): 1041 -1047 (2000). Additional therapeutic agents that can be administered in combination with a Compound disclosed herein can include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzuniab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, iucatumumab, dacetuzumab, HLL1, huN901-DMl, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, /ABT-737, oblimersen, plitidepsin, tahnapimod, P276-00, enzastaurin, tipifamib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), amebaciclib (LY2835219), HDM201, fblvestrant (Faslodex), exemestane

(Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

In certain embodiments, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs may “coat” the cancer cell surface, triggering its destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels. MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their norma! growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.

In certain aspects of the present invention, the bioactive agent is an immunosuppressive agent. The immunosuppressive agent can be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g. Siroflmus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a S IP receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequlnar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15 -deoxy spergualin, tresperimus, Leflunomide ARAYA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g„ etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®), Enlimomab, gavilimomab, antithymocytc immunoglobulin, siplizumab, Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.

In some embodiments, the bioactive agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment, hi some embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a folly human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anticancer response, or antagonizes an antigen important for cancer. Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-1- 131 ); RAPTTVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LLUUCCEENNTTIISS®® (ranibizumab); SSOOUURRIISS®® (eculizumab); CIMZIA® (certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canaklnumab); STELARA® (ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX® (motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY® (ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (ado- trastuzumab emtansine); and GAZYVA® (obinutuzumab). Also included are antibodydrug conjugates.

The combination therapy may include a therapeutic agent which is a non-dnig treatment. For example, the compound could be administered in addition to radiation therapy, cryotherapy, hyperthermia, and/or surgical excision of tumor tissue.

In certain embodiments the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 1 1 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hows up to 20 hours, up to 21 hours, up to 22 hows, up to 23 hows up to 24 hours or up to 1-7, 1-14, 1- 21 or 1-30 days before or after the second therapeutic agent.

In certain embodiments the second therapeutic agent is administered on a different dosage schedule than the compound of the present invention. For example the second therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In another embodiment the first therapeutic agent has a treatment holiday. For example the first therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In certain embodiments both the first and second therapeutic have a. treatment holiday.

VII. PHARMACEUTICAL COMPOSITIONS

A compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a therapeutically active substance, e.g. in the form of a pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. In other embodiments the compound is administered paternally, for example by intravaneous administration. In other embodiments the pharmaceutical composition is administered rectally, e.g. in the form of suppositories. A compound of the present invention or a pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, com starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

Medicaments containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also provided by the present invention, as is a process for their production, which comprises bringing one or more compounds of the present invention and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of the present invention or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

In certain embodiments the pharmaceutical composition is in a dosage form that contains 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 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 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt. In some embodiments, compounds disclosed herein or used as described are administered once a day (QD), twice a day (BID), or three times a day (TID). In some embodiments, compounds disclosed herein or used as described are administered at least once a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or longer.

In certain embodiments the compound of the present invention is administered once a day, twice a day, three times a day, or four times a day.

In certain embodiments the compound of the present invention is administered orally once a day. In certain embodiments the compound of the present invention is administered orally twice a day. In certain embodiments the compound of the present invention is administered orally three times a day. In certain embodiments the compound of the present invention is administered orally four times a day.

In certain embodiments the compound of the present invention is administered intravenously once a day. In certain embodiments the compound of the present invention is administered intravenously twice a day. In certain embodiments the compound of the present invention is administered intravenously three times a day. In certain embodiments the compound of the present invention is administered intravenously four tunes a day.

In some embodiments the compound of the present invention is administered with a treatment holiday in between treatment cycles. For example the compound may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle.

In some embodiments a loading dose is administered to begin treatment. For example, the compound may be administered about 1.5x, about 2x, about 2.5x, about 3x, about 3.5x, about 4x, about 4.5x, about 5x, about 5,5x, about 6x, about. 6.5x, about 7x, about 7.5x, about 8x, about 8.5x, about 9x, about 9.5x, or about 10x higher dose on the first day of treatment than the remaining days of treatment in the treatment cycle. Additional exemplary loading doses include about 1.5x, about 2x, about 2.5x, about 3x, about 3.5x, about 4x, about 4.5x, about 5x, about 5.5x, about 6x, about 6.5x, about 7x, about 7.5x, about 8x, about 8.5x, about 9x, about 9.5x, or about 10x higher dose on the first 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of treatment titan the remaining days of treatment in the treatment cycle.

The pharmaceutical composition may also include a molar ratio of the active compound and an additional active agent. For example the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or from about 1.5:1 to about 4:1 of an anti-inflammatoiy or immunosuppressing agent.

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.

A pharmaceutically or therapeutically effective amount of the composition will be delivered to the patient. The precise effective amount will vary from patient to patient, and will depend upon the species, age, the subject’s size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. The effective amount for a given situation can be determined by routine experimentation. For purposes of the disclosure, a therapeutic amount may for example be in the range of about 0.01 mg/kg to about 250 mg/kg body weight, more typically about 0.1 mg/kg to about 10 mg/kg, in at least one dose. The subject can be administered as many doses as is required to reduce and/or alleviate the signs, symptoms, or causes of the disorder in question, or bring about any other desired alteration of a biological system. When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. hr certain embodiments the dose ranges from about 0.01-100 mg/kg of patient bodyweight, for example about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg, -kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or It can be the appropriate number of any of these in packaged form.

Tn certain embodiments the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactoblonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

Thus, the composition of the disclosure can be administered as a pharmaceutical formulation including one suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous), injections, inhalation or spray, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, or by other means of administration containing conventional pharmaceutically acceptable carriers. A. typical manner of administration is oral, topical or intravenous, using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.

Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrup, suspensions, creams, ointments, lotions, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, a transdermal patch, a subcutaneous patch, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution, or the like, preferably in unit dosage form suitable for single adm inistration of a precise dosage.

Some dosage forms, such as tablets and capsules, are subdi vided into sui tably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. The compositions will include an effective amount of the selected drag in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like.

Gamers include excipients and diluents and must be of sufficiently high purity and sufficiently low' toxicity to render them suitable for administration 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 adjuvants, binders, buffering agents, coloring agents, diluents, disintegrants, excipients, emulsifiers, flavorants, gels, glidents, lubricants, preservatives, stabilizers, surfactants, solubilizer, tableting agents, wetting agents or solidifying material.

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, petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers and vegetable oils. Optional active agents may be included hi a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.

Some excipients include, but are not limited, to liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like. The compound can be provided, for example, in the form of a solid, a liquid, spray dried material, a microparticle, nanoparticle, controlled release system, etc., as desired according to the goal of the therapy. Suitable excipients for non-liquid formulations are also known to those of skill in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).

Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, can be present in such vehicles. A biological buffer can be any solution which is pharmacologically acceptable, and which provides the formulation with the desired pH, i.e,, a pH in the physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like.

For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc. cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. Actual methods of preparing such dosage form s are known, or will be apparent, to those skilled in this art; for example, see Remington’s Pharmaceutical Sciences, referenced above.

In yet another embodiment provided is the use of permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (vV-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan- thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).

In certain embodiments the excipient is selected from butylated hydroxytoluene (BHT), calcium, carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (com), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

The pharmaceutical eompositions/combinations can be formulated for oral administration. For oral administration, the composition will generally take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are typical oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. Typically, the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

When liquid suspensions are used, the active agent can be combined with any oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents can be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.

For ocular delivery, the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcomeal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device.

Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions. Typically, sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents. The sterile injectable formulation can also be a sterile injectable solution or a suspension in a acceptably nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media. In addition, parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is m aintained.

Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Administration via certahi parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system. A formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.

Preparations according to the disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.

Sterile injectable solutions are prepared by incorporating one or more of the compounds of the disclosure in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, typical methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

Alternatively, the pharmaceutical compositions of the disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the ait of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.

Formulations for buccal administration include tablets, lozenges, gels and the like. Alternatively, buccal administration can be effected using a transmucosal delivery system as known to those skilled in the art. The compounds of the disclosure can also be delivered through the skin or muscosal tissue using conventional transdermal drag delivery systems, i.e., transdermal “patches” wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface. In such a structure, the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer. The laminated device can contain a single reservoir, or it can contain multiple reservoirs. In certain embodiments, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like.

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.

In certain embodiments an oral formulation is provided.

VIII. PHARMACOLOGICAL TEST’S

The compounds of the present invention and their pharmaceutically acceptable salts possess valuable pharmacological properties. The compounds were investigated in accordance with the test given hereinafter.

Genetic Tests for KRAS Mutation Status

In some aspects, a compound as described herein, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, is used as a medicament in therapeutic and/or prophylactic treatment of a patient with KRAS activating mutations as determined with a test selected from Agilent Resolution ctDx FIRST assay, cobas KRAS Mutation Test, FoundationOne CDx, Guardant360 CDx, ONCO/Reveal Dx Lung & Colon Cancer Assay (O/RDx-LCCA), tlierascreen KRAS RGQ PCR Kit, Praxis Extended RAS Panel, or a combination thereof, suffering from cancer, comprising determining the KRAS mutation status in said patient and then administering the compound, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition to said patient.

IX. SYNTHETIC METHODS

The compounds of the present invention may contain one or more asymmetric centers and can therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry' may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary', with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

In the embodiments, where optically pure enantiomers are provided, optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound. Chirally pure or chirally enriched compounds may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate.

Isolation and purification of the compounds Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of the present invention can be separated using chiral HPLC. Racemic mixtures of chiral synthetic intermediates may also be separated using chiral HPLC.

Salts of compounds of the present invention

In cases where the compound of the present invention is basic they may be converted to a corresponding acid addition salt. The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p~toluenesulfonic acid, salicylic acid and the like. A specific salt is the fumarate. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0 °C and 50 °C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent,

Insofar as their preparation is not described in the examples, compounds of the present invention as well as intermediate products can be prepared according to analogous methods or according to the methods set forth herein. Starting materials are commercially available, known in the art or can be prepared by methods known in the art or in analogy thereto.

It will be appreciated that the compounds of the present invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. X. GENERAL SYNTHETIC SCHEMES Non-limiting distinct methods for preparing compounds of the present invention include those provided in Schemes 1-4. As illustrated in these Schemes and the Examples below, compounds for use in the present invention can be synthesized by one skilled in the art using a range of different retrosynthetic paths. As shown in Scheme 1, compounds for use in the present invention can be prepared by chemically combining a Heterocyclic Moiety and a Linker followed by subsequent addition of a Targeting Ligand. In certain aspects the Heterocyclic Moiety, Linker, or Targeting Ligand of Scheme 1 is a precursor intermediate that is then fully functionalized later in the synthesis. For example, where Targeting Ligand is the skilled artisan may choose to use it in a protected form and then remove the protecting groups after preparing a protected compound of the present invention (see for example Scheme 1-a).

Scheme 1-a Similarly, one or more moieties of Linker may be installed on the KRAS Targeting Ligand before the molecule is fully assembled or even before the KRAS Targeting Ligand portion of the molecule is fully assembled (see for example Scheme 1-b). Scheme 1-b In certain aspects protecting group strategies and splitting the linker into multiple moieties are both used to prepare compounds of the present invention (see for example Scheme 1-c).

In the alternative, in Scheme 2 compounds for use in the present invention are prepared by chemically combining a Targeting Ligand and Linker first, followed by subsequent addition of a Heterocyclic Moiety. Like Scheme 1, this process can be accomplished with the use of protecting groups and/or adding Linker portion wise if desired. Additionally, in certain aspects Linker or a portion of Linker is installed on the Targeting Ligand before the Targeting Ligand is completed. For example, in Scheme 2-a a linker is installed on the bicyclic Targeting Ligand core in advance of installation of the R³² and R²⁹ groups.

In Scheme 3, in Step 1, a nucleophilic Heterocyclic Moiety displaces a leaving group on the Linker to make a Heterocyclic Moiety Linker fragment. In Step 2, the protecting group is removed by methods known in the art to free a nucleophilic site on the linker. In Step 3, the nucleophilic Heterocyclic Moiety Linker fragment displaces a leaving group on the Targeting Ligand to form a compound for use in the present invention. In an alternative embodiment Step 1 and/or Step 2 is accomplished by a coupling reaction instead of a nucleophilic attack. Scheme 4 In Scheme 4, in Step 1, a nucleophilic Targeting Ligand displaces a leaving group on the Linker to make a Targeting Ligand Linker fragment. In Step 2, the protecting group is removed by methods known in the art to free a nucleophilic site on the linker. In Step 3, the nucleophilic Targeting Ligand Linker fragment displaces a leaving group on the Heterocyclic Moiety to form a compound for use in the present invention. In an alternative embodiment Step 1 and/or Step 2 is accomplished by a coupling reaction instead of a nucleophilic attack. XI. EXPERIMENTAL PROCEDURES Abbreviations

References for the Synthesis of Building Blocks EXAMPLE 1: SYNTHESIS OF TARGET LIGANDS Synthesis A1: Synthesis of tert-butyl (1R,5S)-3-(2-(((S)-1-(2-aminoethyl)pyrrolidin-2- yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (A-1)

Step 1:

Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of

[(2.S)-pyrrolidin-2-yl]methanol (2: 0.5 g, 4.71 (mol, 0.5 mL ) in MeOH (20 mL) were added tert-butyl A-(2-oxoethyl)carbamate (1: 0.5 g, 3.14 mmol) and triethylamine (635.68 mg, 6.28 mmol, 0.8 mL) at ambient temperature. The resulting mixture was stirred for 2 hours. Thereafter, sodium cyanoborohydride (394.78 mg, 6.28 mmol) was added to the reaction mixture at 0 °C and the resulting mixture was stirred at ambient temperature for 6 h After complete consumption of the starting material as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230- 400 mesh; 25 g SNAP; liquid loading) column with 18-20% MeOH/DCM to afford tert-butyl N-[2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl]carbamate hydrochloric acid (3; 572 mg, 2.28 mmol, 97.5% purity) as a light yellow solid. Yield-72.67%; LCMS (ESI): [M+H]⁺ m/z Calculated: 245.1. Found: 245.2. Step 2: Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl N-[2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl]carbamate (3; 1.3 g, 5.32 mmol) in dry DCM (30 mL) was added 4N HCl in 1,4-dioxane (13 mL) at 5 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 hours and the progress of the reaction was monitored. After complete consumption of the starting material as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure to afford [(2S)-1- (2-aminoethyl)pyrrolidin-2-yl]methanol hydrochloride (4; 1.1 g, 7.63 mmol, 100% purity) as an off-white solid and the crude mass was taken to the next step without purification. LCMS (ESI): [M+H] ⁺ m/z Calculated: 145.1. Found: 145.2. Step 3: Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of [(2S)-1-(2-aminoethyl)pyrrolidin-2-yl]methanol hydrochloride (4; 1.1 g, 6.08 mmol) in MeOH (20 mL) was added triethylamine (3.08 g, 30.42 mmol, 4.24 mL). The reaction mixture was cooled to 5 °C and then ethyl 2,2,2-trifluoroacetate (950.83 mg, 6.69 mmol, 0.8 mL) was added. The reaction mixture was stirred at ambient temperature for 5 hours. The reaction progress was monitored by TLC and LCMS-ELSD. After complete consumption of the starting material as indicated by LCMS, the reaction mixture was concentrated under reduced pressure, diluted with water (30 mL) and then extracted with EtOAc (3 x 50 mL). Combined organic phases were washed with cold water (2 x 50 mL), dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford 2,2,2-trifluoro-N-[2-[(2S)-2- (hydroxymethyl)pyrrolidin-1-yl]ethyl]acetamide (5; 0.7 g, 2.91 mmol, 99.89% purity) as an off- white solid. Yield-47.84%; LCMS (ESI): [M+H]⁺ m/z Calculated: 241.1. Found: 241.2. Step 4: Into a 20 mL screw-capped glass-vial containing a well stirred solution of tert-butyl 3- (2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (6; 0.62 g, 1.43 mmol)^a and 2,2,2-trifluoro-N-[2-[(2S)-2-(hydroxymethyl)pyrrolidin- 1-yl]ethyl]acetamide (5; 618.50 mg, 2.57 mmol) in dry acetonitrile (15 mL) was added cesium carbonate (1.16 g, 3.57 mmol). The reaction mixture was stirred at 70 °C for 2 hours and the progress of the reaction was monitored by TLC and LCMS. After complete consumption of the starting material as indicated by LCMS, reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while the desired compound was eluting at 60-70% of the mobile phase to afford tert-butyl 3-[7-chloro-8-fluoro- 2-[[1-[2-[(2,2,2-trifluoroacetyl)amino]ethyl]pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin- 4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7; 0.54 g, 0.85 mmol, 100% purity) as a light yellow gummy solid. Yield-59.8%; LCMS (ESI): [M+H]⁺ m/z Calculated: 632.2. Found: 632.2. This reaction was performed as 0.3g x 2 batches to avoid the formation of hydroxy impurity. Step 5: Into a 20 mL screw-capped glass-vial containing a well stirred solution of tert-butyl 3- [7-chloro-8-fluoro-2-[[(2S)-1-[2-[(2,2,2-trifluoroacetyl)amino]ethyl]pyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7; 1.45 g, 2.22 mmol) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (8; 0.85 g, 1.66 mmol) in THF (15 mL) and water (1.5 mL) was added potassium phosphate tribasic (1.41 g, 6.66 mmol) then added XPhos-Pd-G₂ (175 mg, 0.1 eq). The resulting mixture was purged with nitrogen gas (3 x 2 minutes) and then stirred at 70 °C for 1 hour. The progress of the reaction was monitored by TLC and LCMS. After 2 hours, the reaction mixture was cooled to room temperature and purged with nitrogen for 2 minutes, then another batch of 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (8; 0.85 g, 1.66 mmol) and XPhos- Pd-G2 (72.2 mg, 0.1 eq) were added to the reaction mixture. The resulting mixture was purged with nitrogen gas for 2 minutes and then stirred at 70 °C for further 1 hour and the progress of the reaction was monitored by TLC and LCMS. After complete consumption of the starting material as indicated by LCMS, the reaction mixture was concentrated to afford a crude mass. The crude mass was purified by reversed-phase column chromatography (Column: RediSep C 18-100g, Mobile phase: A = 0.1% Formic acid in water, B = Acetonitrile) and fractions having desired product were concentrated under reduced pressure to remove acetonitrile and then diluted with 10% sodium bicarbonate solution until pH~9 (200 mL), brine (50 mL) and then extracted with EtOAc (3 x 200 mL). Combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 3- [8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[(2S)- 1-[2-[(2,2,2-trifluoroacetyl)amino]ethyl]pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9; 1.16 g, 1.03 mmol, 87.53% purity) as a light brown gummy solid. Yield-46.6%; LCMS (ESI): [M+H]⁺ m/z Calculated: 982.46. Found: 982.40. Step 6: Into a 8 mL screw-capped glass-vial containing a well-stirred solution of tert-butyl 3- [8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[(2S)- 1-[2-[(2,2,2-trifluoroacetyl)amino]ethyl]pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9; 0.5 g, 0.45 mmol) in acetonitrile (1.5 mL) was added cesium fluoride (338.44 mg, 2.23 mmol, 0.1 mL). The reaction mixture was stirred at room temperature and the progress of the reaction was monitored by TLC and LCMS. After 16 hours, the reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 3-[7-[8-ethynyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2S)-1-[2-[(2,2,2- trifluoroacetyl)amino]ethyl]pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate and the crude was taken to the next step without purification. (10; 0.36 g, 0.41 mmol, 93.24% purity). Yield-91.22%; UP-LCMS (ESI): [M+ H]⁺ m/z Calculated: 826.80. Found: 826.20. Step 7: Into a 20 mL screw-capped glass-vial containing a well stirred solution of tert-butyl 3- [7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2S)-1-[2-[(2,2,2- trifluoroacetyl)amino]ethyl]pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (10; 0.36 g, 0.41 mmol) in THF (4 mL) and water (0.4 mL) was added lithium;hydroxide;hydrate (170.57 mg, 4.06 mmol, 0.11 mL). The reaction mixture was stirred at 55 °C for 5 hours and the progress of the reaction was monitored by TLC and LCMS. After complete consumption of the starting material as indicated by LCMS, the reaction mixture was filtered through an anhydrous Na2SO4 bed and washed with THF (30 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 3-[2-[[(2S)-1-(2- aminoethyl)pyrrolidin-2-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (A-1; 0.34 g, 0.40 mmol, 85.4% purity). Yield-97.9%; UP-LCMS (ESI): [M+H]⁺ m/z Calculated: 730.80. Found: 731.0. Synthesis A2: Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1- ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (A-2) Step 1: Into a 20 mL screw-capped glass vial containing a well-stirred solution of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate formate (1; 500 mg, 1.00 mmol) in 1,4-dioxane (5 mL) were added cyclopropane- 1,1-diyldimethanol (2; 153.42 mg, 1.50 mmol) and cesium carbonate (815.73 mg, 2.50 mmol) and the resulting reaction mixture was stirred at 80 °C for 6 hours. After complete consumption of the starting material as indicated by UPLC, the reaction mixture was diluted with water (70 mL) and extracted with EtOAc (2 x 100 mL). Combined organic phase was washed with cold water (3 x 50 mL), dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by flash silica-gel (230-400 mesh; 25 g SNAP) column with 0-100% EtOAc/petroleum ether while desired compound was eluting at 50-60% of the mobile phase to afford tert-butyl (1R,5S)-3-(7-chloro- 8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (3; 160 mg, 0.246 mmol, 89.7% purity) as a white solid. Yield-38.8%; LCMS (ESI): [M+H]⁺ m/z calculated: 494.96. Found: 494.2. Step 2: Into a 20 mL screw-capped glass vial containing a well-stirred solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3; 300 mg, 0.538 mmol) and 2- [2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- naphthyl]ethynyl-triisopropyl-silane (4; 413.79 mg, 0.807 mmol) in a mixture of 1,4-dioxane (5 mL) and water (0.8 mL) was added potassium phosphate tribasic anhydrous (342.74 mg, 1.61 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas for 10 minutes. Subsequently, Xphos-Pd-G2 (42.35 mg, 0.053 mmol) was added to the reaction mixture and the reaction mixture was heated to 90 °C and stirred for 3 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while the desired compound was eluting at 50-60% of the mobile phase to afford tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5; 290 mg, 0.309 mmol, 90% purity) as a brown solid. Yield-57.4%; LCMS (ESI): [M+H]⁺ m/z calculated: 844.42. Found: 844.4. Step 3: Into a 250 mL double-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5; 400 mg, 0.421 mmol) in dry DCM (20 mL) was added Dess–Martin Periodinane, DMP (536.6 mg, 1.27 mmol) at 0 °C under nitrogen atmosphere and the resulting mixture was stirred at ambient temperature for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with DCM (100 mL). The filtrate was washed with saturated sodium bicarbonate solution (50 mL) followed by brine (50 mL) and dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while the desired compound was eluting at 50-60% of the mobile phase to afford tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6; 200 mg, 0.223 mmol, 94.3% purity) as a yellow solid. Yield-53.1%; LCMS (ESI): [M+H]⁺ m/z calculated: 842.40. Found: 842.4. Step 4: Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6; 400 mg, 0.441 mmol) and piperazine (7; 190.26 mg, 2.21 mmol) in dry MeOH (10 mL) was added acetic acid (132.65 mg, 2.21 mmol) at ambient temperature. Resulting reaction mixture was allowed to stir at ambient temperature under nitrogen atmosphere for 3 hours. Subsequently, sodium cyanoborohydride (138.81 mg, 2.21 mmol) was added to the flask and the resulting mixture was stirred for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated in vacuo to afford a crude mass. The crude mass was diluted with water (40 mL) and aqueous phase was extracted with EtOAc (2 x 100 mL). Combined organic phase was washed successively with saturated sodium bicarbonate solution (30 mL) followed by brine (30 mL), dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1- ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (A-2; 390 mg, 0.245 mmol, 57.5% purity) as a yellow solid. Yield-55.6%; LCMS (ESI): [M+H]⁺ m/z calculated: 912.19. Found: 912.4. Synthesis A3: Synthesis of tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-methyl-5-(piperazin-1- ylmethyl)pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (A-3) Step 1: Into a 500 mL single-necked round-bottomed flask equipped with a condenser, containing a well stirred solution of diethyl (2S,5R)-2,5-dibromohexanedioate (1; 10 g, 27.77 mmol) in dry THF (100 mL) was added 2M Methylamine in THF (41.66 mL) dropwise for the period of 30 minutes at 0 °C under nitrogen atmosphere and the resulting reaction mixture was stirred at ambient temperature for 18 hours at ambient temperature. Progress of the reaction was monitored by TLC (1:4 EtOAc/petroleum ether) and LCMS-ELSD. After completion of the reaction, solid formed was filtered off through a pad of Celite and Celite bed was washed with EtOAc (50 mL). The combined filtrate was concentrated under reduced pressure to afford a crude residue, which was purified by flash silica-gel (230-400 mesh) column with 5-50% EtOAc/petroleum ether while desired compound eluting at 5-10% of the mobile phase to afford diethyl (2R,5S)-1-methylpyrrolidine-2,5-dicarboxylate (2; 6.02 g, 22.05 mmol, 83.972% purity) as a yellow oil. Yield: 79.38%; LCMS (ESI): [M+ H]⁺ m/z Calculated: 229.3. Found: 230.2. Step 2: Into a 50 mL two-necked round-bottomed flask equipped with a condenser, containing a well-stirred solution of diethyl (2R,5S)-1-methylpyrrolidine-2,5-dicarboxylate (2; 250 mg, 1.09 mmol) in dry THF (15 mL) was added 2M Lithium aluminum hydride in THF (1.64 mL) at 0° C. The resulting reaction mixture was heated to 60°C for 3 hours. The progress of the reaction was monitored by TLC and LCMS-ELSD. After consumption of the starting material as indicated by TLC, reaction mixture was quenched with 30 mL of EtOAc, solid formed was filtered off through a pad of Celite and the Celite bed was washed with THF (40 mL) followed by EtOAc (40 mL). The combined filtrate was concentrated under reduced pressure to afford a crude residue, which was purified by flash silica-gel (230-400 mesh) column with 5-20% of 20% ammonium Hydroxide solution in MeOH /DCM, while the desired compound was eluting at 20% of the mobile phase to afford [(2R,5S)-5-(hydroxymethyl)-1-methyl-pyrrolidin-2- yl]methanol (3; 80 mg, 0.523 mmol, 95.004% purity) as yellow soil. Yield: 48%; LCMS (ESI): [M+H]⁺ m/z Calculated: 145.2. Found: 146.2. Step 3: Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of [(2R,5S)-5-(hydroxymethyl)-1-methyl-pyrrolidin-2-yl]methanol (3; 339.02 mg, 2.33 mmol) in dry toluene (10 mL) were added tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4; 500 mg, 1.17 mmol) followed and cesium carbonate (950.94 mg, 2.92 mmol) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was heated to 80 °C for 18 hours . The progress of the reaction was monitored by TLC and UPLC-MS. After completion of the reaction, the resulting mixture was diluted with water (20 mL), extracted with EtOAc (3 x 20 mL) and combined organic phases were dried (anhydrous Na₂SO₄). The reaction mixture was filtered through a pad of Celite bed and the filtrate was concentrated under reduced pressure to afford a crude residue, which was purified by flash silica-gel (230-400 mesh) column with 5-20% MeOH/DCM while desired compound was eluting at 9-10% to afford tert-butyl 3-[7-chloro-8-fluoro-2-[[5- (hydroxymethyl)-1-methyl-pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5; 410 mg, 0.633 mmol, 82.9% purity) as a yellow solid. Yield: 54.3%; LCMS (ESI): [M+H]⁺ m/z Calculated: 537.0. Found: 537.2. The stereochemistry for intermediates 5-11 and A-3 is relative cis stereochemistry at the pyrrolidine (i.e., a mixture of (R)(S) and (S)(R) stereochemistry). Step 4: Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl 3-[7-chloro-8-fluoro-2-[[5-(hydroxymethyl)-1-methyl-pyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5; 1.8 g, 3.35 mmol) in anhydrous DCM (25 mL) was added TEA (1.02 g, 10.06 mmol, 1.40 mL) at ambient temperature and the resulting mixture was cooled to 0 °C. Methanesulfonyl chloride (575.92 mg, 5.03 mmol, 389.93 μL) was added dropwise and the resulting reaction mixture was stirred at ambient temperature for 1 hour. Progress of reaction was monitored by TLC and UPLC-MS. After completion of the reaction, the reaction mixture was quenched with ice-water, extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 3- [7-chloro-8-fluoro-2-[[1-methyl-5-(methylsulfonyloxymethyl)pyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6; 2.5 g) as a yellowish sticky solid and the crude mass was taken to the next step without purification. Step 5: Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl 3-[7-chloro-8-fluoro-2-[[1-methyl-5-(methylsulfonyloxymethyl)pyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6; 1.8 g, 2.93 mmol) in dry DMF (1.46 mL) was added triethylamine (1.18 g, 11.71 mmol, 1.63 mL) followed by 2,2,2-trifluoro-1-piperazin-1-yl-ethanone (7; 1.73 g, 8.78 mmol) at ambient temperature and the resulting reaction mixture was stirred at 70 °C for 18 hours. Reaction progress was monitored by UPLC-MS and TLC. After completion of the reaction, reaction mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure to afford a crude mass, which was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while desired compound eluting at 80% of the mobile phase to afford tert-butyl 3-[7-chloro-8-fluoro-2-[[1-methyl-5-[[4-(2,2,2- trifluoroacetyl)piperazin-1-yl]methyl]pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8; 1.26 g, 1.42 mmol, 78.9% purity) as a brown solid. Yield: 48.5%; LCMS (ESI): [M+H]⁺ m/z Calculated: 701.1. Found: 701.2. Step 6: Into a 50 mL sealed-tube reactor containing a well-stirred solution of tert-butyl 3-[7- chloro-8-fluoro-2-[[1-methyl-5-[[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]methyl]pyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8; 1.26 g, 1.80 mmol) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (9; 1.38 g, 2.70 mmol) in dry THF (18 mL) and H₂O (2 mL) was added potassium phosphate tribasic anhydrous (1.14 g, 5.39 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas for 10 minutes. Subsequently, Xphos PdG3 (152.11 mg, 0.18 mmol) was added and the reaction mixture was again degassed by bubbling nitrogen gas for 5 minutes, and then reaction mixture was heated to 70 °C for 5 hours with stirring. The reaction was monitored by UPLC-MS and TLC. After completion of the reaction, the reaction mixture was diluted with water (20 mL), extracted with EtOAc (3 x 30 mL), the combined organic phases were dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude residue which was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while desired compound eluting at 80% to afford tert-butyl 3-[8-fluoro- 7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[1-methyl-5- [[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]methyl]pyrrolidin-2-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10; 502 mg, 0.386 mmol, 80.8% purity) as a brown solid. Yield: 21.5%; LCMS (ESI): [M+H]⁺ m/z Calculated: 1051.3. Found: 1052.2. Step 7: Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl 3-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1- naphthyl]-2-[[1-methyl-5-[[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]methyl]pyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10; 800 mg, 760.99 μmol) in anhydrous acetonitrile (10 mL) was added cesium fluoride (1.16 g, 7.61 mmol, 280.92 μL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 18 hours. After completion of the reaction as indicated by UPLC, the mixture was concentrated under reduced pressure, the residue was diluted with H₂O (20 mL), extracted with EtOAc (3 x 20 mL) and combined organic layers were dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 3-[7-[8-ethynyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-methyl-5-[[4-(2,2,2- trifluoroacetyl)piperazin-1-yl]methyl]pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (11; 726 mg, 0.6 mmol, 73% purity) as a brown solid. Yield: 77.8%; UPLC-MS (ESI): [M+H]⁺ m/z Calculated: 894.9. Found: 895.8. Step 8: Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-methyl-5- [[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]methyl]pyrrolidin-2-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (11; 726 mg, 0.625 mmol) in a mixture of anhydrous THF (9 mL) and H₂O (1 mL) was added Lithium hydroxide monohydrate (262.13 mg, 6.25 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 18 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure, the residue thus obtained was diluted with H₂O (30 mL) and extracted with EtOAc (3 x 20 mL). Combined organic layers were dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-methyl-5- (piperazin-1-ylmethyl)pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (A-3; Scaffold amine; 600 mg, 588.92 μmol, 78.4% purity) as a brown solid. Yield: 94.3%; LC-MS (ESI): [M+H]⁺ m/z Calculated: 798.9. Found: 799.2. Synthesis A4: Synthesis of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(piperazin-1-

ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (A-4) Step 1: Into a 250 mL sealed-tube containing a well-stirred solution of tert-butyl (1R,5S)-3-(2,7- dichloro-8-fluoropyrido[4',3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1; 5 g, 11.61 mmol) and cyclopropane-1,1-diyldimethanol (2; 1.78 g, 17.42 mmol, 1.67 mL) in 1,4- dioxane (50 mL) was added cesium carbonate (9.46 g, 29.03 mmol) and the resulting reaction mixture was stirred at 90 °C for 6 h. The progress of the reaction was monitored by TLC and LCMS. After complete consumption of the starting material as indicated by UPLC, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2 x 100 mL). Combined organic phase was washed with cold water (3 x 10 mL), dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh: 100 g SNAP)) column with 0-100% EtOAc/pet. ether while the desired compound was eluting at 50-60% of the mobile phase to afford tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3; 2 g, 3.67 mmol, 90.7% purity) as a white solid. Yield-31.6%; LCMS (ESI): [M+H]⁺ m/z Calculated: 494.19. Found: 494.2. Step 2: Into a 20 mL glass-vial containing a well-stirred solution of tert-butyl (1R,5S)-3-(7- chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (3; 1 g, 1.84 mmol) and 2-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4; 992.28 mg, 2.75 mmol) in 14:1 of 1,4-dioxane/water (15 mL) was added tripotassium phosphate (1.17 g, 5.51 mmol) at ambient temperature under nitrogen atmosphere and the resulting reaction mixture was degassed by bubbling nitrogen gas for 10 minutes. Subsequently, Catacxium®A-Pd-G3 (200.61 mg, 0.27 mmol) was added and the reaction mixture was stirred at 90 °C for 24 h. After completion of the reaction as indicated by LCMS, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/pet. ether while the desired product was eluting at 50-60% of the mobile phase to afford tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5; 850 mg, 1.17 mmol, 95.3% purity) as a brown color solid. Yield-63.7%; LCMS (ESI): [M+H]⁺ m/z Calculated: 692.32. Found: 692.2. Step 3: Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5; 1 g, 1.36 mmol) in dry DCM (20 mL) was added Dess-Martin periodinane (1.73 g, 4.08 mmol) at 0 °C and the reaction mixture was stirred at ambient temperature for 16 h under nitrogen atmosphere. The progress of reaction mass was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with DCM (100 mL). The filtrate was washed with saturated sodium bicarbonate solution (40 mL) followed by brine (60 mL), dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while the desired product was eluting at 50-60% of the mobile phase to afford tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro- 2-((1-formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (6; 760 mg, 1.09 mmol, 98.7% purity) as a yellow solid. Yield-80%; LCMS (ESI): [M+H]⁺ m/z Calculated: 690.3. Found: 690.2. Step 4: Into a 50 mL single-necked round-bottomed flask containing a well stirred solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (6; 400 mg, 0.54 mmol) and piperazine (7; 232.28 mg, 2.70 mmol) in dry MeOH (10 mL) was added acetic acid (2.70 mmol, 0.15 mL) at ambient temperature. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. Subsequently, sodium cyanoborohydride (169.46 mg, 2.70 mmol) was added to the reaction mixture and the mixture was stirred for 16 h. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure to afford a crude mass. The crude mass was diluted with water (20 mL) and the aqueous phase was extracted with EtOAc (2 x 20 mL). Combined filtrate was washed with cold water (50 mL), followed by saturated sodium bicarbonate solution, dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(piperazin-1- ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (A-4; 360 mg, 0.39 mmol, 83% purity) as a yellow solid. Yield-72.9%; LCMS (ESI): [M+H]⁺ m/z Calculated: 760.39. Found: 760.3. The material was used in the next step without further purification. Synthesis A5: Synthesis of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((R)-2-methyl-3-(piperazin-1- yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (A- 5) Step 1: Into a 20 mL screw-capped glass vial containing a well-stirred solution of (2S)-3-bromo- 2-methyl-propan-1-ol (2; 1.0 g, 6.54 mmol) in dry acetonitrile (10 mL) was added benzyl piperazine-1-carboxylate (1; 2.16 g, 9.80 mmol, 1.89 mL) followed by K₂CO₃ (2.71 g, 19.61 mmol) at ambient temperature and heated at 90 °C for 18 hours. After completion of the reaction as indicated by UPLC. The reaction mixture was diluted with 80 mL of water and extracted with EtOAc (3 x 40 mL). Combined organic phase was washed with brine (40 mL), dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by reverse phase column chromatography using C18 column, mobile phase: A:0.1% Formic acid in water; B: Acetonitrile to afford benzyl (R)-4-(3- hydroxy-2-methylpropyl)piperazine-1-carboxylate (3; 1.0 g, 3.41 mmol, 99.8% purity) as a colorless liquid. Yield-52.2%; LCMS (ESI): [M+H]⁺ m/z Calculated: 293.18. Found: 293.2. Step 2: Into a 250 mL double-necked round-bottomed flask containing a well-stirred solution of benzyl (R)-4-(3-hydroxy-2-methylpropyl)piperazine-1-carboxylate (3; 2.00 g, 6.84 mmol) in anhydrous THF (40 mL) was added NaH (820.79 mg, 34.20 mmol) and the resulting mixture was stirred for 10 minutes. tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4; 2.34 g, 5.47 mmol) was added to the reaction mixture and the mixture was stirred at ambient temperature for 16 h. After completion of the reaction as indicated by UPLC, the excess reagent was quenched with ice-cold water (100 mL) and extracted with EtOAc (2 x 100 mL). Combined organic phase was washed with brine (200 mL), dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(2-((R)-3-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2- methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (5; 2.0 g, 2.69 mmol, 92% purity) as a brown sticky solid. Yield-39.3%; LCMS (ESI): [M+H]⁺ m/z Calculated: 684.2. Found: 684.2. Step 3: Into a 20 mL screw-capped glass vial containing a well-stirred solution of 2-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6; 600 mg, 1.67 mmol) and tert-butyl (1R,5S)-3-(2-((R)-3-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2- methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (5; 1.14 g, 1.67 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added potassium phosphate tribasic anhydrous (1.06 g, 5.0 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas for 10 minutes. Subsequently, cataCXium® A Pd G3 (181.95 mg, 0.249 mmol) was added and the resulting mixture was heated to 90 °C for 24 h. After completion of the reaction as indicated by UPLC, reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford a crude mass which was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while desired compound eluting at 50-60% of the mobile phase to afford tert-butyl (1R,5S)-3-(2-((R)-3-(4-((benzyloxy)carbonyl)piperazin- 1-yl)-2-methylpropoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7; 400 mg, 0.387 mmol, 85.5% purity) as a brown solid. Yield-23.3%; LCMS (ESI): [M+H]⁺ m/z Calculated: 882.43. Found: 882.6. Step 4: Into a 50 mL single-necked round-bottomed flask was added a solution tert-butyl (1R,5S)-3-(2-((R)-3-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-methylpropoxy)-7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (7; 400 mg, 0.453 mmol) in 1,4-dioxane (5 mL) and the mixture was degassed with nitrogen gas for 5 minutes. Palladium hydroxide on carbon, 20 wt.% 50% water (127.38 mg, 0.181 mmol, 20% purity) was added to the reaction mixture and the mixture was stirred under H₂ bladder pressure at ambient temperature for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-((R)-2-methyl-3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (A-5; Scaffold amine; 340 mg, 0.345 mmol, 76% purity) as a pale white solid and it was used in the next step without further purification. Yield- 76.2%; UP-LCMS (ESI): [M+H]⁺ m/z Calculated: 748.89. Found: 749.4. Synthesis A6: Synthesis of (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl)-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-3-methylpiperidin-3-ol (A-6)

Step 1: Into a 250 mL single-necked round-bottomed flask containing a well-stirred solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1; 5 g, 19.81 mmol) in anhydrous DCM (20 mL) was added DIPEA (3.07 g, 23.77 mmol, 4.14 mL) and (3R)-3-methylpiperidin-3-ol hydrochloride (2; 1.82 g, 12.03 mmol) in portions at-40 ^°C under nitrogen atmosphere. The reaction was allowed to stir for 30 minutes at ambient temperature. Reaction was monitored by UPLC. The reaction mixture diluted with water (300 mL) and extracted with DCM (2 x 350 mL). Combined organic layers were dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh; 50 g SNAP) column with 0-100% EtOAc/petroleum ether while desired compound eluting at 25-26% of the mobile phase to afford (R)-1-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (3; 4.0 g, 11.11 mmol, 92.0% purity) as a pale yellow solid. Yield-56%; UPLC-MS (ESI): [M+H]⁺ m/z Calculated: 331.0. Found: 331.1. Step 2: Into a 20 mL glass-vial containing a well-stirred solution of (R)-1-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (3; 600 mg, 1.67 mmol) and [1- (hydroxymethyl)cyclopropyl]methanol (4; 255 mg, 2.50 mmol) in 1,4-dixoane (10 mL) was added Cesium carbonate (1.63 g, 5.00 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. Reaction was monitored by UPLC. Thereafter, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2 x 100 mL). Combined organic layers were dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure. The crude thus obtained was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while desired compound eluting at 70-80% of the mobile phase to afford (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethy343l)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (5; 220 mg, 0.522 mmol, 94.3% purity) as a pale yellow solid. Yeild-31%; LCMS (ESI): [M+H]⁺ m/z Calculated: 397.1. Found: 397.2. Step 3: Into a 20 mL glass-vial containing a well-stirred solution of (R)-1-(7-chloro-8-fluoro-2- ((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3- ol (5; 500 mg, 1.16 mmol) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (6; 891.16 mg, 1.74 mmol) in a mixture of THF (7 mL) and water (0.4 mL) was added Potassium phosphate tribasic (1.23 g, 5.8 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas for 10 minutes. Subsequently, CataCXium® A Pd G3 (84.42 mg, 0.115 mmol) was added to the reaction mixture and the reaction mixture was heated to 80 °C and stirred under closed condition for 3 hours. After completion of the reaction as monitored by UPLC, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with EtOAc (200 mL). Combined filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh) column with 0- 100% EtOAc/petroleum ether while desired compound eluting at 70-80 % of the mobile phase to afford (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8--((triisopropylsilyl)ethynyl) naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (7; 300 mg, 0.371 mmol, 92.6% purity) as a pale yellow solid. Yield-32%; LCMS (ESI): [M+H]⁺ m/z Calculated: 747.3. Found: 747.2. Step 4: Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8--((triisopropylsilyl)ethynyl) naphthalen-1- yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (7; 900 mg, 1.19 mmol) in anhydrous DCM (15 mL) was added Dess- Martin Periodinane (1.51 g, 3.56 mmol) 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 16 h. After completion of the reaction as monitored by UPLC, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with DCM (300 mL). The filtrate thus obtained was washed successively with saturated Sodium bicarbonate solution (150 mL) and brine, dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while desired compound eluting at 60-70 % of the mobile phase to afford (R)-1-(((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (8; 800 mg, 0.940 mmol, 87.6% purity) as a pale yellow solid. Yield-79%; LCMS (ESI): [M+H]⁺ m/z Calculated: 745.3. Found: 745.2. Step 5: Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of (R)-1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropane-1-carbaldehyde (8; 1.0 g, 1.21 mmol) and piperazine (9; 520.32 mg, 6.04 mmol) in dry MeOH (10 mL) was added Acetic acid (362.75 mg, 6.04 mmol, 345.80 μL) at ambient temperature. The reaction mixture was stirred for 3 hours at room temperature under nitrogen atmosphere, Subsequently, Sodium cyanoborohydride (379.60 mg, 6.04 mmol) at room temperature. The reaction mixture was stirred at ambient temperature for 16 h, as monitored by UPLC. The reaction mixture was concentrated to remove the excess solvent, crude obtained was diluted with water (200 mL) and aqueous phase was extracted with EtOAc (2 x 300 mL). Combined organic layers were dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure to afford (R)-1-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(piperazin-1- ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (10; 850 mg, 0.883 mmol, 84.7% purity) as a pale yellow solid. Yield-73%; LCMS (ESI): [M+H]⁺ m/z Calculated: 815.4. Found: 815.2. Step 6: Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (10; 850 mg, 0.855 mmol) in dry THF (15 mL) was added 1M TBAF in THF (4.2 mL, 4.28 mL) at 0 °C under nitrogen atmosphere and the reaction mixture was stirred at ambient temperature for 3 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was cooled to 0 °C and excess reagent was quenched with ammonium chloride solution (20 mL) and aqueous phase was extracted twice with EtOAc (2 x 100 mL). Combined organic phase was washed with water (80 mL) followed by brine (70 mL) and then dried (anhydrous Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to afford a crude mass. The crude mass was purified by reverse phase column chromatography C18 Redisep Rf Gold (100g HP C18) ; Mobile phase A : 0.1% Ammonium bicarbonate in MQ-water and B: Acetonitrile; Flow rate: 10 mL/minutes while the desired compound was eluting at 50-60% of the mobile phase to afford (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (A-6; Scaffold amine; 500 mg, 0.657 mmol, 86.7% purity) as a pale yellow gummy solid. Yield-76%; LCMS (ESI): [M+H]⁺ m/z Calculated: 659.3. Found: 659.2.

Synthesis A7: Synthesis of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3-methylpiperidin-3-ol (A-7) Step 1: Into a 250 mL single-necked round-bottomed flask containing a well-stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1; 5 g, 19.81 mmol) in anhydrous DCM (19 mL) was added DIPEA (29.71 mmol, 5.17 mL) and (R)-3-hydroxy-3-methylpiperidin-1-ium chloride (2; 1.50 g, 9.90 mmol) in portions at -40 °C under nitrogen atmosphere. The reaction mixture was allowed to stir at ambient temperature for 30 minutes. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with DCM (100 mL) and washed with water (2 x 40 mL). Combined organic phase was dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while the desired compound eluting at 25-26% of the mobile phase to afford (R)-1-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (3; 4.6 g, 12.92 mmol, 93% purity) as a yellow solid. Yield-65.2%; LCMS (ESI): [M+ H]⁺ m/z Calculated: 331.05. Found: 331.0. Step 2: Into a 40 mL glass-vial containing a well-stirred solution of (R)-1-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (3; 2 g, 5.62 mmol) in 1,4-dioxane (10 mL) were added cesium carbonate (5.49 g, 16.85 mmol) and cyclopropane-1,1- diyldimethanol (4; 860 mg, 8.42 mmol) and the resulting reaction mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After complete consumption of the starting material as indicated by UPLC, the reaction mixture was diluted with water (70 mL) and the product was extracted with EtOAc (2 x 100 mL). Combined organic phase was washed with cold water (3 x 50 mL), dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while the desired compound eluting at 70-80% of the mobile phase to afford (R)-1-(7-chloro-8-fluoro- 2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin- 3-ol (5; 600 mg, 1.27 mmol, 84% purity) as an off-white solid. Yield-22.6%; LCMS (ESI): [M+ H]⁺ m/z Calculated: 397.14. Found: 397.2. Step 3: Into a 40 mL glass-vial containing a well-stirred solution of (3R)-1-[7-chloro-8-fluoro- 2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin- 3-ol (5; 1.2 g, 2.54 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6; 2.29 g, 6.35 mmol) in a mixture of 1,4-dioxane (12 mL) and water (3 mL) was added potassium phosphate tribasic anhydrous (1.62 g, 7.62 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas for 10 minutes. Subsequently, cataCXium® A Pd G3 (462.46 mg, 0.63 mmol) was added and the reaction mixture was stirred at 90 °C for 24 h. After completion of the reaction as indicated by UPLC. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while desired compound eluting at 50-60% of the mobile phase to afford (R)-1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (7; 650 mg, 1.03 mmol, 94% purity) as a brown solid. Yield-40.4%; LCMS (ESI): [M+ H]⁺ m/z Calculated: 595.27. Found: 595.2. Step 4: Into a 100 mL two-necked round-bottomed flask containing a well-stirred solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (7; 650 mg, 1.03 mmol) in dry DCM (5 mL) was added Dess-Martin Periodinane (1.31 g, 3.08 mmol) at 0 °C and the reaction mixture was stirred at ambient temperature for 16 h under nitrogen atmosphere. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with DCM (100 mL), the filtrate was washed with saturated sodium bicarbonate solution (40 mL) followed by brine (40 mL) and dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while the desired product eluting at 78-85% of the mobile phase to afford (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropane-1-carbaldehyde (8; 420 mg, 0.65 mmol, 91% purity) as a brown solid. Yield-62.8%; LCMS (ESI): [M+ H]⁺ m/z Calculated:593.25. Found: 593.2. Step 5: Into to a 100 mL single-necked round-bottomed flask containing a well-stirred solution of (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde (8; 350 mg, 0.54 mmol) and piperazine (9; 231.46 mg, 2.69 mmol) in dry MeOH (3.94 mL) was added acetic acid (2.69 mmol, 0.15 mL) at ambient temperature and the mixture was stirred for 3 hours. Subsequently, sodium cyanoborohydride (168.86 mg, 2.69 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure to afford a crude mass. The crude mass was diluted with water (30 mL) and the product was extracted with EtOAc (2 x 40 mL). Combined organic phase was washed with cold water (2 x 20 mL), dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure to afford (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(piperazin-1- ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (A-7; Scaffold amine; 500 mg, 0.54 mmol, 71.1% purity) as a brown colour solid. Yield-99.8%; LCMS (ESI): [M+ H]⁺ m/z Calculated: 663.34. Found: 663.3. Synthesis A8: Synthesis of (R)-3-(methyl-d3)piperidin-3-ol Step 1: A solution of 1-benylpiperidine-3-one (1.0 equiv.) in THF is cooled to -78 °C. To the reaction is added methyl-d3-magesium iodide solution (1-2 equiv.) dropwise. The reaction is stirred at -78 °C for 30 min, and then is quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate; the organic layer is concentrated. The crude product is purified by column chromatography to afford 1-benzyl-3-(methyl-d3)piperidin-3-ol. The racemic mixture is purified via SFC to afford (R)-1-benzyl-3-(methyl-d3)piperidin-3-ol. Step 2: A solution of (R)-1-benzyl-3-(methyl-d3)piperidin-3-ol (1.0 equiv.) and Pd/C in ethanol is stirred under hydrogen atmosphere until the reaction is completed. The reaction mixture is filtered through celite and concentrated under reduced pressure to afford (R)-3-(methyl- d3)piperidin-3-ol. Synthesis A9: Synthesis of 4-methyl-2-azabicyclo[4.1.0]heptan-4-ol Step 1: To a solution of pyridin-3-ol (1 equiv.), NaHCO₃ (0.5 – 2 equiv.) in MeOH under -78 °C, NaBH₄ (2 -6 equiv.) is added portion wise to maintain the temperature below -60 °C, followed by the addition of CbzCl (10 – 20 equiv.) under -78 ℃. The reaction mixture is stirred at -78℃ until reaction completion. The reaction is quenched with 1 M NaOH solution and extract with ethyl acetate. The combined organic layer is washed with aq. NaCl, anhydrous Na₂SO₄, and concentrated under reduced pressure. The resulting residue is purified by column chromatography to afford benzyl 3-hydroxy-3,4-dihydropyridine-1(2H)-carboxylate. Step 2: To a solution of benzyl 3-hydroxy-3,4-dihydropyridine-1(2H)-carboxylate (1.0 equiv.) in DCE under 0 °C, Et₂Zn (1M in cyclohexane, 1 – 3 equiv.) and CH₂I₂ (1 – 3 equiv.) are slowly added and the reaction mixture is warmed to room temperature and stirred until the reaction is completed. The reaction mixture is quenched with aq. NaHCO₃ and extracted with DCM. The combined organic layer is washed with aq. NaCl, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The resulting residue is purified by column chromatography to afford benzyl 4-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylate. Step 3: To a solution of benzyl 4-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylate (1.0 equiv.) in DCM at room temperature, Dess–Martin periodinane (1 – 5 eq.) is added and the reaction mixture is stirred at room temperature until completion. The reaction mixture is quenched with aq. NaHCO₃ and extracted with DCM. The combined organic layer is washed with aq. NaCl, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The resulting residue is purified by column chromatography to afford benzyl 4-oxo-2-azabicyclo[4.1.0]heptane-2- carboxylate. Step 4: A solution of benzyl 4-oxo-2-azabicyclo[4.1.0]heptane-2-carboxylate (1.0 equiv.) in THF is cooled to -78 °C. To the reaction is added methyl magnesium iodide solution (1-2 equiv.) dropwise. The reaction is stirred at -78 °C for 30 min, and then is quenched with saturated aqueous NaHCO₃ solution and extracted with ethyl acetate; the organic layer is concentrated. The crude product is purified by column chromatography to afford benzyl 4-hydroxy-4-methyl- 2-azabicyclo[4.1.0]heptane-2-carboxylate. Step 5: A solution of benzyl 4-hydroxy-4-methyl-2-azabicyclo[4.1.0]heptane-2-carboxylate (1.0 equiv.) and Pd/C in ethanol is stirred under hydrogen atmosphere until the reaction is completed. The reaction mixture is filtered through celite and concentrated under reduced pressure to afford 4-methyl-2-azabicyclo[4.1.0]heptan-4-ol. Synthesis A10: Synthesis of 2-oxa-6-azabicyclo[5.1.0]octane Step 1: K₂CO₃ (12.30 g, 88.98 mmol) is added into THF (30 mL) and then 1,4-oxazepane (3 g, 29.66 mmol) and CbzCl (6.07 g, 35.59 mmol, 5.02 mL) are added. The mixture is stirred at 20 °C for 16hr. After complete consumption of starting material, water (20mL) is added and stirred at 20 °C for 1 hour. The reaction mixture is extracted with ethyl acetate (50mL × 2). The organic layer is collected, dried over with anhydrous sodium sulphate and concentrated in vacuo to afford crude. The crude is purified by column chromatography using silica 100-200 mesh size eluted with 15-20% ethyl acetate in petroleum ether to afford pure benzyl 1,4-oxazepane-4-carboxylate (6.3 g, 24.10 mmol, 81.25% yield). TLC: 30% ethyl acetate in petroleum ether, KMnO4 staining, Rf = 0.3. Step 2: To a stirred solution of benzyl 1,4-oxazepane-4-carboxylate (2 g, 8.50 mmol) in methanol (15 mL) is added 4-methylbenzenesulfonate;tetraethylammonium (1.28 g, 4.25 mmol) at 25°C and then stirred at room temperature on 28 Å in electrolysis equipment for 16h. The progress of the reaction is monitored by TLC until completion. The reaction mixture is concentrated under reduced pressure to afford the crude product. The residue mass is purified by column chromatography (40% ethyl acetate/hexane) to afford benzyl 3-methoxy-1,4-oxazepane-4- carboxylate (1.7 g, 2.29 mmol, 26.90% yield) as a colorless liquid. LCMS (ESI): m/z 190.16 [M-78]⁺. Retention time (min):0.82. Step 3: To a stirred solution of benzyl 3-methoxy-1,4-oxazepane-4-carboxylate (1.7 g, 6.41 mmol) in DCM (25 mL) is added DIPEA (828.14 mg, 6.41 mmol, 1.12 mL) at 25 °C and then stirred for 5 min, TMSOTf (1.42 g, 6.41 mmol, 1.16 mL) is added at 0 °C. The reaction mixture is stirred at 25 °C for 2 hours. The progress of reaction is monitored by LCMS and TLC until the reaction reached completion. The reaction mixture is concentrated under reduced pressure to afford the crude product. The residue mass is purified by column chromatography (40% ethyl acetate/hexane) to afford benzyl 6,7-dihydro-5H-1,4-oxazepine-4-carboxylate (1.3 g, 3.14 mmol, 49.02% yield) as a colorless liquid. LCMS (ESI): m/z 234.19 [M+H]⁺. Retention time (min):0.78. Step 4: To a stirred solution of benzyl 6,7-dihydro-5H-1,4-oxazepine-4-carboxylate (1.2 g, 5.14 mmol) in DCM (15 mL) is added diethylzinc, 96% (3.18 g, 25.72 mmol, 2.69 mL) at 25 °C and then stirred for 15 min, diiodomethane (6.89 g, 25.72 mmol, 2.07 mL) is added at 0 °C. The reaction mixture is stirred at 25 °C for 16 hr. The progress of reaction is monitored by LCMS and TLC. After complete consumption of starting material, reaction mixture is diluted with water (20 mL), extracted with ethyl acetate (3 x 20 mL), and the organic layer separated is dried over sodium sulphate, concentrated under reduced pressure to afford crude compound, which is column purified using (davisil silica) with 0-30 % ethyl acetate in petroleum ether as an eluent to afforded benzyl 2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (0.7 g, 2.17 mmol, 42.09% yield) as a liquid. LCMS (ESI): m/z 248.20 [M+ H] ⁺, Retention time (min): 0.74. Step 5: A solution of benzyl 2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (1.0 equiv.) and Pd/C in ethanol is stirred under hydrogen atmosphere until the reaction is completed. The reaction mixture is filtered through celite and concentrated under reduced pressure to afford 2- oxa-6-azabicyclo[5.1.0]octane. Synthesis A11: Synthesis of 2-(hydroxymethyl)-3-methylpiperidin-3-ol Step-1: Into a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert- butyl glycinate 1 (5 g, 38.12 mmol) in dry DCM (50 mL) was added triethylamine (15 mL, 114.35 mmol) and stirred for 5 minutes.4-Nitrobenzenesulfonyl chloride (12.67 g, 57.18 mmol) was added to the reaction mixture at room temperature and the resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction as indicated by TLC, reaction mixture was quenched with ice-cold water (20 mL) and extracted twice with DCM (2 x 200 mL). The combined organic phases were washed with water (150 mL), dried over anhydrous Na2SO4, filtered and filtrate was concentrated under reduced pressure to get crude residue, which was purified by flash silica-gel chromatography [230-400 mesh silica gel: 100 g SNAP; 30% EtOAc/petroleum ether] to afford tert-butyl ((4-nitrophenyl)sulfonyl)glycinate 2 (3.76 g, 11.66 mmol, 30% yield) as a white solid. LC-MS (ES⁺): m/z 315.2 [M-H] -. Step-2: Into a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert- butyl ((4-nitrophenyl)sulfonyl)glycinate 2 (3.6 g, 11.16 mmol) and 5-hydroxypentan-2-one 3 (1.37 g, 13.39 mmol) in THF (50 mL) were added triphenylphosphine (4.39 g, 16.74 mmol) and DEAD (2.92 g, 16.74 mmol) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 4 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to get crude compound that was purified by flash silica-gel chromatography [230-400 mesh silica gel: 100 g SNAP; 30% EtOAc/petroleum ether] to afford tert-butyl N-((4- nitrophenyl)sulfonyl)-N-(4-oxopentyl)glycinate 4 (2.7 g, 6.41 mmol, 57% yield) as an off-white sticky solid. UPLC-MS (ES⁺): m/z 345.2 [M-isobutene +H] ⁺. Step-3: Into a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert- butyl N-((4-nitrophenyl)sulfonyl)-N-(4-oxopentyl)glycinate 4 (2.7 g, 6.41 mmol) in THF (5 mL) was added 2M LDA in THF (3.84 mL, 7.69 mmol) at -78 °C. The resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with aqueous 1.5 N HCl solution (40 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to get crude compound which was purified by flash silica-gel chromatography [230-400 mesh silica gel: 100 g SNAP; 30% EtOAc/petroleum ether] to afford tert-butyl 3-hydroxy-3-methyl-1-((4-nitrophenyl)sulfonyl)piperidine-2-carboxylate 5 (520 mg, 0.936 mmol, 14% yield) as an off-white solid. LC-MS (ES⁺): m/z 401.0 [M+H]⁺. Step-4 & Step-5: Into a 25mL single-neck round-bottom flask, containing a well-stirred solution of tert- butyl 3-hydroxy-3-methyl-1-((4-nitrophenyl)sulfonyl)piperidine-2-carboxylate 5 (520 mg, 0.936 mmol) in dry ACN (1.49 mL) were added K₂CO₃ (258.90 mg, 1.87 mmol) followed by thiophenol (309.59 mg, 2.81 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h and then heated at 60 °C for 4 h. After completion of the reaction as indicated by LCMS and TLC, the reaction mixture was diluted with 10% methanol in DCM (100 mL). The organic phase was filtered through celite bed and filtrate was concentrated under reduced pressure to get crude compound. The crude material was dissolved in DCM (1 mL) and to the solution 4M HCl in 1,4- dioxane (0.2 mL) was added and stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to get crude material and triturated by methyl tertiary butyl ether to afford 3-hydroxy-3-methylpiperidine-2-carboxylic acid 6 (200 mg, 0.925 mmol, 98% yield, HCl salt) as a white solid. LC-MS (ES⁺): m/z 160.2 [M+H] ⁺. Step-5: Into a 50 mL single-neck round-bottom flask containing a well-stirred solution of 3- hydroxy-3-methylpiperidine-2-carboxylic acid 6 (222.22 mg, 1.02 mmol; HCl salt) in THF (3 mL) was added borane tetrahydrofuran (1 M, 2.04 mL, 2.04 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with methanol (1 mL) and 4N HCl in 1,4-dioxane (1 mL) and heated to 50 °C for 1 hour. After completion of the reaction as indicated by LCMS and TLC, the reaction mixture was cool to room temperature and the reaction mixture was concentrated under reduced pressure to get crude compound that was triturated with MTBE (30 mL) to afford 2-(hydroxymethyl)-3- methylpiperidin-3-ol 7 (100 mg, 0.544 mmol, 53% yield; HCl salt) as an off-white sticky solid. LC-MS (ES⁺): m/z 146.1 [M+H]⁺. The following compounds are synthesized according to the following references: Synthesis A12: Synthesis of (3R)-6-allyl-3-methylpiperidin-3-ol

Synthesis A13: Synthesis of 1-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)prop- 2-en-1-ol Synthesis A14: Synthesis of 1-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)but-3- en-1-ol Synthesis A15: Synthesis of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol Into a 250 mL single-necked round-bottomed flask containing a well-stirred solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1; 5 g, 19.81 mmol) in anhydrous DCM (20 mL) was added DIPEA (3.07 g, 23.77 mmol, 4.14 mL) and (3R)-3-methylpiperidin-3-ol hydrochloride (2; 1.82 g, 12.03 mmol) in portions at-40 °C under nitrogen atmosphere. The reaction was allowed to stir for 30 minutes at ambient temperature. Reaction was monitored by UPLC. The reaction mixture diluted with water (300 mL) and extracted with DCM (2 x 350 mL). Combined organic layers were dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh; 50 g SNAP) column with 0-100% EtOAc/petroleum ether while desired compound eluting at 25-26% of the mobile phase to afford (R)-1-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (A-8; 4.0 g, 11.11 mmol, 92.0% purity) as a pale yellow solid. Yield-56%; UPLC-MS (ESI): [M+H]⁺ m/z Calculated: 331.0. Found: 331.1. The following compounds are synthesized following a similar experimental procedure. Synthesis A16: Synthesis of 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4(3H)-one (A-33) Into a 100 mL single-neck round-bottom flask containing a well-stirred solution of 5,7- dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one 1 (1.3 g, 3.85 mmol) in dimethylacetamide (15 mL) and methanol (3.79 mL) was added sodium methoxide, 25% in methanol (1.07 mL, 19.26 mmol) at 0 °C. The resulting mixture was heated at 50 °C for 16 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was cooled to ambient temperature, diluted with conc. HCl by adjusting pH to ~3. The precipitated solid was filtered, washed with water (100 mL) and dried in vacuo to get 7-chloro-8-fluoro-5-methoxy-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one A-33 (850 mg, 2.48 mmol, 64% yield) as an off- white solid. LC-MS (ES⁺): m/z 276.0 [M+H] ⁺. The following compounds are synthesized following a similar experimental procedure. Synthesis A17: Synthesis of (R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (A-42) Into a 50 mL single-neck round-bottom flask containing a well-stirred solution of 7- chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one A-33 (550 mg, 1.56 mmol) in DMF (5 mL) were added N,N-diisopropylethylamine (0.813 mL, 4.67 mmol) and PyBOP (404.89 mg, 0.778 mmol) and stirred for 5 minutes. (3R)-3-methylpiperidin-3-ol (215.07 mg, 1.87 mmol) was added to the reaction mixture and stirred at ambient temperature for 16 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get a crude residue. The crude residue was purified by reverse phase column chromatography using (Column: RediSep C18-30g, Mobile phase: A: 0.1% HCOOH in water, B: MeCN) Flow rate: 25 mL/minutes; while desired compound eluting at 40% of the mobile phase to afford (R)-1-(7-chloro-8-fluoro-5-methoxy-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol A-42 (0.210 g, 0.506 mmol, 32% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 373.2 [M+H]⁺. The following compounds are synthesized following a similar experimental procedure.

Synthesis A18: Synthesis of (R)-1-(7-chloro-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (A-52) Step-1: To a solution of (R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1.0 equiv.) in DCM at room temperature, meta- chloroperoxybenzoic acid (1 -5 equiv.) was added and the reaction mixture was stirred at room temperature. The reaction progressed was monitored by UPLC-MS. After completion, the reaction mixture was subjected to standard workup conditions to afford (R)-1-(7-chloro-8- fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)- 3-methylpiperidin-3-ol. Step-2: To a solution of (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)- 5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1 equiv.) and cyclopropane- 1,1-diyldimethanol (1 – 5 equiv.) in anhydrous THF solution under 0 ℃ with N2 protection, lithium bis(trimethylsilyl)amide (1 -5 equiv.) was added and the reaction mixture was stirred at 0℃ and the reaction progress is monitored by UPLC-MS. After completion, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by reverser phase HPLC (acetonitrile with 0.05% of TFA in water: 20% to 95%) to afford (R)-1-(7-chloro-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol. The following compounds can be synthesized following a similar experimental procedure. Synthesis A19: Synthesis of (R)-1-(7-chloro-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3- ol (A-62) Into a 20 mL glass-vial containing a well-stirred solution of (R)-1-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (600 mg, 1.67 mmol) and [1- (hydroxymethyl)cyclopropyl]methanol (255 mg, 2.50 mmol) in 1,4-dixoane (10 mL) was added Cesium carbonate (1.63 g, 5.00 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. Reaction was monitored by UPLC. Therafter, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2 x 100 mL). Combined organic layers were dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure. The crude thus obtained was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while desired compound eluting at 70-80% of the mobile phase to afford (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethy343l)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (A-62; 220 mg, 0.522 mmol, 94.3% purity) as a pale yellow solid. Yield-31%; LCMS (ESI): [M+H]⁺ m/z Calculated: 397.1. Found: 397.2. The following compounds are synthesized following a similar experimental procedure. Synthesis A20: Synthesis of (R)-1-(7-chloro-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)-1,6-naphthyridin-4-yl)-3-methylpiperidin-3-ol (A- 91) Synthesis A21: Synthesis of (E)-3-chloro-4-fluoro-8-(1-(hydroxymethyl)cyclopropyl)-14- methyl-11,11a,12,13,14,15-hexahydro-8H-6,17-(azeno)dipyrido[4,3-d:1',2'- g][1]oxa[3,7]diazacyclododecin-14-ol (A-92) Following similar experimental procedures, A-93 can be synthesized. Synthesis A22: Synthesis of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (A-94) Into a 40 mL glass-vial containing a well-stirred solution of (3R)-1-[7-chloro-8-fluoro- 2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin- 3-ol (1.2 g, 2.54 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (2.29 g, 6.35 mmol) in a mixture of 1,4-dioxane (12 mL) and water (3 mL) was added potassium phosphate tribasic anhydrous (1.62 g, 7.62 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas for 10 minutes. Subsequently, cataCXium® A Pd G3 (462.46 mg, 0.63 mmol) was added and the reaction mixture was stirred at 90 °C for 24 hours. After completion of the reaction as indicated by UPLC. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while desired compound eluting at 50-60% of the mobile phase to afford (R)-1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (A-94; 650 mg, 1.03 mmol, 94% purity) as a brown solid. Yield-40.4%; LCMS (ESI): [M+ H]⁺ m/z Calculated: 595.27. Found: 595.2. The following compounds are synthesized following a similar experimental procedure.

The following compounds are separated by SFC from stereoisomers mixture.

Synthesis A23: Synthesis of 8-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-3-(8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-14-methyl- 9,10,11,11a,12,13,14,15-octahydro-8H-6,17-(azeno)dipyrido[4,3-d:1',2'- g][1]oxa[3,7]diazacyclododecin-14-ol (A-146) The following compound, A-147 is synthesized based on a similar procedure.

Synthesis A24: Synthesis (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-((R)-3-hydroxy-2-methylpropoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (A-148) Into a 100 mL single neck round bottom flask containing a well stirred solution of (3R)- 1-[2-[(2S)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propoxy]-7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol (2.50 g, 3.25 mmol) in THF (18.25 mL) was added TBAF (1.0 M in THF ) (1 M, 8.75 mL) at 0 °C and the reaction mixture was stirred at ambient temperature for 4 hours. The progress of reaction was monitored by UPLC-MS. After completion of the reaction, the reaction mixture was cooled to 0 °C and quenched with ammonium chloride solution and aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over sodium sulphate and concentrated under vacuum to afford crude compound. Then it was purified by flash silica-gel (230-400 mesh) column with 0-100% Petroleum ether/EtOAc while desired compound eluting at 100% EA , to afford (3R)-1-[7-[8- ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[(2R)-3-hydroxy-2-methyl- propoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol (1.45 g, 2.41 mmol, 73.93% yield, 96.685% purity) as a pale yellow solid. LCMS (ESI): m/z 583.27 [M+H]⁺. Found: 583.4. The following compounds are synthesized following a similar experimental procedure.

Synthesis A25: Synthesis of (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3- methylpiperidin-3-ol (A-154)

Reference procedure: WO2021107160 page 136-139 Synthesis A26: Synthesis of (3R)-1-(7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)- 7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (A-155)

Reference procedure: WO2021106231 page 114-119 Synthesis A27: Synthesis of 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6- azabicyclo[5.1.0]octane (A-12) To a stirred solution of 2,4,7-trichloro-8-fluoro-pyrido [4, 3-d] pyrimidine 1 (0.9 g, 3.56 mmol) and 2-oxa-6-azabicyclo [5.1.0] octane 2 (363.06 mg, 3.21 mmol) in acetonitrile (10 mL) was added N, N-Diisopropylethylamine (921.46 mg, 7.13 mmol, 1.24 mL) at 0 °C and continue the stirring at same temperature for 1 hour. The reaction mixture was diluted with ice water, the solid precipitate was filtered, dried, and purified by flash column chromatography using (devisal silica) with 50% ethyl acetate in pet. ether as an eluent to afforded 6-(2,7-dichloro-8-fluoro- pyrido[4,3-d] pyrimidin-4-yl)-2-oxa-6-azabicyclo [5.1.0] octane A-12 (0.75 g, 57 % yield) as an off white solid. LCMS (ESI): m/z 329.37 [M+H]⁺ _.

Synthesis A28: Synthesis of (R)-1-(2,7-dichloro-5-cyclopropyl-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (A-28) Step-1: To a stir a solution of 6-bromo-2-chloro-3-fluoro-pyridine 1 (12 g, 57.03 mmol) in THF (100 mL) was added LDA (2M in THF, 57.03 mL) dropwise at -78 °C over a period of 15 min and stirred for 45 minutes. Iodine (28.95 g, 114.05 mmol) in THF solution was added to the resulting reaction mixture and continued at -78 °C for 2 hours. The reaction mixture was quenched saturated ammonium chloride solution and extracted with ethyl acetate, the organic layer was washed with saturated sodium thiosulfate solution and brine solution . The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to get crude which was purified by silica gel (100-200 mesh) column chromatography using 5% EtOAc in Petroleum ether as an eluent to afford 6-bromo-2-chloro-3-fluoro-4-iodo-pyridine 2 (14 g,69% yield) as an off white solid.¹H NMR (400MHz, CDCl₃): δ 7.81 (d, J =3.6 Hz, 1H). Note: Position of iodine was confirmed by ¹H NMR. Step-2: To a stirred solution of 6-bromo-2-chloro-3-fluoro-4-iodo-pyridine 2 (10 g, 29.73 mmol) and tert-Butyl carbamate 3 (4.18 g, 35.68 mmol) in 1,4-Dioxane (100 mL) was added Cs2CO3 (24.22 g, 74.33 mmol) and degassed with nitrogen for 10 min followed by addition of Pd₂(dba)₃ (544.54 mg, 594.66 μmol) and Xantphos (860.20 mg, 1.49 mmol). The reaction mixture was heated to stir at 80 ℃ for 3 hours and concentrated under reduced pressure to get crude, which was purified by column chromatography (100-200 silica gel) using 0-3% ethyl acetate in petroleum ether as an eluent to afford tert-butyl N-(6-bromo-2-chloro-3-fluoro-4- pyridyl)carbamate 4 (6.5 g, 63% yield) as an off white solid, LCMS (ESI):m/z 327.19[M+H]⁺. Step-3: To a stirred solution of tert-butyl N-(6-bromo-2-chloro-3-fluoro-4-pyridyl) carbamate 4 (2 g, 6.14 mmol) and cyclopropylboronic acid 5 (1.06 g, 12.29 mmol) in a mixture of 1, 4 Dioxane (8 mL) and Water (2 mL) was added K3PO4 (3.91 g, 18.43 mmol). The reaction mixture was degassed with argon for 5 minutes. Pd(dppf)Cl₂ (449.50 mg, 614.32 μmol) was added, and the resulting reaction mixture was heated to stir at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to afford crude compound, which was purified by flash column chromatography (100-200 silica gel) using 10% ethyl acetate in petroleum ether as an eluent to afford tert-butyl N-(2-chloro-6-cyclopropyl-3-fluoro-4-pyridyl)carbamate 6 (1.2 g,63% yield) as an off white solid, LCMS (ESI): m/z 287.32 [M+H]⁺. Step-4: To stirred a solution of tert-butyl N-(2-chloro-6-cyclopropyl-3-fluoro-4- pyridyl)carbamate 6 (1.2 g, 4.19 mmol) in dichloromethane (5 mL) was added 4 M HCl in 1,4- dioxane (1 mL) at 0°C and resulting reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to get crude which was triturated with diethyl ether to afford 2-chloro-6-cyclopropyl-3-fluoro-pyridin-4-amine 7 (900 mg, 91% yield) as an off white solid, LCMS (ES+): m/z 186.72 [M+H] ⁺. Step-5: To a stirred solution of 2-chloro-6-cyclopropyl-3-fluoro-pyridin-4-amine 7 (900 mg, 4.03 mmol, Hydrochloric acid salt) in acetonitrile (5 mL) were added p-toluenesulfonic acid (48.63 mg, 282.42 μmol) and N-iodosuccinimide (NIS) (998.46 mg, 4.44 mmol).The resulting reaction mixture was heated to stir at 70 °C for 3 hours. The reaction mixture was diluted with water (50 mL) and aqueous layer was extracted with ethyl acetate (100 mL). The Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude 2-chloro-6-cyclopropyl-3-fluoro-5-iodo-pyridin-4-amine 8 (1.4 g, 70% yield) as brown solid, LCMS (ESI): m/z 312.84 [M+H]⁺. Step-6: To a stirred solution of 2-chloro-6-cyclopropyl-3-fluoro-5-iodo-pyridin-4-amine 8 (1.4 g, 4.48 mmol) in ethanol (7.10 mL) were added bis(triphenylphosphine)palladium(II)dichloride (157.02 mg, 223.99 μmol), triethyl amine (2.27 g, 22.40 mmol) in 100 mL steel bomb. The reaction mixture was degassed with nitrogen for 10 minutes. The resulting reaction mixture was heated to stir at 80 °C for 24 hours under CO (50 Psi) in a steel bomb, the reaction mixture was concentrated under reduced pressure to get crude which was purified by column chromatography (100-200 silica gel) using 10-20% ethyl acetate in petroleum ether as an eluent to afford ethyl 4- amino-6-chloro-2-cyclopropyl-5-fluoro-pyridine-3-carboxylate 9 (630 mg,47% yield) as a yellow solid, LCMS (ESI): m/z 259.14[M+H] ⁺. Step-7: To a stirred solution of ethyl 4-amino-6-chloro-2-cyclopropyl-5-fluoro-pyridine-3- carboxylate 9 (630 mg, 2.44 mmol) in THF (5 mL) was added 2, 2, 2-trichloroacetyl isocyanate 10 (458.84 mg, 2.44 mmol) and stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure to afford crude ethyl 6-chloro-2-cyclopropyl- 5-fluoro-4-[(2, 2, 2-trichloroacetyl) carbamoylamino] pyridine-3-carboxylate 11 (1 g, 41% yield) as yellow oil, LCMS (ESI): m/z 448.21 [M+H]⁺. Step-8: To a stirred solution of ethyl 6-chloro-2-cyclopropyl-5-fluoro-4-[(2, 2, 2-trichloroacetyl) carbamoyl amino] pyridine-3-carboxylate 11 (1 g, 2.24 mmol) in methanol (5 mL) was added 7 M ammonia in methanol (7 M, 1.60 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to get crude which was triturated with petroleum ether to afford 7-chloro-5-cyclopropyl-8-fluoro-pyrido [4, 3-d] pyrimidine-2, 4-diol 12 (800 mg, 82 % yield) as an off white solid, LCMS (ESI): m/z 256.16 [M+H]⁺. Step-9: To a stirred solution of 7-chloro-5-cyclopropyl-8-fluoro-pyrido [4, 3-d] pyrimidine-2, 4- diol 12 (600 mg, 2.35 mmol) in Toluene (2 mL) was added POCl3 (719.77 mg, 4.69 mmol) and DIPEA (455.01 mg, 3.52 mmol). The resulting reaction mixture was heated to stir at 100°C for 2 hours. the reaction mixture was concentrated under reduced pressure afford crude 2, 4, 7- trichloro-5-cyclopropyl-8-fluoro-pyrido [4, 3-d] pyrimidine 13 (600 mg, 87% yield) as a thick brown liquid which was directly taken for next step. Step-10: To a stirred solution of 2,4,7-trichloro-5-cyclopropyl-8-fluoro-pyrido[4,3-d]pyrimidine 13 (600 mg, 2.05 mmol) in acetonitrile (10 mL) was cooled to -15 °C. DIPEA (265.09 mg, 2.05 mmol) and (3R)-3-methylpiperidin-3-ol 14 (236.23 mg, 2.05 mmol) was added and continue the reaction at -15 °C temperature for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude which was purified by flash column chromatography (silica gel,100-200 ) using 35-40% ethyl acetate in petroleum ether as an eluent to afford (3R)-1-(2,7-dichloro-5-cyclopropyl-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3-methyl- piperidin-3-ol A-28 (110 mg, 12 % yield) as an pale yellow solid, LCMS (ESI): m/z 371.17 [M+H]⁺. Synthesis A29: Synthesis of (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3- methylpiperidin-3-ol (A-30) Into a 100 mL round bottom flask containing a well-stirred solution of 7-bromo-2,4- dichloro-6,8-difluoroquinazoline 1 (3.0 g, 9.56 mmol) in anhydrous DCM (30 mL) under nitrogen atmosphere was added (R)-3-methylpiperidin-3-ol HCl salt 2 (2.17 g, 14.34 mmol) and cooled to -40 °C. DIPEA (2.5 mL, 14.34 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was diluted with EtOAc (90 mL), washed with water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get the crude material that was purified by flash silica-gel (230-400 mesh 100 g SNAP) column with 0-100% EtOAc/ petroleum ether while desired compound eluting at 20-30% of the mobile phase to afford (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3- methylpiperidin-3-ol A-30 (3.0 g, 7.56 mmol, 79% yield) as an off-white solid. LCMS (ES⁺): m/z 392.0 [M+H] ⁺ Synthesis A30: Synthesis of (R)-1-(7-chloro-5-cyclopropyl-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3- ol (A-84) To a stirred solution of [1-(hydroxyethyl) cyclopropyl] methanol (27.51 mg, 269.37 μmol) in THF (2 mL) was added NaH (60% dispersion in oil) (6.46 mg, 269.37 μmol) at 0 °C and stirred for 5 min, (3R)-1-(2,7-dichloro-5-cyclopropyl-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl)-3-methyl-piperidin-3-ol A-28 (100 mg, 269.37 μmol) was added to reaction mixture and the reaction mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was diluted with water (20 mL) and aqueous layer was extracted with ethyl acetate (40 mL). The organic layers was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford (3R)-1-[7-chloro-5-cyclopropyl-8-fluoro-2-[[1- (hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol A-84 (90 mg, 55% yield) as thick yellow liquid, LCMS (ESI): m/z 437.34 [M+H] ⁺. Synthesis A31: Synthesis of (R)-1-(7-bromo-6,8-difluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (A-86) Into a 20 mL vial containing a well-stirred solution of (R)-1-(7-bromo-2-chloro-6,8- difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol A-30 (0.6 g, 1.53 mmol) in DMF (3.88 mL), THF (3.88 mL) was added cyclopropane-1,1-diyldimethanol 1 (312.15 mg, 3.06 mmol) and cesium carbonate (1.49 g, 4.58 mmol). The resulting reaction mixture was stirred at ambient temperature for 5 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 50 mL). Combined organic phases were washed with cold water (2 x 30 mL), dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase column chromatography (Column: RediSep C 18-50g, Mobile phase: A: 0.1% HCOOH in water, B: ACN) and fractions were lyophilized to afford (R)-1-(7-bromo-6,8- difluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol HCOOH salt A-86 (0.65 g, 1.16 mmol, 76% yield) as pale-yellow solid. LCMS (ES⁺): m/z 460.1 [M+H]⁺. Synthesis A32: Synthesis of (3R)-1-[5-cyclopropyl-7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1- (hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin- 3-ol (A-125) To a stirred solution of (3R)-1-[7-chloro-5-cyclopropyl-8-fluoro-2-[[1- (hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol A-84 (90 mg, 205.99 μmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (148.41 mg, 411.99 μmol) in a mixture of Water (0.2 mL) and THF (0.8 mL) was added K3PO4 (174.90 mg, 823.97 μmol), the resulting mixture was degassed with argon for 5 minutes followed by addition of Catacxium® A Pd G3 (37.50 mg, 51.50 μmol). The reaction mixture was irradiated in microwave at 110 °C for 1 hour. The reaction mixture concentrated under reduced pressure to get crude which was purified by column chromatography (100-200 silica gel) using 0-70% ethyl acetate in petroleum ether as an eluent to afford (3R)-1- [5-cyclopropyl-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1- (hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol A-125 (50 mg, 32 % yield) as brown solid, LCMS (ESI): m/z 635.65[M+H]⁺. Synthesis A33: Synthesis of (R)--7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 6,8-difluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3- methylpiperidin-3-ol (A-127a & A-127b) Step 1: Into a 20 mL vial containing a well-stirred solution of (R)-1-(7-bromo-6,8-difluoro-2- ((1-(hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol A-86 (250 mg, 0.545 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane 1 (294.75 mg, 0.818 mmol) in 2-methyl tetrahydrofuran (3 mL) was added K₃PO₄ (34.74 mg, 0.163 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas for 3 minutes. Subsequently Pd(dppf)Cl2·DCM (66.82 mg, 0.081 mmol) was added to the reaction mixture and stirred at 60 °C for 16 hours. After completion of the reaction as indicated by LCMS and TLC, the reaction mixture was filtered through a pad of Celite and concentrated in vacuo to get the crude material that was purified by reversed-phase column chromatography [Column: RediSep C18-50g, Mobile phase: A: 0.1% HCOOH in water; Mobile phase B: ACN] to afford (3R)-1-(7-(8-ethyl- 7-fluoro-3-(methoxymethoxy) naphthalen-1-yl)-6,8-difluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol A-127 (100 mg) as an off white solid. Step 2: SFC separation (Configurations are arbitrarily assigned) The isomers of (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6,8- difluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]quinazolin-4-yl]-3-methyl-piperidin-3-ol A-127 (100 mg) were separated by SFC [Column: YMC Cellulose SZ (250 mm x 30 mm; 10 μm); Condition: IPA+ACN (1:1) in Supercritical CO2; Flow Rate: 3 mL/min; Cycle Time: 3 min, total time: 60 min; Single injection volume: 5 μL; Back Pressure:100 bar to keep the CO₂ in Supercritical flow]. The first peak was concentrated under vacuum at 30 °C to get (R)-1-((S)-7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol A-127a (Early eluting peak from SFC, 35 mg, 0.056 mmol, 10% yield) as a white solid. LCMS (ES⁺): m/z 612.3 [M+H] ⁺. The second peak was concentrated under vacuum at 30 °C to get (R)-1-((S)-7-(8-ethyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol A-127b (Late eluting peak from SFC) ( 30 mg, 0.048 mmol, 9% yield) as a white solid. LCMS (ES⁺): m/z 612.3 [M+H]⁺. Synthesis A34: Synthesis of 7-chloro-5-ethoxy-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4(3H)-one (A-156) Into a 25 mL single-neck round-bottom flask containing well stirred solution of 5,7- dichloro-8-fluoro-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one 1 (1 g, 3.57 mmol) in DMA (15 mL) and ethanol (3 mL) was added sodium ethoxide (728.83 mg, 10.71 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction as indicated by UPLC, reaction mixture was acidified with aqueous 1.5 N HCl solution to precipitate a white solid that was filtered and dried under reduced pressure to afford 7-chloro-5-ethoxy-8-fluoro-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one A-156 (0.82 g, 2.78 mmol, 78% yield). LC-MS (ES⁺): m/z 290.0 [M+H]⁺. Synthesis A35: Synthesis of 7-chloro-8-fluoro-5-isopropoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4(3H)-one (A-34) Into a 100 mL single-neck round-bottom flask containing well stirred solution of 2- propanol 2 (643.63 mg, 10.71 mmol, 0.820 mL) in DMA (6 mL) was added LHMDS; 1 M in THF (1 M, 10.71 mL) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 30 minutes. 5,7-Dichloro-8-fluoro-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one 1 (1 g, 3.57 mmol) in DMA (6 mL) was added at 0 °C and stirred at 45 °C for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was acidified with aqueous 1.5 N HCl solution and filtered the precipitated compound. This solid material was dried under reduced pressure to afford 7-chloro-8-fluoro-5-isopropoxy-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one A- 34 (0.81 g, 2.65 mmol, 74% yield) as white solid which was used in the next step without further purification. LC-MS (ES⁺): m/z 304.0 [M+H]⁺. Synthesis A36: Synthesis of 7-chloro-5-cyclopropoxy-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4(3H)-one (A-35) Into a 100 mL single-neck round-bottom flask containing a well stirred solution of cyclopropanol 2 (622.04 mg, 10.71 mmol) in DMA (8 mL) was added 1M LiHMDS in THF (1 M, 10.71 mL) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 30 minutes. Then 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one 1 (1.0 g, 3.57 mmol) in DMA (8 mL) was added at 0 °C. The resultant reaction mixture was stirring at 45 °C for 16 hours. After completion of the reaction as indicated LCMS, the reaction mixture was quenched with aqueous 1.5 N HCl solution at 0 °C to get a white solid that was filtered and dried under reduced pressure to afford 7-chloro-5-cyclopropoxy-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4(3H)-one A-35 (1.1 g, 2.81 mmol, 78% yield). LC-MS (ES-): m/z 300.0 [M-H]-. Synthesis A37: Synthesis of 7-chloro-8-fluoro-5-((3-hydroxy-3-methylpiperidin-2- yl)methoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (A-36) Into a 25 mL single-neck round-bottom flask containing a well stirred solution of 2- (hydroxymethyl)-3-methylpiperidin-3-ol 2 (101.01 mg, 0.550 mmol; HCl salt) in DMF (2 mL) was added sodium hydride (88.07 mg, 2.20 mmol, 60% purity) at 0 °C. The resulting reaction mixture was stirred at room temperature for 0.5 hours. A solution of 5,7-dichloro-8-fluoro-2- (methylthio) pyrido[4,3-d]pyrimidin-4(3H)-one 1 (154.19 mg, 0.550 mmol) in DMF (2 mL) was added to the reaction mixture and stirred at room temperature for 2 hours. After completion of the reaction as indicated by LCMS and TLC, the reaction mixture was quenched with water and lyophilized to get crude material that was purified by reverse phase column chromatography [column: Redisep Rf Gold C18- 50g; mobile phase: 0.1% Formic acid in water and mobile phase B: Acetonitrile] to afford 7-chloro-8-fluoro-5-((3-hydroxy-3-methylpiperidin-2-yl)methoxy)-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one A-36 (130 mg, 0.326 mmol, 59% yield) as light- yellow solid. LC-MS (ES⁺): m/z 389.2 [M+H] ⁺. Synthesis A38: Synthesis of (S)-5-((1,4-oxazepan-3-yl)methoxy)-7-chloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (A-38) Into a 100 mL single-neck round-bottom flask containing a well stirred solution of (R)- (1,4-oxazepan-3-yl)methanol 2 (450 mg, 3.43 mmol) in DMF (4 mL) was added NaH (60% dispersion in oil) (600 mg, 25 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 30 minutes. 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one 1 (256.25 mg, 0.914 mmol) was added at 0 °C and the resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was diluted with water (70 mL) and extracted twice with EtOAc (2 x 100 mL). The combine organic phases were washed with cold water (50 mL), dried (anhydrous Na₂SO₄), filtered and concentrated under reduced pressure to get a crude residue that was purified by column chromatography [Column: Redisep Rf Gold C18-30g, Mobile phase A: 0.1% ammonium bicarbonate in water, Mobile phase B: acetonitrile] to afford (S)-5-((1,4-oxazepan-3- yl)methoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one A-38 (140 mg, 0.351 mmol, 30% yield) as an off-white solid. LC-MS (ES⁺): m/z 374.9 [M+H]⁺. Synthesis A39: Synthesis of (S)-5-(azepan-2-ylmethoxy)-7-chloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (A-41) Step 1: To a stirred solution of azepane-2-carboxylic acid 1 (0.5 g, 3.49 mmol) in a mixture of water (3 mL) and THF (7 mL) were added, and potassium carbonate (1.21 g, 8.73 mmol) followed by di-tert-butyl dicarbonate 2 (1.52 g, 6.98 mmol, 1.60 mL) over a period of 30 minutes at room temperature. The reaction mixture was stirred for 2 hours. After completion of the reaction as indicated by LCMS, the resulting mixture was diluted with ethyl acetate (25 mL) and the organic layer was separated. The aqueous layer was acidified to pH~2 using 5% aqueous potassium hydrogen sulfate (KHSO₄) and the resulting mixture extracted with ethyl acetate (2 x 100 mL). The combined organic phases were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 1-(tert-butoxycarbonyl)azepane-2-carboxylic acid 3 (850 mg, 3.49 mmol, 99% yield) as a white solid. LC-MS (ES⁺): m/z 144.1 [M-Boc+H]⁺. Step 2: Into a 100 mL two-neck round-bottom flask containing a well stirred solution of 1-(tert- butoxycarbonyl)azepane-2-carboxylic acid 3 (850 mg, 3.49 mmol) in THF (10 mL) at 0 ℃ was added borane;tetrahydrofuran (1 M, 10.48 mL,10.48 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by LCMS, the reaction mixture was cooled to 0 °C, quenched with methanol (20 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to get crude compound which was purified by column chromatography (230-400 silica gel 50 g SNAP) column with 0-100% EtOAc/petroleum ether using ELSD detector to afford tert-butyl 2- (hydroxymethyl)azepane-1-carboxylate 4 (550 mg, 2.29 mmol, 65% yield) as a clear oil. LC- MS (ES⁺): m/z 174.1 [M-tBu+H] ⁺. Step 3: The enantiomers of tert-butyl 2-(hydroxymethyl)azepane-1-carboxylate 4 (550 mg, 2.29 mmol) were separated by SFC [Column Name: Chiralpak IG, Flowrate: 3 mL/min, Co-solvent: 10%, Co-solvent: 0.5% Isopropyl amine in methanol, Injected volume: 0.01 mL, Temperature: 35 °C, Outlet Pressure: 100 bar]. After separation, the first eluted isomer tert-butyl (S)-2-(hydroxymethyl)azepane-1-carboxylate 4a (190 mg, 0.827 mmol, 36% yield) was obtained as a white solid. LCMS (ES⁺): m/z 174.0 [M- tBu+H] ⁺. [α]^22.5 =-55.26°, c = 0.33, CHCl₃ (consistent with the literature) [α] = -58.4° (C = 0.3, CHCl3) reported for s enantiomer in J. Org. Chem.2001, 66, 26, 9056–9062. Similarly, the second eluted isomer tert-butyl (R)-2-(hydroxymethyl)azepane-1-carboxylate 4b (150 mg, 0.648 mmol, 28% yield) was obtained as a white solid. LCMS (ES⁺): m/z 174.0 [M- tBu+H] ⁺. [α]^22.5 = 46.25°, c = 0.33, CHCl₃ Step 4: Into a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert- butyl (S)-2-(hydroxymethyl)azepane-1-carboxylate 4a (1.4 g, 6.10 mmol) in dry DCM (15 mL) was added 4.0 M HCl in 1,4-dioxane (15.25 mL, 61.0 mmol) at 5 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. After complete consumption of the starting material as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure to get (S)-azepan-2-ylmethanol HCl salt 5 (1 g, 6.03 mmol, 99% yield) as a brown solid and the crude mass was taken to the next step without purification. LC-MS (ES⁺): m/z 130.2 [M+H]⁺. Step 5: Into a 100 mL two-neck round-bottom flask containing a well-stirred solution of (S)- azepan-2-ylmethanol HCl salt 5 (319.49 mg, 1.93 mmol) in THF (15 mL) was added sodium hydride (115.67 mg, 2.89 mmol, 60% purity) at 0 °C. The resulting reaction mixture was stirred at 0 ℃ for 30 minutes. Then 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin- 4(3H)-one 6 (270 mg, 0.963 mmol) was added at 0 °C and stirring was continued at 65 ℃ for 1 hour. After complete consumption of the starting material as indicated by UPLC-MS, reaction mixture was acidified with aqueous 1.5 N HCl solution. The precipitate thus obtained was filtered and dried under vacuum to afford (S)-5-(azepan-2-ylmethoxy)-7-chloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one A-41 (150 mg, 0.398 mmol, 41% yield) as an off-white solid. LC-MS (ES⁺): m/z 373.0 [M+H]⁺. Synthesis A40: Synthesis of (R)-1-(7-chloro-8-fluoro-5-isopropoxy-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (A-44) Into a 20 mL vial containing well-stirred solution of 7-chloro-8-fluoro-5-isopropoxy-2- methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one A-34 (500 mg, 1.63 mmol) in DMF (5 mL) were added PyBOP (1.11 g, 2.12 mmol), DIPEA (1.42 mL, 8.17 mmol) and (3R)-3- methylpiperidin-3-ol (297.23 mg, 1.96 mmol, HCl salt) and stirred at ambient temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the crude material that was purified by a reversed-phase column chromatography [Column: RediSep C18; Mobile phase: 0.1% Formic acid in water and MeCN] to afford (3R)-1- (7-chloro-8-fluoro-5-isopropoxy-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-3-methyl- piperidin-3-ol A-44 (0.57 g, 1.40 mmol, 86% yield) as an off-white solid. LC-MS (ES⁺): m/z 401.1 [M+H]⁺. Synthesis A41: Synthesis of 2-chloro-1-fluoro-6-methyl-11-(methylthio)-5,5a,6,7,8,9- hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-6-ol (A- 46) Into a 20 mL screw-capped vial containing a well-stirred solution of 7-chloro-8-fluoro- 5-((3-hydroxy-3-methylpiperidin-2-yl)methoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)- one A-36 (110 mg, 0.276 mmol) in chloroform (4 mL) were added BOP-Cl (105.41 mg, 0.414 mmol) and DIPEA (0.24 mL, 1.38 mmol) at room temperature. The resulting reaction mixture was stirred at 70 ℃ for 16 hours. After completion of the reaction as indicated by LCMS, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and filtrate was concentrated under reduced pressure to get crude compound that was purified by flash silica-gel chromatography [230-400 mesh silica gel: 100 g SNAP; 60% EtOAc/petroleum ether] to afford 2-chloro-1-fluoro-6-methyl-11-(methylthio)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12- tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-6-ol A-46 (70 mg, 0.152 mmol, 55% yield) as off white solid. UPLC-MS (ES⁺): m/z 371.1 [M+H]⁺. Synthesis A42: Synthesis of (S)-2-chloro-1-fluoro-12-(methylthio)-5a,6,9,10-tetrahydro- 5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalene (A-48)

Into a 20 mL screw-capped vial containing a well-stirred solution of (S)-5-((1,4- oxazepan-3-yl)methoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one A-38 (100 mg, 0.250 mmol) in anhydrous CHCl3 (7 mL) were added DIPEA (0.43 mL, 2.51 mmol) and BOP-Cl (191.52 mg, 0.752 mmol) at room temperature. The resultant reaction mixture was stirred at 60 °C for 2 hours. After completion of the reaction as indicated by TLC and LCMS, the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic phases were washed with water (30 mL), dried (anhydrous Na₂SO₄), filtered and concentrated under reduced pressure to get the crude compound. The crude compound was purified by flash silica-gel chromatography [230- 400 mesh silica gel: 100 g SNAP; 60% EtOAc/petroleum ether] to afford (S)-2-chloro-1-fluoro- 12-(methylthio)-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8- ab]heptalene A-48 (30 mg, 0.083 mmol, 33% yield) as a pale-yellow sticky solid. LC-MS (ES⁺): m/z 357.0 [M+H]⁺. Synthesis A43: Synthesis of (S)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10- hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalene (A-51) Into a 40 mL vial containing a well-stirred solution of (S)-5-(azepan-2-ylmethoxy)-7- chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one A-41 (0.5 g, 1.30 mmol) in chloroform (10 mL) was added BOP-Cl (496.71 mg, 1.95 mmol) and degassed by sparging nitrogen for 2 minutes. Subsequently, DIPEA (0.67 mL, 3.90 mmol) was added, and the reaction mixture was heated at 60 °C for 1 hour. After complete consumption of starting material as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure to get the crude material that was purified column chromatography (230-400 silica gel 50 g SNAP column with 0-100% EtOAc/petroleum ether while the desired compound was eluted at 70-80%) to get (S)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13- tetraazanaphtho[1,8-ab]heptalene A-51 (400 mg, 1.12 mmol, 86% yield) as an off-white solid. LC-MS (ES⁺): m/z 355.0 [M+H]⁺. Synthesis A44: Synthesis of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (A-130) Step 1: Into a 40 mL screw capped vial containing a well-stirred solution of (R)-1-(7-chloro-8- fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol A-42 (600 mg, 1.61 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane 1 (1.74 g, 4.83 mmol) in 1,4-dioxane (10 mL), water (1 mL) was added Cs₂CO₃ (2.10 g, 6.44 mmol) at room temperature and purged with nitrogen gas for 2 minutes. Pd(dppf)Cl₂.CH₂Cl₂ (394.25 mg, 0.482 mmol) was added to the reaction mixture and stirred at 110 °C for 16 hours. After the completion of reaction as indicated by UPLC, the reaction mixture was filtered through a pad of celite and washed with EtOAc (150 mL). The filtrate was concentrated under reduced pressure to get a crude mass which was purified by reverse phase column chromatography using [Column: RediSep C18; Mobile phase A: 10 mm NH₄HCO₃ in MQ-water; B: acetonitrile; Flow rate: 25 mL/minutes; while desired compound eluting at 40% of the mobile phase] to afford (R)-1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5- methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 2 (500 mg, 0.843 mmol, 52% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 571.2 [M+H]⁺. Step 2: Into a 100 mL round bottom flask was stirred a solution of (R)-1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5- methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 2 (500 mg, 0.832 mmol) in DCM (10 mL) was added m-CPBA (662.98 mg, 2.50 mmol, 65% purity) and stirred at ambient temperature for 2 hours. After completion of reaction as indicated by UPLC, the reaction mixture was diluted with DCM (100 mL), washed with water (40 mL) and brine solution (40 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methoxy-2- (methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 3 (300 mg, 0.432 mmol, 52% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 603.6 [M+H]⁺. Step 3: Into a 100 mL single-neck round-bottom flask containing a well-stirred solution of (R)- 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methoxy-2- (methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 3 (300 mg, 0.443 mmol) and [1-(hydroxymethyl)cyclopropyl]methanol 4 (135.75 mg, 1.33 mmol) in anhydrous THF (10 mL) was added LiHMDS (1.0 M) in THF (2.66 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was quenched with aqueous 1.5 N HCl (30mL) solution. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). Combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to get crude residue. This crude residue was purified by reverse phase column chromatography [Column: Redisep C18- 100 g; Mobile phase:10 mM NH₄HCO₃ in water and MeCN; Flow rate: 25 mL/minutes; while desired compound eluting at 40% of the mobile phase] to afford (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol A-130 (180 mg, 0.279 mmol, 63% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 624.8 [M+H] ⁺. Synthesis A45: Synthesis of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-isopropoxypyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (A-132) Step 1: Into a 40 mL vial containing well-stirred solution of (3R)-1-(7-chloro-8-fluoro-5- isopropoxy-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-3-methyl-piperidin-3-ol A-44 (470 mg, 1.16 mmol), 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane 1 (1.25 g, 3.47 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added cesium carbonate (1.51 g, 4.62 mmol) and purged with nitrogen gas for 2 minutes. PdCl₂(dppf).CH₂Cl₂ (283.26 mg, 0.347 mmol) was added and stirred at 110 ℃ for 16 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was passed through a pad of celite and concentrated under reduced pressure to get crude residue. The crude residue was purified by flash silica gel (230-400 mesh) column chromatography (50% EtOAc in petroleum ether) and re-purified by reverse phase column chromatography by using Redisep C18 column; mobile phase: A: 0.1%Ammonium bicarbonate in water and B: acetonitrile, Flow rate: 25 mL/minutes; while desired compound eluting at 40% of the mobile phase to afford (3R)-1- [7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-5-isopropoxy-2- methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol 2 (600 mg, 0.919 mmol, 80% yield) as off-white solid. LC-MS (ES⁺): m/z 599.2 [M+H]⁺. Step-2: Into a 25 mL single-neck round-bottom flask containing well stirred solution of (3R)-1- [7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-5-isopropoxy-2- methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol 2 (400 mg, 0.613 mmol) in dry DCM (15 mL) was added m-CPBA (325.60 mg, 1.23 mmol, 65% purity) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 1.5 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was diluted with EtOAc (100 mL), washed with aqueous NaHCO₃ solution (50 mL), brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to get compound (3R)- 1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-5-isopropoxy-2- methylsulfonyl-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol 3 (410 mg, 0.442.05 mmol, 72% yield) as off-white solid. LC-MS (ES⁺): m/z 631.5 [M+H]⁺. Step 3: Into a 50 mL single-neck round-bottom flask containing well-stirred solution of (3R)-1- [7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-5-isopropoxy-2- methylsulfonyl-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol 3 (410 mg, 0.442 mmol), [1-(hydroxymethyl)cyclopropyl]methanol 4 (0.127 mL, 1.33 mmol) in anhydrous THF (6 mL) was added 1M LHMDS in THF (2.5 mL, 2.5 mmol) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 1.5 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was quenched with aqueous 1.5 N HCl solution (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to get crude residue. The crude residue was purified by reversed-phase column chromatography by using Redisep C18 column; mobile phase A: 0.1% ammonium bicarbonate in water and B: acetonitrile, Flow rate: 25 mL/minutes; while desired compound eluting at 60% of the mobile phase to afford (3R)-1-[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]-5- isopropoxy-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol A-132 (220 mg, 0.329 mmol, 74% yield) as off white solid. LC-MS (ES⁺): m/z 652.8 [M+H]^+. Synthesis A46: Synthesis of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1- fluoro-11-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-methyl-5,5a,6,7,8,9-hexahydro-4- oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-6-ol (A-134) Step 1: Into a 40 mL vial containing a well-stirred solution of 2-chloro-1-fluoro-6-methyl-11- (methylthio)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3- de]naphthalen-6-ol A-46 (70 mg, 0.152 mmol), 2-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1 (165.24 mg, 0.458 mmol) in 1,4-dioxane (2 mL) and water (0.3 mL) was added cesium carbonate (249.09 mg, 0.764 mmol) at room temperature. The reaction mixture was degassed with nitrogen for 5 minutes. PdCl₂(dppf).CH₂Cl₂ (37.46 mg, 0.045 mmol) was added to the reaction mixture and stirred at 110 ℃ for 16 hours. After completion of the reaction as indicated by LCMS, the reaction mixture was passed through a pad of Celite and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to get crude compound, which was purified by flash silica-gel chromatography [230-400 mesh silica gel: 100 g SNAP; 50% EtOAc/petroleum ether] to afford 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-6-methyl- 11-(methylthio)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3- de]naphthalen-6-ol 2 (70 mg, 0.086 mmol, 56% yield) as an off-white solid. UPLC-MS (ES⁺): m/z 569.3 [M+H]⁺. Step 2: Into a 25 mL single-neck round-bottom flask containing a well stirred solution of 2-(8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-6-methyl-11-(methylthio)- 5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-6- ol 2 (70 mg, 0.086 mmol) in anhydrous DCM (4 mL) was added m-CPBA (45.75 mg, 0.172 mmol, 65% purity) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 1.5 hours. After completion of the reaction as indicated by LCMS, the reaction mixture was diluted with ethyl acetate (50 mL), washed with aqueous sodium bicarbonate solution (20 mL), brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and filtrate was concentrated under reduced pressure to get 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl)-1-fluoro-6-methyl-11-(methylsulfonyl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12- tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-6-ol 3 (80 mg, 0.074 mmol, 86% yield) as an off-white solid. UPLC-MS (ES⁺): m/z 601.3 [M+H]⁺. Step 3: Into a 25 mL single-neck round-bottom flask containing a well-stirred solution of 2-(8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-6-methyl-11-(methylsulfonyl)- 5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-6- ol 3 (80 mg, 0.074 mmol) and cyclopropane-1,1-diyldimethanol 4 (22.85 mg, 0.223 mmol) in anhydrous THF (2 mL) was added 1 M LHMDS in THF (1 mL, 1.00 mmol) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by LCMS, the reaction mixture was quenched with aqueous 1.5 N HCl solution and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to get crude compound that was purified by reverse phase column chromatography [column: Redisep Rf Gold C18- 50g; mobile phase A: 0.1% Ammonium bicarbonate in water and mobile phase B: Acetonitrile] to afford 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-11-((1- (hydroxymethyl)cyclopropyl)methoxy)-6-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12- tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-6-ol A-134 (40 mg, 0.054 mmol, 73% yield) as off white solid. UPLC-MS (ES⁺): m/z 623.5 [M+H]⁺. Synthesis A47: Synthesis of (S)-(1-(((2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl)-1-fluoro-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8- ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methanol (A-136) Step 1: Into a 20 mL glass vial containing a well-stirred solution of (S)-2-chloro-1-fluoro-12- (methylthio)-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8- ab]heptalene A-48 (70 mg, 0.188 mmol) and 2-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1 (135.69 mg, 0.376 mmol) in water (0.2 mL) and THF (4 mL) was added K₃PO₄ (119.94 mg, 0.565 mmol) and degassed with nitrogen for 3 minutes. CataCXium-A-Pd-G3 (13.72 mg, 0.018 mmol) was added to the reaction mixture and heated at 90 °C for 12 hours. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure to get a crude residue that was purified by reversed-phase column chromatography [Column: Redisep Rf Gold C18-30g, Mobile phase A: 0.1%Ammonium bicarbonate in water, Mobile phase B: Acetonitrile] to get (S)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl)-1-fluoro-12- (methylthio)-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8- ab]heptalene 2 (50 mg, 0.070 mmol, 37% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 555.2 [M+H]⁺. Step 2: Into a 50 mL round-bottom flask containing a well-stirred solution of (S)-2-(8-ethyl-7- fluoro-3-(methoxymethoxy) naphthalen-1-yl)-1-fluoro-12-(methylthio)-5a,6,9,10-tetrahydro- 5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalene 2 (74.47 mg, 0.126 mmol) in DCM (5 mL) was added m-CPBA (100.53 mg, 0.378 mmol, 65% purity) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by UPLC and TLC, the reaction mixture was diluted with water (15 mL) and extracted twice with DCM (2 x 40 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get (S)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl)-1-fluoro-12-(methylsulfonyl)-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa- 3,10a,11,13-tetraazanaphtho[1,8-ab] heptane 3 (60 mg, 0.069 mmol, 55% yield) as a pale yellow gummy solid. LC-MS (ES⁺): m/z 587.0 [M+H]⁺. Step 3: Into a 50 mL single-neck round-bottom flask containing a well-stirred solution of (S)-2- (8-ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl)-1-fluoro-12-(methylsulfonyl)- 5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab] heptalene 3 (60 mg, 0.068 mmol) and cyclopropane-1,1-diyldimethanol 4 (21.00 mg, 0.205 mmol) in anhydrous THF (5.10 mL) was added dropwise 1 M Li-HMDS in THF (0.41 mL, 0.411 mmol) at 0 ℃ under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was quenched with aqueous 1.5 N HCl (6 mL) solution and extracted with EtOAc (3 x 50 mL). Combined organic phase was dried over anhydrous Na₂SO_4, filtered and filtrate was concentrated under reduced pressure to get crude compound, which was purified by reverse phase column chromatography [Column: Redisep Rf Gold C18-30g, Mobile phase A: 0.1% ammonium bicarbonate in water, Mobile phase B: Acetonitrile] to afford (S)-(1-(((2-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa- 3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methanol A-136 (40 mg, 0.054 mmol, 79% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 609.2 [M+H] ⁺. Synthesis A48: Synthesis of (S)-(1-(((2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8- ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methanol (A-139) Step 1: Into a 40 mL screw capped vail, containing a well-stirred solution of (S)-2-chloro-1- fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8- ab]heptalene A-51 (400 mg, 1.12 mmol) and 2-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1 (810.06 mg, 2.25 mmol) in dioxane (8 mL) and water (2 mL) was added potassium phosphate tribasic (716.00 mg, 3.37 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas for 5 minutes. Subsequently cataCXium® A Pd G3 (81.88 mg, 0.112 mmol) was added to the reaction mixture and heated at 90 ℃ for 16 hours. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to get a crude residue that was purified by reverse phase column chromatography (Column: RediSep C 18-100g, mobile phase: 0.1% Ammonium bicarbonate in water : ACN) to afford (S)-2-(8-ethyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(methylthio)-5a,6,7,8,9,10- hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalene 2 (530 mg, 0.944 mmol, 84% yield) as a brown solid. LC-MS (ES⁺): m/z 553.0 [M+H]⁺. Step 2: Into a 50 mL single-neck round-bottom flask containing well-stirred solution of (S)-2- (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(methylthio)- 5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalene 2 (500 mg, 0.891 mmol) in anhydrous DCM (10 mL) was added mCPBA (473.20 mg, 1.78 mmol, 65% purity) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by UPLC-MS and TLC, the reaction mixture was diluted with DCM (100 mL) and washed with aqueous NaHCO₃ solution (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na₂SO_4, filtered and concentrated under reduced pressure to get (S)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12- (methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8- ab]heptalene 3 (450 mg, 0.338 mmol, 38% yield) as an off-white solid. UPLC-MS (ES⁺): m/z 585.3 [M+H]⁺. Step 3: Into a 50 mL single-neck round-bottom flask containing well stirred solution of (S)-2-(8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(methylsulfonyl)- 5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalene 3 (450 mg, 0.338 mmol) and cyclopropane-1,1-diyldimethanol 4 (103.67 mg, 1.02 mmol) in anhydrous THF (10 mL) was added LiHMDS (1 M, 2.03 mL, 2.03 mmol) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by UPLC-MS and TLC, the reaction mixture was quenched with aqueous 1.5 N HCl solution. The Aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with water (20 mL), brine (10 mL), dried (anhydrous Na₂SO₄), filtered and concentrated under reduced pressure to afford the crude material which was purified by a reversed-phase HPLC [Column: Redisep C18, 120 g gold; Mobile phase A: 0.1% Ammonium bicarbonate in water and Mobile Phase B: ACN, Flow rate: 25 mL/min] to afford (S)-(1-(((2-(8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4- oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methanol A- 139 (120 mg, 0.177 mmol, 52% yield) as an off-white solid. UPLC-MS (ES⁺): m/z 607.4 [M+H]⁺. Synthesis A49: Synthesis of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-1,6-naphthyridin-4-yl)-3- methylpiperidin-3-ol (A-140) Step 1: In a 100 mL round bottom flask containing a stirred solution of ethyl 4-amino-6-chloro- 5-fluoronicotinate 1 (3 g, 13.72 mmol) in acetic acid (68.10 mL, 823.38 mmol) was added acetyl chloride (2.50 mL, 41.17 mmol) and stirred at 70 ℃ for 16 hours. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was directly concentrated under reduced pressure to get a crude compound. The crude compound was purified by flash silica-gel chromatography [230-400 mesh silica gel: 100 g SNAP; 30% EtOAc/petroleum ether] to afford ethyl 4-acetamido-6-chloro-5-fluoronicotinate 2 (2.9 g, 11.01 mmol, 80 % yield) as a white solid. LC-MS (ES⁺): m/z 261.1 [M+H]⁺. Step 2: In a 100 mL round-bottom flask, containing a well-stirred solution of ethyl 4-acetamido- 6-chloro-5-fluoronicotinate 2 (2.9 g, 11.01 mmol) in DMF (35 mL) was added KOH (803.45 mg, 14.32 mmol) followed by drop-wise addition of benzyl bromide (1.57 mL, 13.22 mmol) at 0 ℃. The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction as indicated by TLC and UPLC-MS, the reaction mixture was poured into ice cold water (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic phase was washed with brine (100 mL) dried over Na₂SO₄, filtered and concentrated the filtrate under reduced pressure to get crude residue. The crude residue was purified by flash silica-gel chromatography [230-400 mesh silica gel: 100 g SNAP; 30% EtOAc/petroleum ether] to afford ethyl 4-(N-benzylacetamido)-6-chloro-5-fluoronicotinate 3 (3.2 g, 8.01 mmol, 73% yield) as a light-yellow viscous liquid. LC-MS (ES⁺): m/z 351.0 [M+H]⁺. Step 3: In a 100 mL round-bottom flask containing a well-stirred solution of ethyl 4-(N- benzylacetamido)-6-chloro-5-fluoronicotinate 3 (4.0 g, 10.01 mmol) in THF (40 mL) was added 1 M LiHMDS in THF (20.02 mL, 20.02 mmol) slowly at 0 ℃ and the resulting reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with ice-cold water and adjusted pH ~ 4-5 with 1 N aqueous HCl solution. The reaction mixture was extracted with EtOAc (3 x 100 mL) and the combined organic phases were washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to get a crude residue. The crude residue was triturated with petroleum ether/EtOAc (5/1, v/v), dried under reduced pressure to afford 1-benzyl-7-chloro-8- fluoro-4-hydroxy-1,6-naphthyridin-2(1H)-one 4 (2.7 g, 8.68 mmol, 86% yield) as a white solid. LC-MS (ES⁺): m/z 305.1 [M+H]⁺. Step 4: In a 100 mL round-bottom flask containing a well stirred solution of 1-benzyl-7-chloro- 8-fluoro-4-hydroxy-1,6-naphthyridin-2(1H)-one 4 (2.7 g, 8.68 mmol) in POCl3 (27.24 mL, 292.22 mmol) was added DIPEA (4.54 mL, 26.05 mmol) at 0 ℃ and the reaction mixture was stirred at 110 ℃ for 16 hours. After completion of the reaction as indicated by TLC and UPLC- MS., the reaction mixture was concentrated under reduced pressure to get crude residue. The crude residue was poured into ice-cold water (150 mL) and extracted with EtOAc (3 x 150 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to get crude compound, which was purified by flash silica-gel chromatography [230-400 mesh silica gel: 100 g SNAP; 20% EtOAc/petroleum ether] to get 1-benzyl-4,7-dichloro-8-fluoro-1,6-naphthyridin-2(1H)-one 5 (2.1 g, 6.41 mmol, 74% yield) as a light-yellow solid. LC-MS (ES⁺): m/z 323.8 [M+H]⁺. Step 5: Into a 100 mL round-bottom flask, containing a well-stirred solution of 1-benzyl-4,7- dichloro-8-fluoro-1,6-naphthyridin-2(1H)-one 5 (2.1 g, 6.41 mmol) and (R)-3-methylpiperidin- 3-ol 6 (885.58 mg, 7.69 mmol) in DMSO (20 mL) was added cesium fluoride (2.24 g, 14.74 mmol) at room temperature and the mixture was stirred at 60 ℃ for 16 hours. After completion of the reaction as indicated by TLC and UPLC-MS, the reaction mixture was poured into ice- cold water (50 mL). The precipitated solid material was filtered off, rinsed with cold water and concentrated under reduced pressure to afford (R)-1-benzyl-7-chloro-8-fluoro-4-(3-hydroxy-3- methylpiperidin-1-yl)-1,6-naphthyridin-2(1H)-one 7 (2.5 g, 5.57 mmol, 87% yield) as a white solid. LC-MS (ES⁺): m/z 401.9 [M+H]⁺. Step 6: Into a 30 mL vial containing a well stirred solution of (R)-1-benzyl-7-chloro-8-fluoro- 4-(3-hydroxy-3-methylpiperidin-1-yl)-1,6-naphthyridin-2(1H)-one 7 (1.6 g, 3.56 mmol) and 2- (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane 8 (2.57 g, 7.13 mmol) in 1,4-dioxane (14 mL), water (2 mL) was added cesium carbonate (4.64 g, 14.25 mmol) and degassed with nitrogen for 2 minutes. Pd(dppf)Cl2·DCM (873.01 mg, 1.07 mmol) was added to the reaction mixture and the reaction mixture was heated at 110 ℃ for 16 hours. After completion of reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure to get a crude residue. The crude residue was purified by flash silica-gel chromatography [230-400 mesh silica gel: 100 g SNAP; 50% EtOAc/petroleum ether] to afford (R)-1-benzyl-7-(8-ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-1,6-naphthyridin-2(1H)-one 9 (1.5 g, 2.29 mmol, 64% yield) as a yellow solid. LC-MS (ES⁺): m/z 600.0 [M+H]⁺. Step 7: Into a 100 mL round-bottom flask containing a well-stirred solution of (R)-1-benzyl-7- (8-ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3- methylpiperidin-1-yl)-1,6-naphthyridin-2(1H)-one 9 (1.5 g, 2.50 mmol) in THF (10 mL), methanol (10 mL) was added 20% Pd(OH)₂ on carbon (351.28 mg, 2.50 mmol) at room temperature under nitrogen atmosphere. The resulting suspension was stirred at room temperature under hydrogen bladder pressure for 16 hours. After completion of the reaction as indicated by UPLC-MS and TLC, the reaction mixture was filtered through a pad of celite and washed with THF: methanol: EtOAc (1:1:1) (100 mL). The filtrate was concentrated under reduced pressure to get a crude residue that was purified by flash silica-gel chromatography [230-400 mesh silica gel: 100 g SNAP; 50% EtOAc/petroleum ether] to afford (R)-7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)- 1,6-naphthyridin-2(1H)-one 10 (0.550 g, 0.946 mmol, 37% yield) as a light-yellow solid. LC- MS (ES⁺): m/z 510.2 [M+H]⁺. Step 8: Into a 20 mL vial containing a well-stirred solution of (1-(((tert- butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol 11 (323.29 mg, 1.42 mmol) in THF (6 mL) were added (R)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3- hydroxy-3-methylpiperidin-1-yl)-1,6-naphthyridin-2(1H)-one 10 (550 mg, 0.946 mmol) and cyanomethylenetributylphosphorane (570.91 mg, 2.37 mmol) at room temperature under nitrogen atmosphere and stirred at 90 ℃ for 16 hours. After completion of the reaction as indicated by UPLC-MS and TLC, the reaction mixture was concentrated under reduced pressure to get a crude residue. The crude residue was purified by flash silica-gel chromatography [230- 400 mesh silica gel: 100 g SNAP; 40% EtOAc/petroleum ether] to afford (R)-1-(2-((1-(((tert- butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-1,6-naphthyridin-4-yl)-3-methylpiperidin-3-ol 12 (450 mg, 0.580 mmol, 61% yield) as a white solid. LC-MS (ES⁺): m/z 708.4 [M+H]⁺. Step 9: In a 50 mL round-bottom flask containing a well-stirred solution of (R)-1-(2-((1-(((tert- butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-1,6-naphthyridin-4-yl)-3-methylpiperidin-3-ol 12 (450.00 mg, 0.578 mmol) in THF (6 mL) was added 1M TBAF in THF (0.86 mL, 0.867 mmol) at 0 ℃ under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for two hours. After completion of the reaction as indicated by UPLC-MS and TLC, the reaction mixture was diluted with ice-cold water (50 mL) and extracted EtOAc (100 mL). The organic layer was concentrated under reduced pressure to get a crude residue. The crude residue was purified by a reverse-phase HPLC [Column: Redisep Rf Gold C18, 120 g; mobile phase A: 0.1% Formic acid in water and mobile phase B: Acetonitrile] to afford (R)-1-(7-(8- ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl) cyclopropyl) methoxy)-1,6-naphthyridin-4-yl)-3-methylpiperidin-3-ol A-140 (320 mg, 0.522 mmol, 90% yield) as pale-yellow solid. LC-MS (ES⁺): m/z 594.4 [M+H] ⁺. EXAMPLE 2: SYNTHESIS OF CRBN BINDERS 3-(6-(aminomethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (B-1) Compound 3-(6-(aminomethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione was prepared using the method described on page 322-324 of WO2023019166 A1. Synthesis B1: Synthesis of 3-[1-methyl-7-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione (B- 2)

Step-1: To a stirred solution of 7-bromo-1H-indazole 1 (20 g, 101.51 mmol) in DMF (200 mL) were added molecular iodine (51.42 g, 203.01 mmol) and KOH (11.39 g, 203.01 mmol, 5.57 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was diluted water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 7-bromo-3-iodo-1H-indazole 2 (30 g, 73.22% yield) as an off-white solid. LC-MS (ES⁺): m/z 322.47 [M+H] ⁺. Step-2: To a stirred solution of 7-bromo-3-iodo-1H-indazole 2 (120 g, 371.60 mmol) in acetone (1000 mL) were added potassium hydroxide (41.70 g, 743.20 mmol, 20.40 mL) at 0°C followed by methyl iodide (105.49 g, 743.20 mmol, 46.27 mL). The reaction mixture was then stirred at room temperature for 16 h. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (Davisil silica, 3% Ethyl acetate in Petroleum ether as eluent) to afford 7-bromo-3-iodo-1-methyl-indazole 3 (85 g, 153.88 mmol, 41.41% yield) off white solid. LC-MS (ES⁺): m/z 337.08 [M+H] ⁺. Step-3: To a solution of 7-bromo-3-iodo-1-methyl-indazole 3 (5 g, 14.84 mmol) and 2,6- dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 4 (6.19 g, 14.84 mmol) in water (36.00 mL) and dioxane (144.00 mL) was added tripotassium phosphate (9.45 g, 44.52 mmol) at room temperature. The reaction mixture was purged with argon gas for 10 minutes and tetrakis(triphenylphosphine)palladium(0) (1.71 g, 1.48 mmol) was added. The reaction mixture was purged with argon gas for an additional 5 minutes and then stirred at 95 °C for 4 hours. Subsequently, the reaction mixture was concentrated in vacuo and the crude was purified by column chromatography (Davisil silica, 2% EtOAc in petroleum ether as eluent) to afford 7- bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 5 (2.5 g, 2.76 mmol, 18.58% yield) as an off-white solid. LC-MS (ES⁺): m/z 500.14 [M+H] ⁺. Step-4: To a solution of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 5 (1.0 g, 2.00 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylate 6 (926.91 mg, 3.00 mmol) in dioxane (9.91 mL) and water (1.98 mL) was added sodium carbonate (529.54 mg, 5.00 mmol) at room temperature. The reaction mixture was purged with argon gas for 10 minutes before [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (163.20 mg, 199.85 μmol) was added and stirred at 80°C for 2 hours. Upon completion of the reaction, the solvent was removed and the residue was dissolved in water (150 mL) and extracted with ethyl acetate (3 × 75 mL). The combined organic layer was washed with brine and dried over sodium sulfate. The crude product was purified by column chromatography (Davisil silica, 10% petroleum ether in ethyl acetate as eluent) to afford tert-butyl 4-[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate 7 (1.1 g, 1.59 mmol, 79.69% yield) as a colorless oil. LC-MS (ES⁺): m/z 603.45 [M+H] ⁺. Step-5: To a solution of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-7-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 7 (1.1 g, 1.83 mmol) in 1,4-dioxane (40 mL) was added Pd/C (1.11 g, 9.13 mmol) at room temperature and the reaction mixture was stirred at 25 °C for 16 h under hydrogen atmosphere. Upon completion of the reaction, the reaction mixture was filtered through a pad of celite, which was then washed with ethyl acetate (150 mL). The combined filtrate was concentrated under reduced pressure to afford tert-butyl 4-[3-(2,6-dioxo-3- piperidyl)-1-methyl-indazol-7-yl]piperidine-1-carboxylate 8 (0.65 g, 1.12 mmol, 61.57% yield) as an off-white solid. LC-MS (ES-): m/z 425.39 [M-H] -. Step-6: To a solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-7- yl]piperidine-1-carboxylate 8 (0.5 g, 1.17 mmol) in DCM (15 mL) was added trifluoroacetic acid (1.34 g, 11.72 mmol, 903.18 μL). The reaction mixture was stirred at room temperature for 3 h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford 3-[1-methyl-7-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione B-2 (0.45 g, 899.66 μmol, 76.74% yield, TFA salt) as a white solid. LC-MS (ES⁺): m/z 327.54 [M+H] ⁺. 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione (B-3) Compound 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione was prepared using was prepared using the method described on page 68-70 of WO2023283372 A1. Synthesis B2: Synthesis of tert-butyl 2-(4-(4-((2,6-dioxopiperidin-3- yl)oxy)phenyl)piperidin-1-yl)acetate (B-4) To a stirred solution of 3-[4-(4-piperidyl)phenoxy]piperidine-2,6-dione (1) (0.260 g, 901.71 μmol) in DMF (1.53 mL) was added DIPEA (349.62 mg, 2.71 mmol, 471.18 μL) at 0° C and stirred for 10 minutes at same temperature. tert-butyl 2-bromoacetate (2) (211.06 mg, 1.08 mmol, 158.69 μL) was added dropwise to the reaction mixture at 0 °C and allowed to stir at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice water (10 mL), precipitate formed was filtered, washed with pentane (20 mL) and dried under vacuum to afford the title compound tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1-piperidyl]acetate (B-4) (193.14 mg, 458.28 μmol, 50.82% yield, 95.50% purity) as an off white solid. Mobile phase: (70 % ethyl acetate in Petroleum ether); RF (Product): 0.4; Spot visualization: UV active. LCMS (ES+): 403.39 [M+H]⁺; Retention time: 1.20; ¹H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 7.15 (d, J = 8.80 Hz, 2H), 6.93 (d, J = 8.40 Hz, 2H), 5.13-5.12 (m, 1H), 3.11 (s, 2H), 2.90 (d, J = 11.20 Hz, 2H), 2.68-2.62 (m, 1H), 2.51-2.57 (m, 1H), 2.50-2.41 (m, 1H), 2.29-2.26 (m, 2H), 2.13-2.11 (m, 2H), 1.59-1.58 (m, 4H), 1.42 (s, 9H). 3-(2-oxo-6-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (B-5) Compound 3-(2-oxo-6-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione was prepared using the method described on page 203-205 of WO2021127586 A1. 3-(2-oxo-5-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (B-6) Compound 3-(2-oxo-5-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione was prepared using was prepared using the method described on page 335-338 of WO2023019166 A1. Synthesis B3: Synthesis of 3-(6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (B- 7)

Step-1 To a stirred solution of 6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.0 equiv.) in DMSO is added NIS (1 – 3 equiv.). The reaction mixture is stirred at 90 ℃ and the reaction progress is monitored by TLC. After completion of reaction, the mixture is cooled to room temperature and poured into water and extracted with EtOAc. The combined organic layer is washed with sat. Na₂S₂O₃ solution and water, the organic layer is dried over anhydrous Na₂SO₄, filtrated, and concentrated under reduced press. The crude is purified by column chromatography to afford 6-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. Step-2 To a stirred solution of 6-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.0 equiv.) in THF, the flask is purged with argon, followed by the addition of water, 2,6- bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1 -2 equiv.), Cs₂CO₃ (3- 5 equiv.) and PdCl2(dppf)▪DCM (0.05 – 0.15 equiv.). After adding all reagents, the flask is continuously purged with argon for 10 min, and then the reaction mixture is heated to 65 ^oC. The reaction progress is monitored by TLC. After completion of reaction, the reaction mixture is cooled to room temperature, diluted with EtOAC and washed with water. The organic layer is dried over anhydrous Na2SO4, filtrated and concentrated under vacuum. The crude compound is purified through column chromatography to afford 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. Step-3 To a stirred solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole (1 equiv.) in 1,4-dioxane, water, tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 -2 equiv.), K3PO4 (1- 5 equiv.), and PdCl₂(dppf) ·DCM (0.05 – 0.15 equiv.) is added. The reaction mixture is purged with argon for 10 min, and then the reaction mixture is heated to 65 °C. The reaction progress is monitored by TLC. After completion of reaction, the reaction mixture is cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer is dried over anhydrous Na₂SO₄, filtrated and concentrated under vacuum. The crude compound is purified through column chromatography to afford tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate. Step-4 To a stirred solution of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 equiv.) in EtOAC/EtOH, 10% Pd/C (100% w/w) is added and applied under hydrogen pressure in autoclave (80 Psi) at room temperature. The reaction progress is monitored by TLC and LCMS. After completion of reaction, the reaction mixture is filtered through on celite pad, celite pad is washed with EtOAc. The filtrate is collected, concentrated and purified through column chromatography to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-6-yl)piperidine-1-carboxylate. Step-5: To a stirred solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-6-yl)piperidine-1-carboxylate (1.0 equiv.) in DCM, TFA (10 – 100 equiv.) is added and the reaction mixture is stirred at room temperature until the reaction is judge completed. The reaction mixture is subjected to standard workup conditions to afford 3-(6- (piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione. Synthesis B4: Synthesis of 3-(2-oxo-4-(piperidin-4-yl)indolin-1-yl)piperidine-2,6-dione (B- 8)

Step 1: To a stirred solution of 4-bromo-1H-indole (10 g, 51.01 mmol, 6.40 mL)in THF (250 mL) was added at room temperature under nitrogen atmosphere. The reaction mixture was cooled to 0°C and then Sodium hydride (in oil dispersion) 60% dispersion in mineral oil (13.68 g, 595.04 mmol) was added and refluxed at 60 °C for 48 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated ammonium chloride solution (200 mL) dropwise at 0°C then extracted with EtOAc (2 x 300 mL). The combined organic phases were dried with anhydrous Na₂SO₄, filtered and the filtrate was evaporated under reduced pressure to afford crude product. The combined organic phases were dried with anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure to afford crude product. Desired product mass was observed crude which was followed by washing with MTBE(300ml) to give 3-(4-bromoindol-1-yl)piperidine-2,6-dione (9 g, 28.82 mmol, 56.50% yield, 98.35% purity) . Desired product formation was observed as per LC-MS. LC-MS: m/z (ESI+): 309.0 [M+H]⁺ Step 2: To a stirred solution of 3-(4-bromoindol-1-yl)piperidine-2,6-dione (1.93 g, 6.19 mmol)in Water (40 mL) and Dioxane (20 mL) was added 1-chloro-1,2-benziodoxol-3-one (1.75 g, 6.19 mmol) at RT and stirred the reaction at 120 °C for 2 hours. The reaction was monitored by UPLC. After completion of reaction, extracted with Ethyl acetate (2x 200 ml), combined all organic layers, dried over anhydrous sodium sulphate, filtered and evaporated the solvent under reduced pressure to afford the crude. The crude product was purified by reverse phase [silicycle C18 column mobile phase: 0.1% Ammonium bicarbonate water and acetonitrile] while the product eluted at 40-50% acetonitrile in Ammonium bicarbonate water to give pure material 3- (4-bromo-2-oxo-indolin-1-yl)piperidine-2,6-dione (0.7 g, 2.07 mmol, 33.45% yield, 95.53% purity) as yellow solid. Step 3: To a stirred solution of 3-(4-bromo-2-oxo-indolin-1-yl)piperidine-2,6-dione (1 g, 2.96 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate (914.11 mg, 2.96 mmol)and Potassium phosphate tribasic anhydrous (1.07 g, 5.03 mmol) in 1,4-Dioxane (14 mL)/Water (0.6 mL)was purged with nitrogen for 15 minutes. Palladium Xphos G2 (174.45 mg, 221.72 μmol) was added at room temperature and the reaction mixture was stirred at 80°C for 2 hours. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water (10 mL), extracted with EtOAc (2 x 200 mL). The combined organic phases were dried with anhydrous Na₂SO₄, filtered and the filtrate was evaporated under reduced pressure to afford crude product, which was followed by washing with 30% Dichloromethane in petroleum ether to give tert-butyl 4-[1- (2,6-dioxo-3-piperidyl)-2-oxo-indolin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (0.85 g, 1.86 mmol, 63.05% yield, 93.3% purity) as a yellow solid. Step 4: Into a 500 mL single-necked round-bottomed flask containing a stirred solution of tert-butyl 4- [1-(2,6-dioxo-3-piperidyl)-2-oxo-indolin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.5 g, 5.88 mmol)in Dioxane (200 mL) was added Palladium hydroxide on carbon, 20 wt.% 50% water (3 g, 21.36 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere (bladder, 1kg/cm²) for 48 hours. After complete consumption of the starting material as indicated by TLC, the reaction mixture was filtered through a pad of celite and washed repeatedly with 1:11,4-dioxane/THF (2000mL). The combined filtrate was concentrated under reduced pressure to give tert-butyl 4-[1-(2,6-dioxo-3- piperidyl)-2-oxo-indolin-4-yl]piperidine-1-carboxylate (2.2 g, 4.96 mmol, 84.35% yield, 96.31% purity) as an yellow solid. The desired product was observed % in LC-MS: m/z (ESI+): 372.2[M-Isobutene+H]⁺. Step 5: To a stirred solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-indolin-4-yl]piperidine-1- carboxylate (0.02 g, 46.78 μmol) in DCM (2.08 mL) was added Hydrogen chloride solution 4.0M in dioxane (266.66 mg, 7.31 mmol, 333.33 μL) at 0° C. Then the reaction mixture was stirred at 25 °C for 2 hours. Progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure then the residue was washed with MTBE (3 x 5 mL) to afford the product 3-[2-oxo-4-(4-piperidyl)indolin-1- yl]piperidine-2,6-dione (0.016 g, 40.14 μmol, 85.79% yield, 91.27% purity) as an off white solid. The desired compound was confirmed by LC-MS: m/z (ESI+): 328.1[M+H]⁺ with 91.27% purity. Synthesis B5: Synthesis of 2-(piperidin-4-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (B-9) Synthesis B6: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-oxoimidazolidin-1- yl)piperidine-1-carboxylate (B-10) 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (B-11) Compound 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on page 265 of WO2018237026 A1. 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (B-12) Compound 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on page 268 of WO2018237026 A1. 4-((3-(piperidin-4-yl)phenyl)amino)cyclohexane-1,3-dione (B-13) Compound 4-((3-(piperidin-4-yl)phenyl)amino)cyclohexane-1,3-dione was prepared using the method described on page 79-80 of WO2023283610 A1. Synthesis B7: Synthesis of 3-(3-(piperidin-4-yl)phenoxy)piperidine-2,6-dione (B-14) Step-1: To a stirred solution of 3-bromophenol (1) (2 g, 11.56 mmol, No Salt) and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2) (3.57 g, 11.56 mmol) in Water (30 mL) and 1,4-Dioxane (3 mL) were added Potassium phosphate tribasic(6.13 g, 28.90 mmol) and degassed with nitrogen for 10 minutes, then Pd(dppf)Cl2.CH₂Cl2 (472.03 mg, 578.01 μmol) was added and the reaction mixture was again degassed for 5 minutes, resulted reaction mixture stirred for 16 h at 90 °C. After complete consumption of starting material, reaction mixture was diluted with water (100 mL) and extracted with Ethyl acetate (3 x 250 mL), organic layer separated was dried over sodium sulphate, concentrated under reduced pressure to afford crude compound, which was column purified using (davisil silica) with 25 % Ethyl acetate in Petroleum ether as an eluent to afforded tert-butyl 4-(3-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (3) (1.3 g, 4.02 mmol, 34.76% yield, 85.11% purity, No Salt) as a yellow solid. LCMS (ES-): m/z 274.13 [M-H]- Step-2: To a stirred solution of tert-butyl 4-(3-hydroxyphenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3) (1 g, 3.63 mmol) in Ethyl acetate (15 mL) and THF (15 mL) was added Pd/C (1.11 g, 10.39 mmol) and stirred the reaction mixture at 25 °C under hydrogen atmosphere in pare shaker (70 psi) for 16 h. After completion of starting material, The reaction mixture was filtered through celite bed and washed with ethyl acetate (30 mL), concentrated under reduced pressure to afford crude which was purified using davisil silica in 50% ethyl acetate in petroleum ether to afford tert-butyl 4-(3-hydroxyphenyl)piperidine-1-carboxylate (4) (1 g, 2.37 mmol, 65.22% yield, 65.70% purity, No Salt) as an off-white solid. LCMS: m/z 276.29 [M+H]⁺ Step-3: To a stirred solution of tert-butyl 4-(3-hydroxyphenyl)piperidine-1-carboxylate (4) (50 mg, 180.27 μmol) in DMF (3 mL) was added NaHCO₃ (8.65 mg, 360.55 μmol) and the reaction mixture was allowed to stir for 20 minutes at 50°C. Then 3-bromopiperidine-2,6-dione (5) (276.91 mg, 1.44 mmol) was dissolved with minimum amount of DMF (3 mL) and the reaction mixture was heated to 70°C for 16 h. After complete consumption of the starting material, the reaction mixture was quenched with water and extracted product using ethyl acetate, dried over anhydrous sodium sulphate and concentrated under reduced pressure, to afford tert-butyl 4-(3- ((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-1-carboxylate (6) (37 mg, 0.001619 mmol ,52.85% yield, 91.09% purity) as an off-white solid. LCMS (ES+): m/z 333.40 [M+H]⁺ Step-4: To the stirred solution of tert-butyl 4-(3-((2,6-dioxopiperidin-3- yl)oxy)phenyl)piperidine-1-carboxylate (6) (170 mg, 437.63 μmol) in DCM (1 mL) was added HCl炷4.0 M in 1,4-dioxane炸 (4 M, 109.41 μL) at 0 °C and the resulting reaction mixture was stirred for 1 hour at 25 °C . The reaction mixture was concentrated under reduced pressure to obtained crude compound. The crude product was triturated in diethyl ether (5 mL) to afford 3- (3-(piperidin-4-yl)phenoxy)piperidine-2,6-dione (B-14) (150 mg, 369.46 μmol, 84.42% yield, 80% purity, Hydrochloric acid) as an off white solid. LCMS (ES+): m/z 289.34 [M+H]+ 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 2,6-dione (B-15) Compound 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione was prepared using the method described on page 119-122 of WO2023283610 A1. 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 2,6-dione (B-16) Compound 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione was prepared using the method described on page 190-191 of WO2023019166 A1. 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 2,6-dione (B-17) Compound 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione was prepared using the method described on page 167-170 of WO2023019166 A1. 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (B-18) Compound 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione was prepared using the method described on page 197 WO2021127586 Al. Synthesis B8: Synthesis of 3-[1-methyl-7-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione (B- 19) Step-1: To a stirred solution of 7-bromo-1H-indazole 1 (20 g, 101.51 mmol) in DMF (200 mL) were added molecular iodine (51.42 g, 203.01 mmol) and KOH (11.39 g, 203.01 mmol, 5.57 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was diluted water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 7-bromo-3-iodo-1H-indazole 2 (30 g, 73.22% yield) as an off-white solid. LC-MS (ES⁺): m/z 322.47 [M+H] ⁺. Step-2: To a stirred solution of 7-bromo-3-iodo-1H-indazole 2 (120 g, 371.60 mmol) in acetone (1000 mL) were added potassium hydroxide (41.70 g, 743.20 mmol, 20.40 mL) at 0°C followed by methyl iodide (105.49 g, 743.20 mmol, 46.27 mL). The reaction mixture was then stirred at room temperature for 16 h. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (Davisil silica, 3% Ethyl acetate in Petroleum ether as eluent) to afford 7-bromo-3-iodo-1-methyl-indazole 3 (85 g, 153.88 mmol, 41.41% yield) off white solid. LC-MS (ES⁺): m/z 337.08 [M+H] ⁺. Step-3: To a solution of 7-bromo-3-iodo-1-methyl-indazole 3 (5 g, 14.84 mmol) and 2,6- dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 4 (6.19 g, 14.84 mmol) in water (36.00 mL) and dioxane (144.00 mL) was added tripotassium phosphate (9.45 g, 44.52 mmol) at room temperature. The reaction mixture was purged with argon gas for 10 minutes and tetrakis(triphenylphosphine)palladium(0) (1.71 g, 1.48 mmol) was added. The reaction mixture was purged with argon gas for an additional 5 minutes and then stirred at 95 °C for 4 hours. Subsequently, the reaction mixture was concentrated in vacuo and the crude was purified by column chromatography (Davisil silica, 2% EtOAc in petroleum ether as eluent) to afford 7- bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 5 (2.5 g, 2.76 mmol, 18.58% yield) as an off-white solid. LC-MS (ES⁺): m/z 500.14 [M+H] ⁺. Step-4: To a solution of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 5 (1.0 g, 2.00 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylate 6 (926.91 mg, 3.00 mmol) in dioxane (9.91 mL) and water (1.98 mL) was added sodium carbonate (529.54 mg, 5.00 mmol) at room temperature. The reaction mixture was purged with argon gas for 10 minutes before [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (163.20 mg, 199.85 μmol) was added and stirred at 80°C for 2 hours. Upon completion of the reaction, the solvent was removed and the residue was dissolved in water (150 mL) and extracted with ethyl acetate (3 × 75 mL). The combined organic layer was washed with brine and dried over sodium sulfate. The crude product was purified by column chromatography (Davisil silica, 10% petroleum ether in ethyl acetate as eluent) to afford tert-butyl 4-[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate 7 (1.1 g, 1.59 mmol, 79.69% yield) as a colorless oil. LC-MS (ES⁺): m/z 603.45 [M+H] ⁺. Step-5: To a solution of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-7-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 7 (1.1 g, 1.83 mmol) in 1,4-dioxane (40 mL) was added Pd/C (1.11 g, 9.13 mmol) at room temperature and the reaction mixture was stirred at 25 °C for 16 h under hydrogen atmosphere. Upon completion of the reaction, the reaction mixture was filtered through a pad of celite, which was then washed with ethyl acetate (150 mL). The combined filtrate was concentrated under reduced pressure to afford tert-butyl 4-[3-(2,6-dioxo-3- piperidyl)-1-methyl-indazol-7-yl]piperidine-1-carboxylate 8 (0.65 g, 1.12 mmol, 61.57% yield) as an off-white solid. LC-MS (ES-): m/z 425.39 [M-H] -. Step-6: To a solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-7- yl]piperidine-1-carboxylate 8 (0.5 g, 1.17 mmol) in DCM (15 mL) was added trifluoroacetic acid (1.34 g, 11.72 mmol, 903.18 μL). The reaction mixture was stirred at room temperature for 3 h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford 3-[1-methyl-7-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione B-19 (0.45 g, 899.66 μmol, 76.74% yield, TFA salt) as a white solid. LC-MS (ES⁺): m/z 327.54 [M+H] ⁺. 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (B- 20) Compound 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)- dione was prepared using the method described on page 595-597 of WO2022261250 A1. 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (B- 21) Compound 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione was prepared using the method described on page 595-597 of WO2022261250 A1. Synthesis B9: Synthesis of 1-(1-methyl-7-(piperidin-4-yl)-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (B-22) Step-1: To the stirred solution of 1-(7-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (1) (0.30 g, 0.92 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2) (0.34 g, 1.11 mmol) in Dioxane (5mL) and Water (1 mL) was added Potassium carbonate (0.384 g, 2.79 mmol). The reaction mixture was purged with nitrogen for 5 minutes and added Pd (dppf) Cl2.DCM (0.037 g, 0.046 mmol). The reaction mixture was heated and stirred for 16 h at 90° C. Up On completion of reaction, the reaction mixture was concentrated under reduced pressure to afford crude which was purified by column (100-200 mesh) eluted in 70 % ethyl acetate in petroleum ether to afford tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-3,6- dihydropyridine-1(2H)-carboxylate (3) (0.200 g, 323.26 μmol, 34.82% yield) as off white solid. LCMS (ES+): m/z 426.51 [M+H] ⁺ Step-2: To a stirred solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3) (0.200 g, 0.470 mmol) in Methanol (5 mL) and ethyl acetate (15 mL) was added 10% Palladium on carbon wet (0.064 g, 0.60 mmol) . The reaction mixture was stirred for 16 h at 25 °C under hydrogen atmosphere (pare saker-60 psi). After complete consumption of the starting material, the reaction mixture was filtered using celite and filtrate was evaporated to afford tert-butyl 4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)piperidine-1-carboxylate (4) (0.060 g, 0.129 mmol, 30% yield, 92.04% purity) as white solid. LCMS (ES-): m/z 426.37 [M- H]- Step-3: To a stirred solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-7-yl)piperidine-1-carboxylate (4) (0.500 g, 1.17 mmol) in DCM (2 mL)was added TFA (2.67 g, 23.39 mmol, 1.79 mL) at 25 °C and then the reaction mixture was stirred at 25 °C for 3 hours. Completion of the reaction mixture was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to afford of 1-(1- methyl-7-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (B-22) (0.450 g, 0.90 mmol, 77.24% yield, 88.62% purity) as an off- white solid. LCMS (ES+): m/z 328.42 [M+H] ⁺ Synthesis B10: Synthesis of 3-[7-fluoro-2-methyl-6-(4-piperidyl)indazol-3-yl]piperidine- 2,6-dione (B-23) Step-1: To a stirred solution of 4-bromo-2, 3-difluoro-benzaldehyde (1) (11.8 g, 53.39 mmol) in 1,2 dimethoxyethane (240 mL), were added potassium carbonate anhydrous, 99% (8.86 g, 64.07 mmol, 3.87 mL) and methoxylamine hydrochloride (4.91 g, 58.73 mmol) then reaction mixture was stirred at 90°C for 3h. While monitoring the reaction progress by TLC and LCMS. After completion, the mixture cooled and filtered through celite bed, washed bed with ethyl acetate (500 mL) and evaporated under reduced pressure. The crude was dissolved in 1,2 dimethoxyethane (240 mL), cool the reaction mixture at 0°C then hydrazine monohydrate, 98% (40.09 g, 800.91 mmol, 39.04 mL) was added drop wise and stirred at 90°C for 16h. While monitoring the reaction progress by TLC and LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure and quenched with cold water (300 mL) to afford solid. The obtained solid was filtered through the buchner funnel, washed with water (500 mL) and dried to afford 6-bromo-7-fluoro-1H-indazole (2) (10.5 g, 47.10 mmol, 88.21% yield, 96.45% purity) as a white solid. LCMS (ES+): m/z 216.88 [M+2]⁺ Step-2: To a stirred solution of 6-bromo-7-fluoro-1H-indazole (2) (10.5 g, 48.83 mmol) in ACN (100 mL), was added potassium carbonate, anhydrous, 99% (20.25 g, 146.50 mmol, 8.84 mL) at 0°C and stirred the reaction mixture at RT for 0.5h. Added Iodomethane (10.40 g, 73.25 mmol, 4.56 mL) drop wise over the period of 10 minutes. Then reaction mixture was stirred at 70 °C for 12h. The progress of the reaction was monitored by TLC & LCMS. After completion, the reaction mixture was poured slowly into ice-cold water (300 mL) and extracted by ethyl acetate (150 mL x 2). The combined organic layer was dried over sodium sulphate, concentrate under reduced pressure to obtain crude compound, which was purified by column chromatography using silica gel (100-200 mesh, 30-40% ethyl acetate in petroleum ether as eluent) to afford 6- bromo-7-fluoro-2-methyl-2H-indazole (3) (4.0 g, 16.68 mmol, 34.16% yield, 95.52% purity) as off white solid. LCMS (ES+): m/z 230.96 [M+2H]⁺ Step-3: To a stirred solution of 6-bromo-7-fluoro-2-methyl-indazole (3) (4.0 g, 17.46 mmol) in DMSO (40 mL) was added N-Iodosuccinimide (5.89 g, 26.20 mmol) and stirred the reaction mixture at 90°C for 12h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice cold water (150 mL) to obtained solid, which was filtered and washed with the water (150 mL) and dried under high vacuum to afford 6-bromo-7-fluoro-3-iodo-2-methyl-indazole (4) (5.3 g, 13.59 mmol, 77.81% yield, 91% purity) as off white solid. LCMS (ESI): m/z 355.89 [M+2]⁺ Step-4: To a stirred solution of 6-bromo-7-fluoro-3-iodo-2-methyl-indazole (4) (5.2 g, 14.65 mmol) in water (10 mL) and dioxane (50 mL) were added 2,6-dibenzyloxy-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5) (9.17 g, 21.98 mmol) and potassium phosphate (9.33 g, 43.95 mmol) at RT. The reaction mixture was degassed with argon for 15 minutes before addition of Pd(PPh3)4 (1.69 g, 1.47 mmol) and the reaction mixture was stirred at 90 °C for 12h. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled and evaporated to obtain crude product which was purified by column chromatography by using silica gel (60-120 mesh, 0-20% EtOAc in pet-ether as eluent) to obtained 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-7-fluoro-2-methyl-indazole (6) (5.1 g, 7.33 mmol, 50.04% yield, 74.51% purity) as a yellow solid. LCMS [ES+]: m/z 518.07 [M+H]⁺ Step-5: To a stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-7-fluoro-2-methyl- indazole (6) (5.2 g, 10.03 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylate (7) (4.65 g, 15.05 mmol) in dioxane (50 mL) and water (10 mL) was added potassium carbonate, anhydrous, 99% (4.16 g, 30.09 mmol, 1.82 mL) at RT. The reaction mixture was degassed with argon for 15 minutes before addition of Pd(dppf)Cl2 (734.00 mg, 1.00 mmol) and the reaction mixture was stirred at 90 °C for 5h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was evaporated under reduced pressure to obtain crude product, which was purified by column chromatography by using silica gel (60-120 mesh, 0-20% EtOAc in pet-ether as eluent) to afford tert-butyl 4-[3-(2,6- dibenzyloxy-3-pyridyl)-7-fluoro-2-methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine-1- carboxylate (8) (4.5 g, 5.68 mmol, 56.60% yield, 78.32% purity) as brown gummy solid. LCMS [ES+]: m/z 621.35 [M+H]⁺ Step-6: To the stirred solution of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-7-fluoro-2-methyl- indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (8) (3.1 g, 4.99 mmol) in dioxane (30 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (3.51 g, 24.97 mmol) and the reaction mixture was stirred at RT under hydrogen bladder atmosphere for 16h. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed and washed with ethyl acetate (300 mL). The filtrate was concentrated under reduced pressure to afford cruder product, which was triturated with diethyl ether (500 mL) and to afford tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-7-fluoro-2-methyl-indazol-6-yl]piperidine-1- carboxylate (9) (2.1 g, 3.29 mmol, 65.92% yield, 69.68% purity) as a grey color solid. LCMS (ES-): m/z 442.82 [M-H]- Step-7: To a stirred solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-7-fluoro-2-methyl- indazol-6-yl]piperidine-1-carboxylate (9) (0.4 g, 899.89 μmol) in DCM (15 mL) was added TFA (4.62 g, 40.52 mmol, 3.10 mL) at 0°C dropwise over the period of 5 minutes. followed by stirring at room temperature for 3h. The progress of the reaction monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure and co-distilled with THF (10 mL) followed by triturated with diethyl ether (100 mL) to afforded 3-[7-fluoro-2- methyl-6-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione (B-23) (0.401 g, 798.67 μmol, 88.75% yield, 91.30% purity, Trifluoroacetic acid) as off white solid. LCMS (ES+): m/z 345.26 [M+H]⁺. Synthesis B11: Synthesis of 1-(6-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (B-24)

Step 1: To a solution of 6-bromopyrazolo[1,5-a]pyridine (1; 5 g, 25.38 mmol) in acetonitrile (70 mL), was added N-iodosuccinimide (5.71 g, 25.38 mmol) portion wise. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel, 230- 400 mesh) using 0-100% ethyl acetate in petroleum ether while the desired compound was eluted at 15% ethyl acetate in petroleum ether to afford 6-bromo-3-iodo-pyrazolo[1,5-a]pyridine (2; 7.2 g, 22.01 mmol, 98.73% purity) as an off-white solid. Yield-86.7%; LCMS (ESI): [M+H]+m/z Calculated: 322.8, Found: 322.8. Step 2: To a solution of hexahydropyrimidine-2,4-dione (3; 5 g, 43.82 mmol) and 1- (chloromethyl)-4-methoxy-benzene (8.92 g, 56.97 mmol) in N, N-dimethylformamide (100 mL), was added cesium carbonate (17.13 g, 52.58 mmol). The resulting mixture was stirred at room temperature for 6 h. The reaction mixture was filtered and washed with N, N-dimethylformamide (10 mL). The filtrate was concentrated under reduced pressure, and the solid formed was treated with water and sonicated for 1 minutes. The solid was filtered and washed with water (30 mL), ethyl acetate/petroleum ether (1:1 ratio, 2 x 20 mL), dichloromethane (20 mL) and dried under vacuum to give 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (4; 6.3 g, 26.17 mmol, 97.29% purity) as an off-white solid. Yield-59.7%; LCMS (ESI): [M+H]+m/z Calculated: 235.1, Found: 235.2. Step 3: To a solution of 6-bromo-3-iodo-pyrazolo[1,5-a]pyridine (2; 1.35 g, 4.13 mmol) and 3- [(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (4; 1.29 g, 5.37 mmol) in 1,4- dioxane (15 mL), was added potassium phosphate tribasic (2.19 g, 10.32 mmol). The contents were degassed with nitrogen for 5 min followed by the addition of (1R,2R)-(−)-1,2- diaminocyclohexane (117.83 mg, 1.03 mmol) and copper(I) iodide (196.52 mg, 1.03 mmol). The resulting mixture was heated at 90 °C for 16 h. The reaction mixture was treated with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases 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 50-60% ethyl acetate in petroleum ether to afford 1-(6-bromopyrazolo[1,5-a]pyridin-3-yl)-3-[(4- methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (5; 1.26 g, 2.72 mmol, 92.59% purity) as a brown solid. Yield-65.9%; LCMS (ESI): [M+H]+m/z Calculated: 429.0, Found: 429.0. Step 4: To a solution of 1-(6-bromopyrazolo[1,5-a]pyridin-3-yl)-3-[(4- methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (5; 1 g, 2.16 mmol) in 1,4-dioxane (15 mL) and water (3 mL), was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylate (6; 733.63 mg, 2.37 mmol) and potassium phosphate tribasic (915.71 mg, 4.31 mmol). The contents were degassed with nitrogen for 5 min followed by the addition of XPhos Pd G2 (169.71 mg, 215.69 μmol). The resulting mixture was stirred at 90 °C for 2 hours. The reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic phases 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 40-100% ethyl acetate in petroleum ether to afford tert- butyl 4-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]pyrazolo[1,5- a]pyridin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (7; 1.1 g, 1.94 mmol, 93.80% purity) as a pale brown solid. Yield-90.0%; LCMS (ESI): [M+H]+m/z Calculated: 532.2, Found: 532.2. Step 5: tert-Butyl 4-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1- yl]pyrazolo[1,5-a]pyridin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (3.20 g, 5.64 mmol) was taken in trifluoroacetic acid (44.40 g, 389.41 mmol, 30 mL), was added trifluoromethanesulfonic acid (10.25 g, 68.28 mmol, 6 mL). The resulting mixture was heated at 70 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and co-distilled with toluene (2 x 10 mL) to afford 1-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin- 3-yl]hexahydropyrimidine-2,4-dione trifluoroacetate (8; 2.4 g, 4.65 mmol, 82.39% purity) as a brown gum. Yield-82.4%; LCMS (ESI): [M+H]+m/z Calculated: 312.1, Found: 312.3. The crude product was taken to the next step without purification. Step 6: To a solution of 1-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3- yl]hexahydropyrimidine-2,4-dione trifluoroacetate (8; 2.4 g, 6.35 mmol) in dichloromethane (63 mL), cooled to 0 °C, was added triethylamine (3.21 g, 31.76 mmol, 4.43 mL) followed by the addition of di-tert-butyl dicarbonate (1.39 g, 6.35 mmol, 1.46 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with water (20 mL) and extracted with 10% MeOH in dichloromethane (2 x 100 mL). The combined organic phases were washed with brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered, 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 0- 100% ethyl acetate in petroleum ether while the desired compound eluted at 10% MeOH in dichloromethane to give tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)pyrazolo[1,5- a]pyridin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (9; 2.4 g, 5.78 mmol, 91.05% yield, 99.135% purity) as an off-white solid. Yield-91.1%; LCMS (ESI): [M+H]+m/z Calculated: 412.2, Found: 412.2. Step 7: To a solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)pyrazolo[1,5- a]pyridin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (9; 1 g, 1.95 mmol) in 1,4-dioxane (40 mL), was added palladium hydroxide on carbon (20% dry basis, 700 mg, 1.95 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (~1 kg/cm²) for 16 h. The reaction mixture was filtered through a pad of celite, and washed with ethyl acetate (200 mL) and 1,4-dioxane/ethyl acetate (1:1 ratio, 1000 mL). The filtrate was concentrated under reduced pressure to give a crude product. The crude product was triturated with acetonitrile (10 mL), THF (10 mL), and DMF (10 mL) followed by water (20 mL). The solid obtained was filtered and dried under vacuum to afford tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1- yl)pyrazolo[1,5-a]pyridin-6-yl]piperidine-1-carboxylate (1267.55 mg, 1.02 mmol, 96.17% purity) as an off-white solid. Yield-52.4%; LCMS (ESI): [M-isobutene+H]+m/z Calculated: 358.1, Found: 358.2.¹H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 8.48 (s, 1H), 7.98 (s, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.25 (dd, J = 9.2, 1.2 Hz, 1H), 4.12-4.09 (m, 2H), 3.77 (t, J = 6.8 Hz, 2H), 2.79-2.67 (m, 5H), 1.83-1.80 (m, 2H), 1.62-1.51 (m, 2H), 1.43 (s, 9H) ppm. Step-8: To a solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)pyrazolo[1,5- a]pyridin-6-yl]piperidine-1-carboxylate in DCM is added 4 M HCl in dioxane (10 equiv.) and the reaction is stirred at room temperature for 16 h. Upon completion of the reaction, the solvent is removed under reduced pressure and the crude product is purified by column chromatography to afford 1-(6-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (B-24). Synthesis B12: Synthesis of 1-(7-(piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (B-25) Step 1: To a solution of 7-bromoimidazo[1,2-a]pyridine (1; 6 g, 30.44 mmol) and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2; 9.41 g, 30.44 mmol) in 1,4-dioxane (84 mL) and water (36 mL), was added potassium phosphate tribasic (12.92 g, 60.87 mmol). The contents were purged with nitrogen for 2 minutes. To this, was added XPhos Pd G2 (2.39 g, 3.04 mmol) and purged with nitrogen for 2 minutes. The resulting mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the residue which was treated with water (10 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic phases 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 80-90% ethyl acetate in petroleum ether to give tert-butyl 4-imidazo[1,2-a]pyridin-7-yl-3,6-dihydro-2H-pyridine-1-carboxylate (3; 6 g, 20.04 mmol, 100% purity) as a brown solid. Yield-65.9%; UPLC (ESI): [M+H]+m/z Calculated: 300.2, Found: 300.5. Step 2: To a solution of tert-butyl 4-imidazo[1,2-a]pyridin-7-yl-3,6-dihydro-2H-pyridine-1- carboxylate (3; 6 g, 20.04 mmol) in acetonitrile (150 mL), was added N-iodosuccinimide (4.51 g, 20.04 mmol) portion wise. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and washed with acetonitrile (40 mL), and the solid was dried under vacuum to give tert-butyl 4-(3-iodoimidazo[1,2-a]pyridin-7-yl)-3,6-dihydro- 2H-pyridine-1-carboxylate (4; 6.5 g, 15.09 mmol, 75.30% yield, 98.74% purity) as a brown solid. Yield-65.9%; UPLC (ESI): [M+H]+m/z Calculated: 426.0, Found: 426.5. Step 3: To a solution of tert-butyl 4-(3-iodoimidazo[1,2-a]pyridin-7-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (4; 2.5 g, 5.80 mmol) and 3-[(4- methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (5; 1.90 g, 8.13 mmol) in 1,4-dioxane (20 mL), was added potassium phosphate tribasic (2.46 g, 11.61 mmol). The contents were purged with nitrogen for 2 minutes. To this, were added (1R,2R)-(−)-1,2-diaminocyclohexane (132.57 mg, 1.16 mmol), copper (I) iodide (221.10 mg, 1.16 mmol) and the contents were purged with nitrogen for 2 minutes. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue which was treated with water (10 mL) and extracted using ethyl acetate (3 x 30 mL). The combined organic phases 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 6-7% methanol in dichloromethane to give tert-butyl 4-[3-[3-[(4- methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]imidazo[1,2-a]pyridin-7-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (6; 2.4 g, 3.63 mmol, 80.41% purity) as a brown solid. Yield-62.5%; UPLC (ESI): [M+H]+m/z Calculated: 532.2, Found: 532.8. Step 4: tert-Butyl 4-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1- yl]imidazo[1,2-a]pyridin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (6; 1.1 g, 1.66 mmol) was taken in trifluoroacetic acid (14.80 g, 129.80 mmol, 10 mL), cooled to 0 °C, was added trifluoromethanesulfonic acid (3.42 g, 22.76 mmol, 2 mL). The resulting mixture was heated at 70 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and co-distilled with toluene (30 mL) to afford 1-[7-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3- yl]hexahydropyrimidine-2,4-dione trifluoroacetate (7; 1.28 g, 1.64 mmol, 54.47% purity) as a brown gum. Yield-98.5%; UPLC (ESI): [M+H]+m/z Calculated: 312.1, Found: 312.3. Step 5: To a solution of 1-[7-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3- yl]hexahydropyrimidine-2,4-dione trifluoroacetate (7; 1.28 g, 1.64 mmol) in dichloromethane (25 mL), cooled to 0 °C, was added triethylamine (1.66 g, 16.39 mmol, 2.28 mL) followed by addition of di-tert-butyl dicarbonate (357.74 mg, 1.64 mmol, 376.17 μL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 10% methanol in dichloromethane (500 mL) and washed with water (2 x 100 mL). The 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 the crude product. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 8-10% methanol in dichloromethane to afford tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2- a]pyridin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (8; 0.77 g, 1.11 mmol, 59.41% purity) as a pale brown solid. Yield-67.8%; LCMS (ESI): [M+H]+m/z Calculated: 412.2, Found: 412.2. Step 6: To a solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2- a]pyridin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (8; 0.9 g, 1.30 mmol) in 1,4 dioxane (40 mL), was added palladium hydroxide on carbon (20 wt. % dry basis, 0.56 g, 3.99 mmol). The resulting mixture was stirred at room temperature under a hydrogen atmosphere (~ 1 kg/cm²) for 16 h. The reaction mixture was filtered through a pad of celite and washed with 1,4-dioxane in ethyl acetate (1000 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by prep HPLC [Column: X bridge C18 (150 x 10) mm 5 micron; Mobile phase: A: ammonium bicarbonate in water, B: Acetonitrile]. The fractions containing the product were lyophilized to afford tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin- 1-yl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate (9, 0.23 g, 555.05 μmol, 99.78% purity) as an off-white solid. Yield-42.7%; LCMS (ESI): [M+H]+m/z Calculated: 414.2, Found: 414.2.¹H NMR (400 MHz, DMSO-d6): δ 10.66 (s, 1H), 8.24 (d, J = 7.2 Hz, 1H), 7.51 (s, 1H), 7.39 (s, 1H), 6.96 (dd, J = 7.2, 1.2 Hz, 1H), 4.12-4.09 (m, 2H), 3.79 (t, J = 6.4 Hz, 2H), 2.84- 2.75 (m, 5H), 1.84-1.81 (m, 2H), 1.61-1.50 (m, 2H), 1.43 (s, 9H) ppm. Step-7: To a solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2- a]pyridin-7-yl]piperidine-1-carboxylate in DCM is added 4 M HCl in dioxane (10 equiv.) and the reaction is stirred at room temperature for 16 h. Upon completion of the reaction, the solvent is removed under reduced pressure and the crude product is purified by column chromatography to afford 1-(7-(piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (B-25). Synthesis B13: Synthesis of 3-methyl-3-[1-methyl-6-(4-piperidyl)indazol-3-yl]piperidine- 2,6-dione (B-26)

Step 1: To a solution of methyl 6-bromo-1H-indazole-3-carboxylate (1; 25 g, 98.01 mmol) in acetonitrile (800 mL) was added potassium carbonate (135.46 g, 980.13 mmol) and the resulting mixture was stirred at room temperature for 15 minutes. To this mixture, was added methyl iodide (69.56 g, 490.07 mmol, 30.51 mL) dropwise over 10 minutes. The resulting mixture was stirred at room temperature for 3 hours. 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 35-40% ethyl acetate in petroleum ether to give the regio-isomers, methyl 6-bromo-1-methyl-indazole-3- carboxylate (2; 17 g, 63.17 mmol, 100% purity) as an off-white solid. Yield-64.5%; UPLC (ESI): [M+H]+m/z Calculated: 268.9; Found: 269.0 and methyl 6-bromo-2-methyl-indazole-3- carboxylate (3; 5 g, 18.22 mmol, 98.06% purity) as a pale-yellow solid. Yield-18.6%; UPLC (ESI): [M+H]+m/z Calculated: 268.9, Found: 269.0. Step 2: To a solution of methyl 6-bromo-1-methyl-indazole-3-carboxylate (2; 17 g, 63.17 mmol) in tetrahydrofuran (80 mL), cooled to 0 °C, was added diisobutylaluminium hydride (1 M in toluene, 16.95 g, 126.35 mmol, 126.35 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0 °C, treated with saturated ammonium chloride (100 mL), and extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed with water (150 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give a 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 (6-bromo-1-methyl-indazol-3-yl)methanol (4; 15 g, 61.57 mmol, 98.96% purity) as an off-white solid. Yield-97.5%; UPLC (ESI): [M+H]+m/z Calculated: 241.0, Found: 241.4. Step 3: To a solution of (6-bromo-1-methyl-indazol-3-yl)methanol (4; 20 g, 82.96 mmol) in dichloromethane (150 mL), cooled to 0 °C, was added thionyl chloride (29.61 g, 248.88 mmol, 18.05 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with methyl tert-butyl ether (50 mL). The solid was filtered, washed methyl tert-butyl ether (3 x 20 mL) and dried under vacuum to give 6-bromo-3-(chloromethyl)-1-methyl-indazole (5; 20.5 g, 74.77 mmol, 90.13% yield, 94.66% purity) as an off-white solid. Yield-90.1%; UPLC (ESI): [M+H]+m/z Calculated: 258.9, Found: 260.2. The crude product was taken to the next without purification. Step 4: To a solution of 6-bromo-3-(chloromethyl)-1-methyl-indazole (5; 10 g, 38.53 mmol) in N, N-dimethylformamide (50 mL), was added sodium cyanide (3.78 g, 77.06 mmol). The resulting mixture was heated at 60 °C for 16 h. The reaction mixture was cooled to room temperature, treated with water (50 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic phases 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. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 30-40% ethyl acetate in petroleum ether to give 2-(6-bromo-1-methyl-indazol- 3-yl)acetonitrile (6; 8 g, 31.14 mmol, 97.34% purity) as an off-white solid. Yield-80.8%; UPLC (ESI): [M+H]+m/z Calculated: 250.0, Found: 250.2. Step 5: To a solution of 2-(6-bromo-1-methyl-indazol-3-yl)acetonitrile (6; 9.2 g, 36.42 mmol) in tetrahydrofuran (100 mL), cooled to -78 °C, was added potassium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 36.42 mL) dropwise over 10 minutes. The resulting mixture was stirred at - 78 °C for 1 hour. To this mixture, was added methyl iodide (4.65 g, 32.78 mmol, 2.04 mL) dropwise. The resulting mixture was stirred at -78 °C for 20 minutes. The reaction mixture was warmed to room temperature, treated with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with water (2 x 20 mL), 10% sodium chloride 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 column chromatography (Silica gel, 230-400 mesh) eluted with 35-40% ethyl acetate in petroleum ether to give 2-(6-bromo-1-methyl-indazol-3- yl)propanenitrile (7; 4.2 g, 15.57 mmol, 97.91% purity) as an off-white solid. Yield-42.8%; UPLC (ESI): [M+H]+m/z Calculated: 264.0, Found: 263.9 and 2-(6-bromo-1-methyl-indazol-3- yl)-2-methyl-propanenitrile (8; 1.7 g, 5.21 mmol, 85.28% purity) as a pale brown color solid. Yield-14.3%; UPLC (ESI): [M+H]+m/z Calculated: 278.0, Found: 279.7. Step 6: To a solution of 2-(6-bromo-1-methyl-indazol-3-yl)propanenitrile (7; 7.5 g, 27.82 mmol) in 1,4-dioxane (100 mL) were added methyl acrylate (9; 4.79 g, 55.64 mmol, 5.01 mL), cooled to 0 °C, was added benzyltrimethylammonium hydroxide (40% in water, 5.82 g, 13.91 mmol, 6.12 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with saturated ammonium chloride solution (20 mL) at 0 °C and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with brine solution (20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give methyl 4-(6-bromo-1-methyl-indazol-3-yl)-4-cyano-pentanoate (10; 9.5 g, 14.40 mmol, 53.10% purity) as a yellow oil. Yield-51.8%; UPLC (ESI): [M+H]+m/z Calculated: 350.0, Found: 350.0. Step 7: To a solution of methyl 4-(6-bromo-1-methyl-indazol-3-yl)-4-cyano-pentanoate (10; 9.5 g, 27.13 mmol) in water (10 mL) and methanol (80 mL), cooled to 0 °C, was added sodium hydroxide (10 M in water, 10.85 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to remove organic volatiles, acidified with 1.5 N hydrochloric acid, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 4-(6-bromo-1-methyl-indazol-3-yl)-4-cyano-pentanoic acid (11; 8.5 g, 25.01 mmol, 98.92% purity) as an off-white solid. Yield-92.2%; UPLC (ESI): [M+H]+m/z Calculated: 336.0, Found: 336.1. Step 8: To a solution of 4-(6-bromo-1-methyl-indazol-3-yl)-4-cyano-pentanoic acid (11; 10 g, 29.43 mmol) in acetic acid (91.90 g, 1.53 mol, 87.61 mL), was added sulfuric acid (2.89 g, 29.43 mmol, 1.58 mL). The resulting mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine solution (30 mL). The organic phase was dried over anhydrous sodium sulfate, 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 3-(6- bromo-1-methyl-indazol-3-yl)-3-methyl-piperidine-2,6-dione (12, 8.5 g, 24.18 mmol, 95.63% purity) as a yellow solid. Yield-82.2%; LCMS (ESI): [M+H]+m/z Calculated: 336.0, Found: 336.2.¹H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H), 7.98 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H), 2.60-2.54 (m, 2H), 2.45-2.39 (m, 1H), 2.17-2.10 (m, 1H), 1.65 (s, 3H) ppm. Step 9: To a solution of 3-(6-bromo-1-methyl-indazol-3-yl)-3-methyl-piperidine-2,6-dione (12; 1 g, 2.97 mmol) in 1,4-dioxane (20 mL), was added cesium fluoride (677.76 mg, 4.46 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (13; 1.38 g, 4.46 mmol) and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (291.48 mg, 356.95 μmol). The resulting mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 40-45% ethyl acetate in petroleum ether to give tert-butyl 4-[1-methyl-3-(3-methyl-2,6-dioxo-3-piperidyl)indazol-6-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (14, 0.6 g, 1.20 mmol, 87.34% purity) as an off-white solid. Yield-40.2%; UPLC (ESI): [M+H]+m/z Calculated: 439.2, Found: 439.8. Step 10: To a solution of tert-butyl 4-[1-methyl-3-(3-methyl-2,6-dioxo-3-piperidyl)indazol-6-yl]- 3,6-dihydro-2H-pyridine-1-carboxylate (14, 0.6 g, 1.20 mmol) in ethyl acetate (30 mL), was added 10% palladium on carbon (dry basis, 239.92 mg, 2.03 mmol). The resulting suspension was stirred at room temperature under a hydrogen atmosphere (~1 kg/cm²) for 18 hours. 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 reverse phase chromatography following a method: C18 RediSep Rf Gold (100 g HP C18); Mobile phase A: 0.1% HCOOH in water and B: acetonitrile; Flow rate: 10 mL/minutes. The fractions containing the product were combined and lyophilized to give tert-butyl 4-[1-methyl-3-(3-methyl-2,6- dioxo-3-piperidyl)indazol-6-yl]piperidine-1-carboxylate (15, 0.41 g, 928.46 μmol, 99.76% purity) as an off-white solid. Yield-77.7%; LCMS (ESI): [M+H]+m/z Calculated: 441.2, Found: 441.3.¹H NMR (400 MHz, DMSO-d₆): δ 10.86 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.04 (dd, J = 8.4, 0.8 Hz, 1H), 4.13-4.10 (m, 2H), 3.96 (s, 3H), 2.85-2.79 (m, 3H), 2.60-2.56 (m, 2H), 2.42-2.33 (m, 1H), 2.15-2.08 (m, 1H), 1.82-1.79 (m, 2H), 1.64 (s, 3H), 1.62-1.55 (m, 2H), 1.43 (s, 9H) ppm. Step 11: To a solution of tert-butyl 4-[1-methyl-3-(3-methyl-2,6-dioxo-3-piperidyl)indazol-6- yl]piperidine-1-carboxylate (15; 0.7 g, 1.52 mmol) in dichloromethane (5 mL), cooled to 0 °C, was added hydrogen chloride solution (4 M in 1,4-dioxane, 4.00 g, 109.71 mmol, 5 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the residue which was triturated with methyl tert- butyl ether (3 x 50 mL) to give 3-methyl-3-[1-methyl-6-(4-piperidyl)indazol-3-yl]piperidine- 2,6-dione hydrochloride (B-26; 0.55 g, 1.40 mmol, 95.90% purity) as an off-white solid. Yield- 92.2%; LCMS (ESI): [M+H]+m/z Calculated: 341.2, Found: 341.2.¹H NMR (400 MHz, DMSO- d₆): δ 10.86 (s, 1H), 8.94 (d, J = 9.2 Hz, 1H), 8.71 (d, J = 10.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.03 (dd, J = 8.4, 0.8 Hz, 1H), 3.98 (s, 3H), 3.40 (br s, 2H), 3.07-2.96 (m, 3H), 2.61-2.56 (m, 2H), 2.43-2.34 (m, 1H), 2.16-2.12 (m, 1H), 2.01-1.90 (m, 4H), 1.65 (s, 3H) ppm. Synthesis B14: Synthesis of 3-(6-(piperidin-4-yl)benzo[d]isoxazol-3-yl)piperidine-2,6-dione (B-27)

Step-1:

To a. stirred solution of l-(4-bromo-2-hydroxyphenyl)elhan-l-one (1) (90.0 g, 419 mmol) in toluene (900 mL), sodium hydride. 60% dispersion in mineral oil (100 g, 2.51 mol) and diethyl carbonate (2) (198 g. 1.67 mol) were added at 0 °C. The reaction mixture was stirred at 1 10 °C for 2 hours under nitrogen atmosphere. Upon completion, the reaction mixture was quenched (reverse quenching) by ice and the product was extracted with EtOAc (2 x 2 L). The aqueous layer was acidified (pH 3-4) with 2N HCI (500 mL). and subsequently solid precipitates were formed. The solid residue was filtered through Buchner funnel to afford 7-bromo-4-hydroxy- chromen-2-one (3) (85 g, 336 mmol, 80% yield, 95% purity) as off" white solid. LCMS (ES-): m / 238.94 [M- H]-

Step-2:

To a solution of 7-bromo-4-hydroxy-2H-chromen-2-one (3) (90.0 g, 373 mmol) in ethanol (900 mL) were added NaOAc (91 9 g, 1.12 mol) and hydroxylamine hydrochloride (51.9 g, 747 mmol). The reaction mixture was stirred at 80 °C for 4 hours, while monitoring the progress by TLC and LCMS. Upon completion, the reaction mixture was evaporated under reduced pressure and the crude was diluted with water and acidified (pH 3-4) with 2N HCI (500 mL). Subsequently solid precipitates formed and these were filtered off through Buchner funnel. The residue was dried to afford. 2-(6-bromobenzo[d]isoxazo1-3-yl) acetic acid (4) (78.0 g, 256 mmol, 69% yield, 84% purity) as brown solid. LCMS (ES+): m/z 255.96 [M+H] ⁺

Step-3: To a stirred solution 2-(6-bromobenzo[d]isoxazol-3-yl) acetic acid (4) (80.0 g, 312 mmol) in ethanol (800 mL) was added H₂SO₄ (33.2 mL, 625 mmol). The reaction mixture was stirred at 80 °C for 2 hours. and the progress was monitored by LCMS and TLC. Upon completion, the reaction mixture was concentrated under reduced pressure and the obtained crude was quenched with saturated sodium bicarbonate solution (500 ml). Subsequently the product was extracted with ethyl acetate (2 x 2 L). The combined organic layers was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford ethyl 2-(6- bromobenzo[d]isoxazol-3-yl) acetate (5) (65.0 g, 189 mmol, 61% yield, 83% purity) as brown liquid. LCMS (ES+): m/z 284.24 [M+H]⁺ Step-4: To a stirred solution of ethyl 2-(6-bromobenzo[d]isoxazol-3-yl)acetate (5) (65 g, 229 mmol) in THF (2.0 L) were added prop-2-enamide (6) (16.3 g, 229 mmol) at 0 °C and potassium t-but oxide (25.7 g, 229 mmol). The resulting mixture was stirred at 0 °C for 2 hours, while monitoring the progress by TLC & LCMS. On completion, the reaction mixture was quenched with cold water (2 L) and extracted with ethyl acetate (2 x 2 L). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude was washed with n-pentane to afford the desired product 3-(6-bromo-1,2-benzoxazol-3- yl)piperidine-2,6-dione (7) (33.0 g, 80.9 mmol, 35% yield, 76% purity) as brown solid. LCMS (ES-): m/z 307.21 [M -H]- Step-5: To a stirred solution of 3-(6-bromobenzo[d]isoxazol-3-yl)piperidine-2,6-dione (7) (31.0 g, 100 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (8) (37.2 g, 120 mmol) in 1,4-dioxane (240 mL) and water (60 mL) was added Et3N (30.4 g, 301 mmol, 41.9 mL) at room temperature. The resultant mixture was purged with argon gas for 10 min and subsequently Pd(dppf)Cl₂.DCM (8.18 g, 10.0 mmol) was added. The resulting suspension was stirred at 80 °C for 3 hours. Upon completion, the reaction mixture was diluted with water (1 L) and the product was extracted with ethyl acetate (5 L X 2). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure and the crude was purified by column chromatography using (100-200 mesh) silica gel and 0-100% EtOAc in petroleum ether as eluent to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3- yl)benzo[d]isoxazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9) (20.0 g, 43.6 mmol, 43% yield, 90% purity) as white solid. LCMS (ES-): m/z 410.22 [M-H]- Step-6: To a stirred solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-6-yl)- 3,6-dihydropyridine-1(2H)-carboxylate (9) (1.0 g, 2.43 mmol) in EtOAc (200 mL) was added 10% palladium on carbon, 50% wet basis (0.6 g, 3.38 mmol). The resulting suspension was stirred at RT under H₂ (10 Psi, Parr shaker) for 3 hours. Upon completion, the reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude was triturated with Et₂O (20 mL) to afford tert-butyl 4-(3-(2,6- dioxopiperidin-3-yl)benzo[d]isoxazol-6-yl)piperidine-1-carboxylate (10) (0.6 g, 1.41 mmol, 58% yield, 97% purity) as white solid. LCMS (ES-): m/z 412.43 [M-H]- Step-7: To a solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-6-yl)piperidine-1- carboxylate (10) (0.5 g, 1.21 mmol ) in 1,4-dioxane (5 mL) was added Hydrogen chloride, 4M in 1,4-dioxane, 99% (4 M, 5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to afford the crude product which was triturated with diethyl ether to afford 3-(6-(piperidin-4-yl)benzo[d]isoxazol-3-yl)piperidine-2,6-dione (B-27) (0.4 g, 1.04 mmol, 85.86% yield, 90.80% purity) as an Off-white solid. LCMS (ESI+): m/z 314.43 [M+H] ⁺ Synthesis B15: Synthesis of 3-[7-(4-piperidyl)-1,2-benzoxazol-3-yl]piperidine-2,6-dione (B- 28)

Step-1: To a stirred solution of 1-(2-bromo-6-hydroxy-phenyl)ethanone (1) (50 g, 233 mmol) in toluene (500 mL), sodium hydride, 60% dispersion in mineral oil (55.8 g, 1.40 mol) and diethyl carbonate 2 (110 g, 930 mmol) were added at 0 °C. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen atmosphere. Upon completion, the reaction mixture was quenched (reverse quenching) by ice water (2 L) and extracted with EtOAc (2 x 2 L). The aqueous layer was acidified (pH 3-4) with 2N HCl (500 mL). Subsequently solid precipitates form and these residues were filtered through Buchner funnel to afford 8-bromo-4-hydroxy-chromen-2-one 3 (48 g, 165 mmol, 71% yield, 83% purity) as off white solid. LCMS (ES+): m/z 241.01 [M+H] ⁺ Step-2: To a solution of 8-bromo-4-hydroxy-chromen-2-one (3) (70 g, 290 mmol) in ethanol (722 mL) were added sodium acetate (71.5 g, 871 mmol) and hydroxylamine hydrochloride (40.4 g, 581 mmol). The reaction mixture was stirred at 80 °C for 4h, while monitoring the progress by TLC and LCMS. Upon completion, the reaction mixture was evaporated under reduced pressure and the crude was diluted with water and acidified (pH 3-4)), with 2N HCl (500 mL). Subsequently solid precipitates formed and these were filtered off through Buchner funnel. The residue was dried to afford 2-(7-bromo-1,2-benzoxazol-3-yl) acetic acid (4) (67 g, 230 mmol, 79% yield, 88% purity) LCMS (ES+): m/z 256.21 [M+H]⁺ Step-3: To a stirred solution of 2-(7-bromo-1,2-benzoxazol-3-yl)acetic acid (4) (66 g, 258 mmol) in ethanol (660 mL) was added H₂SO₄ (27.6 mL, 516 mmol). The resultant reaction mixture was heated at 80 °C for 4 hours. Upon completion, the reaction mixture was concentrated under reduced pressure and the obtained crude was quenched with saturated sodium bicarbonate solution (500 mL). Subsequently the product was extracted with ethyl acetate (2 x 2 L). The combined organic layers was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product ethyl 2-(6-bromo-1,2-benzoxazol-3-yl)acetate 5 (65.0 g, 189 mmol, 61% yield, 83% purity) as brown liquid. LCMS (ES+): m/z 284.16 [M+H]⁺ Step-4: To a stirred solution of ethyl 2-(7-bromo-1,2-benzoxazol-3-yl)acetate (5) (48 g, 169 mmol) in THF (2.0 L) were added prop-2-enamide (6) (12.0 g, 169 mmol) at 0 °C and potassium tertiarybutoxide (19.0 g, 169 mmol). The reaction mixture was stirred at 0 °C for 1 hour, while monitoring the progress by TLC & LCMS. On completion, the reaction mixture was quenched with cold water (2 L) and extracted with ethyl acetate (2 x 2 L). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude was washed with n-pentane to afford the desired product 3-(7-bromo-1,2-benzoxazol-3- yl)piperidine-2,6-dione (7) (27 g, 74.6 mmol, 44% yield, 85% purity). LCMS (ES+): m/z 309.20 [M +H]⁺ Step-5: To a stirred solution of 3-(7-bromo-1,2-benzoxazol-3-yl)piperidine-2,6-dione (7) (27 g, 87.4 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (8) (32.4 g, 105 mmol) in dioxane (250 mL) and water (30 mL) was added triethylamine (26.5 g, 262 mmol) at room temperature. The resultant mixture was purged with argon gas for 10 min and subsequently Pd(dppf)Cl2.DCM (7.13 g, 8.73 mmol) was added. The resulting suspension was stirred at 80 °C for 3 hours. Upon completion, the reaction mixture was diluted with water (1 L) and the product was extracted with ethyl acetate (5 L X 2). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure and the obtained crude was purified by column chromatography using (100-200 mesh) silica gel and 0-100% EtOAc in petroleum ether as eluent to afford the desired product tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (9) (17.2 g, 37.8 mmol, 43% yield, 90% purity). LCMS (ES-): m/z 410.43 [M-H]- Step-6: To a stirred solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (9) (4 g, 9.72 mmol) in EtOAc (800 mL) was added 10% palladium on carbon, 50% wet basis (2.4 g, 9.72 mmol). The resulting suspension was stirred at RT under H₂ (10 psi, Parr shaker) for 3 hours. Upon completion, the reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude was triturated with Et₂O (20 mL) to afford the desired product tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]piperidine-1-carboxylate (10) (2.5 g, 5.94 mmol, 61% yield, 98% purity) as white solid. LCMS (ES-): m/z 412.47 [M-H]- Step-7: To a solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]piperidine- 1-carboxylate (10) (0.5 g, 1.21 mmol, No Salt) in 1,4-dioxane (5 mL) was added Hydrogen chloride, 4M in 1,4-dioxane, 99% (4 M, 5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to afford the crude product which was triturated with diethyl ether to afford 3-[7-(4-piperidyl)-1,2-benzoxazol-3-yl]piperidine-2,6- dione (B-28) (0.4 g, 1.06 mmol, 87.59% yield, 92.63% purity, Hydrochloric acid) as an Off- white solid. LCMS (ESI): m/z 314.39 [M+H] ⁺ 1-(6-(piperidin-4-yl)benzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (B-29) Compound 1-(6-(piperidin-4-yl)benzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)- dione was prepared using the method described on page 194-197 of WO2022235945 A1. 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione (B-30) Compound 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione was prepared using was prepared using the method described on page 68-70 of WO2023283372 A1. 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (B-31) Compound 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione was prepared using was prepared using the method described on page 168-170 of WO2022235945 A1. N-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-yl)benzamide (B-32) Compound N-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-yl)benzamide was prepared using was prepared using the method described on page 227 of WO2023055952 A1. Synthesis B16: Synthesis of 3-(4-(piperidin-4-yl)benzyl)piperidine-2,6-dione (B-33) Step-1: Into a 250 mL round bottomed flask containing a well stirred solution of4-(1-tert- butoxycarbonyl-4-piperidyl)benzoic acid (5 g, 16.37 mmol) in THF (100 mL) at 0°C, was added borane;tetrahydrofuran (1 M, 49.12 mL) drop-wise to a solution. After 15 minutes, the ice bath was removed and the clear solution was allowed at 25 °C for 16 hr. After completion of the reaction ( TLC and UPLC ), The reaction mixture was cooled in an ice bath and quenched with water (100 mL) and ethyl acetate (300 mL) was added and the mixture was washed with saturated sodium bicarbonate solution ( 100 mL) and brine ( 100 mL ). Combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give crude product. Which was purified by flash silica-gel (230-400 mesh) column with 0-100% ethyl acetate/petroleum ether while desired compound eluting at 5-7 % to give tert- butyl 4-[4-(hydroxymethyl)phenyl]piperidine-1-carboxylate (4.5 g, 15.43 mmol, 94.24% yield, 99.92% purity, No Salt) as off white solid. LC-MS (ESI): m/z 192.2 [M-COOtBu+H]⁺. Step-2: Into a 500 mL single neck RBF containing the solution of tert-butyl 4-[4- (hydroxymethyl)phenyl]piperidine-1-carboxylate (9 g, 30.86 mmol) in DCM (180 mL) were added triphenylphosphane (12.14 g, 46.29 mmol) and carbon tetrabromide (15.35 g, 46.29 mmol, 4.49 mL) at 0°C under nitrogen atmosphere. Then the reaction mixture was stirred at 25 °C for 1 hour. After consumption of the starting material, the reaction mixture was poured into cold water (200 mL) slowly and extracted with DCM (3 x 500 mL). Organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give crude, which was purified by flash silica-gel (230-400 mesh) column with 0-100% ethyl acetate/petroleum ether while desired compound eluting at 10 % to afford tert-butyl 4-[4- (bromomethyl)phenyl]piperidine-1-carboxylate (9 g, 24.50 mmol, 79.37% yield, 96.43% purity, No Salt) as white solid. LC-MS (ESI): m/z 256.2 [M-COOtBu+H]⁺. Step-3: Into a 250 ml sealed tube containing a well-stirred solution of tert-butyl 4-[4- (bromomethyl)phenyl]piperidine-1-carboxylate (5 g, 13.61 mmol) in anhydrous 1,4 Dioxane (75 mL) was added potassium acetate (2.67 g, 27.22 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 5 minutes. Subsequently, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.18 g, 20.41 mmol) and cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (497.90 mg, 680.46 μmol) were added to the reaction mixture and reaction mixture was heated to 110 °C for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through celite bed and washed with ethyl acetate (250 mL),the combined organic phases were concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography ( silica gel, 230-400 mesh) column with 0-30% ethyl acetate/petroleum ether while desired compound eluting at 5 % to give tert-butyl 4-[4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methyl]phenyl]piperidine-1-carboxylate (5.6 g, 12.65 mmol, 92.96% yield, 90.67% purity, No Salt) as off white solid. LC-MS (ESI): m/z 302.2 [M-COOtBu+H]⁺ Step-4: Into a 20 mL vial containing a well-stirred solution of tert-butyl 4-[4-[(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl]piperidine-1-carboxylate (974.24 mg, 2.20 mmol) and 2,6-dibenzyloxy-3-iodo-pyridine (900.00 mg, 1.83 mmol) in DME (10 mL), were added Potassium carbonate (380.23 mg, 2.75 mmol), disilver;oxygen(2-) (637.55 mg, 2.75 mmol, 89.29 μL) and Triphenylphosphane (240.53 mg, 917.05 μmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 5 minutes. Subsequently, Tetrakis(triphenylphosphine)palladium(0) (211.94 mg, 183.41 μmol) was added to the reaction mixture and reaction mixture was heated to 85 °C for 16 hr. After completion of the reaction as indicated by UPLC, the reaction mixture was cooled to room temperature and poured into water (25 mL ) and extracted with ethyl acetate ( 2 x 50 mL ). Organic phases were combined and washed with brine ( 5 mL ). Combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford a crude product,Which was purified by flash silica-gel (230-400 mesh) column with 0-100% ethyl acetate/petroleum ether while desired compound eluting at 4 % to give tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)methyl]phenyl]piperidine-1-carboxylate (0.415 g, 655.30 μmol, 35.73% yield, 89.17% purity, No Salt) as brown solid. UPLC (ESI): m/z 565.3 [M+H]⁺. Step-5: Into a 25 mL single-necked round-bottomed flask containing a well-stirred suspension of tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)methyl]phenyl]piperidine-1-carboxylate (0.1 g, 157.90 μmol) in 1,4 Dioxane (2 mL) and Ethanol (2 mL) was added Palladium, 10% on carbon, Type 487, dry (16.80 mg, 157.90 μmol) at room temperature under nitrogen atmosphere and the resulting suspension was stirred at room temperature under hydrogen atmosphere (bladder) for 16 hr. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (50 mL ). The combined filtrate was concentrated under reduced pressure to afford tert-butyl 4-[4-[(2,6-dioxo-3- piperidyl)methyl]phenyl]piperidine-1-carboxylate (6) (0.061 g, 155.10 μmol, 98.23% yield, 98.27% purity, No Salt) as white solid. LCMS (ESI): m/z 287.2 [M-COOtBu+H]⁺ Step-6: To a solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)methyl]phenyl]piperidine-1- carboxylate in DCM is added 4 M HCl in dioxane (10 equiv.) and the reaction is stirred at room temperature for 16 h. Upon completion of the reaction, the solvent is removed under reduced pressure and the crude product is purified by column chromatography to afford 3-(4-(piperidin- 4-yl)benzyl)piperidine-2,6-dione (B-33). 3-(6-(aminomethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (B-34) Compound 3-(6-(aminomethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione was prepared using was prepared using the method described on page 322-324 of WO2023019166 A1. 3-(2-oxo-5-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (B-35) Compound 3-(2-oxo-5-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione was prepared using was prepared using the method described on page 335-338 of WO2023019166 A1. 3-(2-oxo-6-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (B-36) Compound 3-(2-oxo-6-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione was prepared using the method described on page 203-205 of WO2021127586 A1. Synthesis B17: Synthesis of 3-[8-(4-piperidyl)-2,3-dihydro-1,4-benzoxazin-4-yl]piperidine- 2,6-dione (B-37) Step-1: To a stirred solution of 2-bromo-6-nitro-phenol 1 (50 g, 229.35 mmol) in THF (200 mL) was added zinc (149.97 g, 2.29 mol, 21.00 mL) and cooled to 0 °C. Then ammonium chloride (122.68 g, 2.29 mol) dissolved in water (100 mL) and added dropwise to the reaction mixture and stirred for 1 hour at room temperature. Upon completion, the reaction mixture was filtered through celite bed, washed with EtOAc and concentrated. The crude was washed with water and extracted with EtOAc (3×500mL). The combined organic layers were dried and concentrated in vacuo and the crude material was triturated with pentane to afford 2-amino-6-bromo-phenol 2 (35 g, 109.31 mmol, 47.66% yield) as a black color solid. LCMS (ES⁺): m/z 188.29 [M+H]⁺. Step-2: To a stirred solution of 2-amino-6-bromo-phenol 2 (35 g, 186.15 mmol) in DMF (300 mL) was added potassium carbonate (64.32 g, 465.37 mmol). The mixture was cooled to 0°C and 2-chloroacetyl chloride 3 (23.13 g, 204.76 mmol, 16.29 mL) was added dropwise. The reaction was stirred at RT overnight. After completion of the reaction, the reaction mixture poured into ice and stirred for 1 hour and filtered the solid and dried under vacuum to afford the 8-bromo-4H-1,4-benzoxazin-3-one 4 (35 g, 101.74 mmol, 54.66% yield) as dark brown solid. LCMS (ES⁺): m/z 228.08 [M+H]⁺. Step-3: To a stirred solution of 8-bromo-4H-1,4-benzoxazin-3-one 4 (20 g, 87.70 mmol) in THF (100 mL) at 0°C, was added borane methyl sulfanylmethane (67.28 g, 885.68 mmol, 84.00 mL) in a drop wise manner. The reaction mixture was heated at 78 °C for 1h. Upon completion, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine solution and dried over sodium sulphate and concentrated. The crude product thus obtained was purified by column chromatography to afford 8-bromo-3,4-dihydro-2H-1,4-benzoxazine 5 (16 g, 65.92 mmol, 75.16% yield) as a white solid. LCMS (ES⁺): m/z 213.83 [M+H]⁺. Step-4: To a solution of 8-bromo-3,4-dihydro-2H-1,4-benzoxazine 5 (16 g, 74.75 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate 6 (23.11 g, 74.75 mmol) in 1,4-dioxane (80 mL) and water (10 mL) was added tripotassium phosphate (47.60 g, 224.24 mmol) at RT. The reaction mixture was degassed with argon purging and Pd(dppf)Cl2 (2.73 g, 3.74 mmol) was added. The reaction mixture was again degassed with argon for 5 min and it was stirred at 90 °C for16 hr. After completion of the reaction, it was concentrated under reduced pressure to afford the crude product, which was purified by column chromatography using Davisil silica and 30% EA in Petroleum ether as eluent to afford tert-butyl 4-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)-3,6-dihydro-2H-pyridine-1- carboxylate 7 (23 g, 62.09 mmol, 83.07% yield) as colourless gum. LCMS (ES⁺): m/z 217.02 [M – Boc+H]⁺. Step-5: A solution of tert-butyl 4-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)-3,6-dihydro-2H- pyridine-1-carboxylate 7 (23 g, 66.37 mmol) in methanol (500 mL) was degassed with N₂ for 10 min and 10% Palladium on carbon (21 g, 66.37 mmol) was added. The reaction mixture was stirred for 16h at 25°C in par shaker under hydrogen pressure (80 psi). After completion of the reaction, it was filtered over celite bed and washed with ethyl acetate. The volatiles were evaporated under reduced pressure to afford the crude product, which was purified by column chromatography to afford tert-butyl 4-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)piperidine-1- carboxylate 8 (22 g, 56.24 mmol, 84.73% yield). LCMS (ES⁺): m/z 263.41 [M- tBu+H]⁺. Step-6: To a solution of t-butyl 4-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)piperidine-1- carboxylate 8 (22 g, 65.95 mmol) and 2,6-dibenzyloxy-3-bromo-pyridine 9 (24.42 g, 65.95 mmol) in toluene (420 mL) was added sodium tert-butoxide (12.68 g, 131.91 mmol) at RT. The reaction mixture was degassed with N₂ for 10 min and Pd2(dba)3 (3.02 g, 3.30 mmol) was added. Subsequently, Xantphos (7.63 g, 13.19 mmol) was added, and the reaction mixture was degassed with N₂ for 5 minutes. The reaction mixture was stirred at 110°C for 16 h. After completion of the reaction, it was concentrated under reduced pressure to give the crude product, which was purified by column chromatography using Davisil silica and 10% EA in Petroleum ether as eluent to afford t-butyl 4-[4-(2,4-dibenzyloxyphenyl)-2,3-dihydro-1,4-benzoxazin-8- yl]piperidine-1-carboxylate 10 (20 g, 26.26 mmol, 39.81% yield) as pale yellow colour gum. LCMS (ES⁺): m/z 552.47 [M- tBu+H]⁺. Step-7: A solution of tert-butyl 4-[4-(2,4-dibenzyloxyphenyl)-2,3-dihydro-1,4-benzoxazin-8- yl]piperidine-1-carboxylate 10 (20 g, 32.96 mmol) in ethanol (200 mL) and ethyl acetate (200 mL) was degassed with N₂ for 10 min and palladium, 10% on carbon (20 g, 32.96 mmol) was added. The reaction mixture was purged with H₂ gas for 5 min and the stirring was continued for 24 hours at RT under hydrogen atmosphere (70 psi) in a Parr shaker. The progress of the reaction was monitored by TLC. After completion of the reaction, it was filtered over celite bed and washed with ethyl acetate and 10% methanol in DCM. The volatiles were removed under reduced pressure to afford the crude product, which was purified by column chromatography over Davisil silica, using 50% EA in Petroleum ether as eluent to afford tert-butyl 4-[4-(2,6- dioxo-3-piperidyl)-2,3-dihydro-1,4-benzoxazin-8-yl]piperidine-1-carboxylate 11 (7 g, 15.13 mmol, 45.90% yield) as red solid. LCMS (ES⁺): m/z 430.32 [M+H]⁺. Step-8: To a stirred solution of t-butyl 4-[4-(2,6-dioxo-3-piperidyl)-2,3-dihydro-1,4-benzoxazin- 8-yl]piperidine-1-carboxylate 11 (7 g, 16.30 mmol) in DCM (100 mL) was added trifluoroacetic acid (14.80 g, 129.80 mmol, 10 mL) at 0°C. The reaction mixture was stirred at RT for 16 hr. Upon completion of the reaction, the solvents were removed under reduced pressure. The crude product obtained was washed with diethyl ether and dried to afford 3-[8-(4-piperidyl)-2,3- dihydro-1,4-benzoxazin-4-yl]piperidine-2,6-dione B-37 (7 g, 14.13 mmol, 86.67% yield, TFA salt). LCMS (ES⁺): m/z 330.27 [M+H]⁺. Synthesis B18: Synthesis of 3-[5-(4-piperidyl)-3,4-dihydro-2H-quinolin-1-yl]piperidine- 2,6-dione (B-38) Step-1: A mixture of 5-bromo-1,2,3,4-tetrahydroquinoline 1 (2 g, 9.43 mmol, 1.0 eq.) and tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate 2 (3.50 g, 11.32 mmol, 1.2 eq.) in 1,4-Dioxane (40 mL), was degassed with nitrogen for 5 minutes. To the reaction mixture, tripotassium;phosphate (6.01 g, 28.29 mmol,3.0 eq.) in water (10 mL)) was added and the mixture was degassed for an additional 5 minutes. Then cyclopentyl(diphenyl) phosphane;dichloromethane;dichloropalladium;iron (770.10 mg, 943.01 μmol,0.1 eq.) was added and the reaction mixture was heated at 95 °C for 16 h. Upon completion of the reaction, it was cooled to room temperature, filtered through celite bed and washed with EtOAc. The filtrate was washed with water and brine solution, dried over anhydrous Na₂SO₄ and evaporated under vacuum to obtain the crude material, which was purified by column chromatography (Davisil Silica, elution solvent 0-30% EtOAc in n-Hex) to afford tert-butyl 4- (1,2,3,4-tetrahydroquinolin-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate 3 (2.2 g, 6.91 mmol, 73.31% yield) as an off white solid. LCMS (ES⁺): m/z 315.34 [M+H]⁺. Step-2: A solution of tert-butyl 4-(1,2,3,4-tetrahydroquinolin-5-yl)-3,6-dihydro-2H-pyridine-1- carboxylate 3 (2.2 g, 7.00 mmol,1.0 eq.) in Methanol (50 mL) was degassed with nitrogen gas for 15 min in a 250 mL Parr-Shaker vessel. Subsequently, 10% palladium on charcoal (2.23 g, 20.99 mmol,3.0 eq.) was added to the reaction mixture and the reaction mixture was stirred under hydrogen atmosphere for 16 h at 25 °C at 70 Psi. Upon completion of the reaction, it was filtered through celite bed, and washed with methanol. The filtrate was evaporated under vacuum to afford the crude residue, which was purified by column chromatography (Davisil silica, 0-50% EtOAc in Pet-ether) to afford t-butyl 4-(1, 2, 3, 4-tetrahydroquinolin-5-yl)-piperidine-1- carboxylate 4 (1.8 g, 5.40 mmol, 77.23% yield) as a white solid. LCMS (ES⁺): m/z 261.57 [M – tBu+H]⁺. Step-3: To a solution of tert-butyl 4-(1,2,3,4-tetrahydroquinolin-5-yl)piperidine-1-carboxylate 4 (1 g, 3.16 mmol, 1.0 eq.) and 3-bromopiperidine-2,6-dione 5 (1.82 g, 9.48 mmol,3.0 eq.) in DMF (10 mL) sodium; hydrogen carbonate (2.65 g, 31.60 mmol, 1.23 mL,10.0 eq.) was added under nitrogen atmosphere. The reaction mixture was heated at 80°C for 16 h. Then the reaction mixture was cooled to room temp and diluted with EtOAc. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated under vacuum to afford the crude compound which was purified by column chromatography (Davisil Silica, 0-50% Ethyl acetate in Pet-ether) to afford tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3,4-dihydro-2H-quinolin-5- yl]piperidine-1-carboxylate 6 (500 mg, 1.13 mmol, 35.90% yield) as a light green solid. LCMS (ES⁺): m/z 428.78[M+H]⁺. Step-4: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert- butyl 4-[1-(2,6-dioxo-3-piperidyl)-3,4-dihydro-2H-quinolin-5-yl]piperidine-1-carboxylate 6 (1.1 g, 2.57 mmol) in anhydrous DCM (5 mL) was added 4 M HCl in dioxane (6.43 mL) at ambient temperature. The resulting mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, excess solvents were removed from the reaction mixture under reduced pressure and the crude product was washed with hexane (50 mL) to afford 3-[5-(4- piperidyl)-3,4-dihydro-2H-quinolin-1-yl]piperidine-2,6-dione B-38 (900 mg, 2.45 mmol, 95.07% yield, HCl salt) as an off white solid. LCMS (ESI): m/z 328 [M+H]⁺. Synthesis B19: Synthesis of 3-[4-(4-piperidyl)indolin-1-yl]piperidine-2,6-dione (B-39) Step-1: To a stirred solution of 4-bromoindoline 1 (5 g, 25.24 mmol) and tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate 2 (8.59 g, 27.77 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was added tripotassium phosphate (16.08 g, 75.73 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1.03 g, 1.26 mmol). The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, reaction mixture was concentrated under reduced pressure to obtain crude, which was partitioned in water (100 mL) and DCM (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude was purified by column chromatography (silica gel, 60-120 mesh) using 0-100% ethyl acetate in petroleum ether as eluent to afford tert-butyl 4-indolin-4-yl-3,6-dihydro-2H-pyridine-1- carboxylate 3 (4.2 g, 13.39 mmol, 53.03% yield) as a brown sticky gum. LCMS (ES⁺): m/z 301.4 [M+H]⁺. Step-2: To a stirred solution of tert-butyl 4-indolin-4-yl-3,6-dihydro-2H-pyridine-1-carboxylate 3 (100 mg, 332.90 μmol) in 1,4-dioxane (25 mL) were added AcOH (0.5 mL) and 10% Pd/C (70.85 mg, 665.79 μmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature under hydrogen (bladder pressure) at room temperature for 16 h. After completion of the reaction, reaction mixture was filtered through celite bed and washed with DCM (100 mL). The resulting filtrate was concentrated under reduced pressure and dried to afford tert-butyl 4-indolin-4-ylpiperidine-1-carboxylate 4 (70 mg, 192.12 μmol, 57.71% yield) as an off-white solid. LCMS (ES⁺): m/z 247.2 [M-tBu+H]⁺. Step-3: To a stirred solution of tert-butyl 4-indolin-4-ylpiperidine-1-carboxylate 4 (1 g, 3.10 mmol) in DMF (10 mL) were added sodium hydrogen carbonate (781.29 mg, 9.30 mmol) and 3-bromopiperidine-2,6-dione 5 (892.88 mg, 4.65 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, reaction mixture was concentrated under reduced pressure. The resulting crude was dissolved in DCM (50 mL) and washed with water (2 × 50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude. The crude was purified by column chromatography (silica gel, 230-400 mesh) using 80% ethyl acetate in petroleum ether as eluent to afford tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)indolin-4- yl]piperidine-1-carboxylate (6) (650 mg) as a brown solid. Step-4: To a single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1- (2,6-dioxo-3-piperidyl)indolin-4-yl]piperidine-1-carboxylate (400 mg, 967.33 μmol) in DCM (5 mL) was added 4.0 M hydrogen chloride solution in dioxane (\ 5.00 mL) at 0°C. The reaction mixture was warmed to RT and stirred for 1 hour at 21°C. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was washed with MTBE (3×15ml) and dried under reduced pressure to afford 3-[4-(4-piperidyl)indolin-1- yl]piperidine-2,6-dione (B-39) (338 mg, 959.93 μmol, 99.24% yield, HCl salt) as a brown solid. LCMS (ES⁺): m/z 314.3 [M+H]⁺. Synthesis B20: Synthesis of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (B- 40-SM) Step-1: To a stirred solution of 7-bromo-1H-indazole (1) (1 g, 5.08 mmol) in DMF (10 mL) was added Potassium Hydroxide (0.569 g, 10.15 mmol) portion wise at 0°C then added molecular iodine (1.42 g, 5.58 mmol) under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 25 °C. After complete consumption of starting material, the reaction mixture was concentrated under vacuum. It was stirred with ethyl acetate (50 mL) and water (100 mL) then separated organic layer then concentrated. That crude was stirred with n-pentane (50 mL) for 15 minutes and filtered to afford 7-bromo-3-iodo-1H-indazole (2) (1 g, 3.03 mmol, 59.63% yield, 97.73% purity) as off white solid.¹H-NMR (400 MHz, DMSO-d6) δ 7.615 (dd, J = 7.8 Hz, 0.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H). Step-2: To a stirred solution of 7-bromo-3-iodo-1H-indazole (2) (65 g, 201.28 mmol) in Acetone (650 mL), was added Potassium Hydroxide (22.59 g, 402.57 mmol, 11.05 mL) portion wise at 0°C then added methyl iodide (31.43 g, 221.41 mmol, 13.78 mL) under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 25°C. After complete consumption of starting material, the reaction mixture was concentrated under vacuum. It was stirred with Ethyl acetate (1500 mL) and water (1000 mL) then separated organic layer dried over anhydrous sodium sulphate, concentrated under reduced pressure to obtain the crude. The crude was stirred with n- pentane (500 mL) for 15 minutes and filtered to afford 7-bromo-3-iodo-1-methyl-indazole (3) (40 g, 117.31 mmol, 58.28% yield, 98.82% purity) as off white solid. LCMS (ESI): m/z [M+H]⁺ 337.15 Step-3: To a stirred solution of 7-bromo-3-iodo-1-methyl-indazole (3) (6 g, 17.81 mmol) in water (15 mL) and Dioxane (80 mL),was added 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (4) (7.43 g, 17.81 mmol, No Salt) and Potassium carbonate (7.38 g, 53.42 mmol) at room temperature, then the reaction mixture was purged with nitrogen for 10 minutes. Then Pd(dppf)Cl₂.CH₂Cl₂ (0.727 g, 0.890 μmol) was added and purged with nitrogen for 10 minutes. Then reaction mixture was stirred at 60 °C for 16 h. After completion of reaction, the reaction was filtered and evaporated to obtain the crude. The crude was purified using silica (200-400 mesh) and eluted with 2% ethyl acetate in petroleum ether to obtained 7-bromo-3-(2,6- dibenzyloxy-3-pyridyl)-1-methyl-indazole (B-40-SM) (3 g, 4.44 mmol, 24.92% yield, 74% purity) as white solid. LCMS(ES+): m/z 500.47 [M+H]⁺. Synthesis B21: Synthesis of 3- [6-(3-azaspiro [5.5] undecan-9-yl)-1-methyl-indazol-3-yl] piperidine-2,6-dione (B-40)

Step-1: To a stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1) (1 g, 2.00 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (2) (659.73 mg, 2.60 mmol) in Dioxane (20 mL) was added Potassium Acetate (588.40 mg, 6.00 mmol, 374.78 μL) and degassed with nitrogen for 10 minutes, Pd(dppf)Cl2.CH₂Cl2 (81.60 mg, 99.92 μmol) was added, the reaction mixture again degassed for 5 minutes, resulted reaction mixture stirred for 16 h at 90 °C. After complete consumption of starting material, reaction mixture was filtered through celite bed, filtrate was concentrated under reduced pressure to afford crude compound, which was purified column chromatography using (davisil silica) eluted at 10 % Ethyl acetate in Petroleum ether to afforded 3-(2,6-dibenzyloxy- 3-pyridyl)-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indazole (3) (0.55 g, 616.26 μmol, 30.84% yield) as a Pale yellow solid. LCMS (ESI): m/z 548.67 [M+1] ⁺ Step-2a: To a stirred solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (A) (2 g, 7.48 mmol) in THF (4.26 mL) was added dropwise a solution of Lithium bis(trimethylsilyl)amide (2 M, 7.48 mL) and stirred at -78 ⁰C after the addition was complete, the reaction mixture was stirred for 1 hour at -78 ⁰C. After 1 hour, 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (B) (2.67 g, 7.48 mmol) was dissolved in 5mL of THF and added dropwise into the reaction solution, and stirred at -78 ⁰C for 1 hour. The mixture was warmed to 25 °C and stirred for 6 h , the reaction mixture was treated with ammonium chloride solution (30 mL) and extracted with ethyl acetate(100 mL). The organic layer and washed with brine, dried over Na₂SO₄ and concentrated to give a residue, which was purified by Davisil silica gel column chromatography eluted at 10% EtOAc in petroleum ether to afford tert-butyl 9-(trifluoromethylsulfonyloxy)-3-azaspiro[5.5]undec-9-ene-3-carboxylate (C) (2 g, 4.61 mmol, 61.58% yield) as a brown oil.¹H NMR (400 MHz, CDCl3) δ- 5.68 (t, J = 4.4 Hz, 1H), 3.46 (m, 2H), 3.31 (m, 2H), 2.33 (m, 2H), 2.03(m, 2H), 1.66 (m, 2H), 1.45 (s, 9 H), 1.42 (m, 4H) Step-2: To a stirred solution of 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)indazole (3) (0.85 g, 1.55 mmol) and tert-butyl 9- (trifluoromethylsulfonyloxy)-3-azaspiro[5.5]undec-9-ene-3-carboxylate (4) (775.21 mg, 1.94 mmol) in Dioxane (15 mL) were added Potassium carbonate (643.76 mg, 4.66 mmol) and degassed with nitrogen for 10 minutes, Pd(dppf)Cl₂.CH₂Cl₂ (126.80 mg, 155.27 μmol) was added, the resulted reaction mixture stirred for 4 hours at 100 °C. After complete consumption of starting material, reaction mixture was filtered through on celite bed, filtrate was concentrated under reduced pressure to afford crude compound, which was purified by column chromatography using (Davisil silica) eluted at 10 % Ethyl acetate in Petroleum ether to afforded tert-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-3-azaspiro [5.5] undec-9- ene-3-carboxylate (5) (0.6 g, 647.46 μmol, 41.70% yield, 72.39% purity, No Salt) as a colourless oil. LCMS (ESI): m/z 671.80 [M+1] ⁺, Step-3: To a stirred solution of tert-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6- yl]-3-azaspiro [5.5] undec-9-ene-3-carboxylate (5) (0.55 g, 819.87 μmol, No Salt) in Ethyl acetate (15 mL) and THF (15 mL) then degassed with nitrogen for 10 minutes was added Palladium, 10% on carbon, Type 487, dry (523.50 mg, 4.92 mmol) at room temperature. The reaction mixture was stir under hydrogen atmosphere (20 psi) using bladder for 16 h. After complete consumption of starting material, the reaction mixture was filtered through celite bed and washed with Ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 9-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-3-azaspiro [5.5] undecane-3-carboxylate (6) (0.3 g, 484.91 μmol, 59.15% yield) as an Off-white solid. LCMS (ES+): m/z 495.45 [M+H] ⁺, Step-4: To the stirred solution of tert-butyl 9-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]- 3-azaspiro [5.5] undecane-3-carboxylate (6) (100 mg, 202.17 μmol, No Salt) in DCM (1 mL) was added HCl in 1,4-dioxane (4 M, 1 mL) at 0 °C and the resulting reaction mixture was stirred for 1 hour at 25 °C. Up on completion the reaction mixture was concentrated under reduced pressure to obtained crude compound which was triturated with diethyl ether (5 mL), to afford 3- [6-(3-azaspiro [5.5] undecan-9-yl)-1-methyl-indazol-3-yl] piperidine-2,6-dione B-40 (60 mg, 113.13 μmol, 55.96% yield ) as an off white solid. LCMS (ES+): m/z 395.55 [M+H] ⁺. The following CRBN binders were prepared substantially following the method described above, using the corresponding starting material 1 and reactant 4. The following CRBN binders are prepared substantially following the method described above, using the corresponding starting material 1 and reactant 4. Synthesis B22: Synthesis of 3-[5-(3-azaspiro[5.5]undecan-9-yl)-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (B-48)

Step-1: To a solution of tert-butyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- azaspiro[5.5]undec-9-ene-3-carboxylate (749.84 mg, 1.99 mmol) and 5-bromo-1-(2,6- dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (855.15 mg, 1.66 mmol) in water (5 mL) and dioxane (20 mL) was added sodium carbonate (526.57 mg, 4.97 mmol) at RT. The reaction mixture was degassed with nitrogen gas for 10 minutes and Pd(dppf)Cl2 (121.17 mg, 165.60 μmol) was added. The reaction mixture was degassed with nitrogen gas for an additional 5 minutes and stirred at 90 °C for 16 h. After completion, the reaction mixture was filtered through celite bed and washed with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine solution (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude was purified by column chromatography (using Davisil silica gel and 45% of ethyl acetate in pet-ether as eluent) to afford tert-butyl 9-(1-(2,6- bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3- azaspiro[5.5]undec-8-ene-3-carboxylate (600 mg, 30.86% yield, 67.87 % purity) as off -white solid. LCMS (ESI): m/z 687.52 [M+H]⁺ Step-2: To a stirred solution of tert-butyl 9-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-5-yl]-3-azaspiro[5.5]undec-9-ene-3-carboxylate (0.66 g, 960.93 μmol) in Ethanol (5 mL) , THF (5 mL) , Ethyl acetate (5 mL) was added 10% Palladium on Carbon (wetted with ca.55% Water) (711.23 mg, 6.68 mmol) at 0 °C and stirred reaction mixture at 25 °C under hydrogen atm for 16 hr. After complete consumption of the starting material, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (30 mL). The combined organic layers were concentrated under reduced pressure and purified using Davisil silica and 50% ethyl acetate in petroleum ether as eluent to afford tert-butyl 9-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3-azaspiro[5.5]undecane-3-carboxylate (0.38 g, 675.80 μmol, 70.33% yield, 90.81% purity) as grey solid. LCMS (ESI): m/z 509.40 [M-H]- Step-3: To a stirred solution of tert-butyl 9-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-3-azaspiro[5.5]undecane-3-carboxylate (75 mg, 146.88 μmol, No Salt) in DCM (1 mL) was added 4.0 M HCl in 1,4-dioxane (0.5 mL) by dropwise at 0°C under nitrogen atmosphere. The reaction mixture was stirred at RT for 1h. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure to afford crude, which was triturated with diethyl ether (2 mL x 2) to afford 3- [5-(3-azaspiro[5.5]undecan-9-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (B- 48) (65 mg, 132.39 μmol, 90.14% yield, 91.04% purity, Hydrochloric acid) as an off white solid. LCMS (ESI): m/z 411.31 [M+H]⁺. Synthesis B23: Synthesis of 3-[5-(2,7-diazaspiro[3.5]nonan-2-yl)-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (B-49) Step-1: To a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one 1 (0.8 g, 1.55 mmol, No Salt) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate 2 (420.74 mg, 1.86 mmol) in toluene (20 mL) was added Sodium t-butoxide (446.64 mg, 4.65 mmol, 435.75 μL) at RT. The reaction mixture was degassed with nitrogen gas for 10 minutes and tBuXPhos Pd G3 (123.07 mg, 154.92 μmol) was added. The reaction mixture was degassed with nitrogen gas for an additional 5 minutes and stirred at 100 °C for 16 h. Reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was filtered through celite bed and washed with ethyl acetate (3 x 50 mL). The organic layer was washed with water (2 x 20 mL) and brine solution (2 x 20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product. The crude was purified by using Davisil silica gel column chromatography using 30% of Ethyl acetate in petroleum ether to afford tert-butyl 2-[1-(2,6- dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-2,7-diazaspiro[3.5]nonane-7- carboxylate 3 (470 mg, 703.38 μmol, 45.40% yield, 99.04% purity, No Salt) as off white solid. LCMS (ESI): m/z 662.64 [M+H]⁺. Step-2: To a stirred solution of tert-butyl 2-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 3 (0.47 g, 710.20 μmol) in Ethanol (5 mL) , THF (5 mL) , Ethyl acetate (5 mL) was added Pd/C炷10% on Carbon (wetted with ca.55% Water)炸 (500 mg, 4.70 mmol) at 0 °C and stirred reaction mixture at 25 °C under hydrogen bladder atm for 16 hr. After completion of starting material, The reaction mixture was filtered through celite bed and washed with ethyl acetate (30 mL), concentrated under reduced pressure to afford crude, was purified using Davisil silica in 50% ethyl acetate in petroleum ether to afford tert-butyl 2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-2,7- diazaspiro[3.5]nonane-7-carboxylate 4 (60 mg, 101.47 μmol, 14.29% yield, 81.78% purity, No Salt) as grey solid. LCMS (ESI): m/z 484.31 [M+H]⁺. Step-3: To a stirred solution of tert-butyl 2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 4 (57 mg, 117.88 μmol) in DCM (1 mL) was added HCl炷4.0 M in 1,4-dioxane炸 (4 M, 0.5 mL) at 0°C. The reaction mixture was stirred at RT for 2h, while monitored by TLC. Upon completion, the reaction mixture was concentrated under reduced pressure to afford crude product. Then the crude compound was triturated with diethyl ether (2 X 20 mL) to afford 3-[5-(2,7-diazaspiro[3.5]nonan-2-yl)-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione B-49 (50 mg, 72.43 μmol, 61.45% yield, 60.83% purity, Hydrochloric acid) as an off-white solid. LCMS (ES+): m/z 382.28 [M+H]⁺. The following CRBN binders were prepared using identical or similar methods as described above, with the corresponding starting material 1 and reactant 2. Alternative Buchwald coupling (Step-1) conditions included 1) Pd₂(dba)₃, NaOtBu, BINAP, toluene.

The following CRBN binders are prepared using identical or similar methods as described above, with the corresponding starting material 1 and reactant 2. Alternative Buchwald coupling (Step-1) conditions include 1) Pd2(dba)3, NaOtBu, BINAP, toluene. Synthesis B24: Synthesis of 1-[6-(3,9-diazaspiro[5.5]undecan-3-yl)-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione (B-55) Step-1: To a stirred solution of 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4- dione (2 g, 6.19 mmol, No Salt) in DMF (30 mL) at 0 °C was added Cesium carbonate (2.75 g, 15.47 mmol) followed by addition 1-(chloromethyl)-4-methoxy-benzene (1.26 g, 8.05 mmol) The reaction mixture was stirred at 25 °C for 16 h. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtained crude. After completion of reaction, the reaction mixture was quenched with ice water to afford the solid product, the obtained solid was washed with petroleum ether to afford the 1-(6-bromo-1-methyl- indazol-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (2.4 g, 4.87 mmol, 78.73% yield, 90% purity, No Salt) . LCMS (ES+): m/z 445.58 Bromo pattern [M +2]⁺ Step-2: To a solution of 1-(6-bromo-1-methyl-indazol-3-yl)-3-[(4- methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (1 g, 2.26 mmol, No Salt) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (745.96 mg, 2.93 mmol, No Salt) in 1,4 dioxane (15 mL) was added K3PO4 (1.44 g, 6.77 mmol) at RT. The reaction mixture was degassed with nitrogen gas for 10 minutes and XPhos-Pd-G3 (152.76 mg, 180.47 μmol) was added. The reaction mixture was degassed with N2 gas for additional 5 minutes and it was stirred at 100 °C for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was filtered through celite bed and washed with ethyl acetate filtrate was concentrated in vacuo to afford the crude product , which was purified by column chromatography using 100-200 silica gel to afforded tert-butyl 9-[3-[3-[(4- methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]-1-methyl-indazol-6-yl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (0.75 g, 1.05 mmol, 46.36% yield, 86% purity, No Salt). LCMS [ES+]: m/z 617.82 [M+H]⁺ Step-3: A stirred solution of tert-butyl 9-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo- hexahydropyrimidin-1-yl]-1-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.03 g, 48.64 μmol, No Salt) in DCM (1 mL) was cooled to 0°C, added trifluoromethanesulfonic acid (146.00 mg, 972.84 μmol, 85.48 μL) , stirred for 15 minutes followed by addition of TFA (55.46 mg, 486.42 μmol, 37.22 μL) at same temperature. Reaction mixture was slowly warmed to 45°C and continued stirring at 45°C for 16h. Reaction was monitored by LCMS. After completion, mixture was concentrated under reduced pressure, followed by triturating with diethyl ether (20ml*2). Mixture was stirred for 2h and then filtered to afford 1-[6-(3,9- diazaspiro[5.5]undecan-3-yl)-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (B-55). LCMS [ES+]: m/z 617.75 [M+H]⁺

The following CRBN binder is prepared substantially following the method described above, using the corresponding starting material 1 and reactant 2. Synthesis B25: Synthesis of 3-[4-(3-azaspiro[5.5]undecan-9-yl)anilino]piperidine-2,6-dione (B-57) Step-1: To a stirred solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1) (2 g, 7.48 mmol) in THF (20 mL) was added dropwise a solution of Lithium bis(trimethylsilyl)amide (2 M, 7.48 mL) at -78 ⁰C and stirred at same temperature for 1 hour. 1,1,1-trifluoro-N-phenyl- N-((trifluoromethyl)sulfonyl)methanesulfonamide (2) (2.67 g, 7.48 mmol) was dissolved in 5 mL of THF and added to the reaction mixture dropwise, stirred at -78 ⁰C for 1.5 hours. The mixture was warmed to 25 °C and stirred for 2 hours, the reaction mixture was quenched with ammonium chloride solution (30 mL) and extracted with ethyl acetate (100 mL × 2). The organic layer and washed with brine, dried over Na₂SO₄ and concentrated to give a residue, which was purified by neutral alumina column chromatography (10% EtOAc in petroleum ether) to give the titled compound tert-butyl 9-(trifluoromethylsulfonyloxy)-3-azaspiro[5.5]undec-9-ene-3- carboxylate (3) (1 g, 2.38 mmol, 31.80% yield, 95% purity) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ- 5.68 (t, 4.4 Hz, 1H), 3.46 (m, 2H), 3.31 (m, 2H), 2.33 (m, 2H), 2.03(m, 2H), 1.66 (m, 2H), 1.45 (s, 9 H), 1.42 (m, 4H) Step-2: To a stirred solution of tert-butyl 9-(trifluoromethylsulfonyloxy)-3-azaspiro[5.5]undec- 9-ene-3-carboxylate (3) (1.5 g, 3.76 mmol) in dioxane (15 mL) were added K2CO3 (1.56 g, 11.27 mmol) and (4-nitrophenyl)boronic acid (4) (626.88 mg, 3.76 mmol) at room temperature. Then reaction mixture was degassed with argon for 5 minutes. After that Pd(dppf)Cl2.CH₂Cl2 (0.153 g, 0.187 mmol) was added to reaction mixture at room temperature and again degassed for 2 minutes. After that reaction mixture was stirred at 80 °C for 16 h. On completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain crude. The crude was purified in silica (mesh 100-200) and eluted with 5-10% ethyl acetate in petroleum ether, afforded tert-butyl 9-(4-nitrophenyl)-3-azaspiro[5.5]undec-9-ene-3-carboxylate (5) (0.700 g, 1.84 mmol) as a white solid. LCMS (ES-): m/z 371.35 [M-H]- Step-3: To a stirred solution of tert-butyl 9-(4-nitrophenyl)-3-azaspiro[5.5]undec-9-ene-3- carboxylate (5) (0.400 g, 1.07 mmol) in THF (5 mL) and Ethanol (5 mL) was added 10% Palladium on carbon wet (228.58 mg, 2.15 mmol) and stirred reaction mixture at 25 °C under hydrogen atmosphere in parr shaker (40 psi) for 16 h. After completion of starting material, the reaction mixture was filtered through celite bed and washed with ethyl acetate (100 mL), concentrated under reduced pressure to afford crude which was purified by using davisil silica in 50% ethyl acetate in petroleum ether to afford tert-butyl 9-(4-aminophenyl)-3- azaspiro[5.5]undecane-3-carboxylate (6) (0.200 g, 0.392 mmol) as grey solid. LCMS: m/z 245.24 [M-Boc+H]⁺ Step-4: To a stirred solution of tert-butyl 9-(4-aminophenyl)-3-azaspiro[5.5]undecane-3- carboxylate (6) (0.400 g, 1.16 mmol ) in DMF (4.90 mL) was added NaHCO₃ (0.487 g, 5.81 mmol, 0.225 mL) and 3-bromopiperidine-2,6-dione (7) (2.23 g, 11.61 mmol) at 25 °C. The reaction mixture was heated and stirred at 65 °C for 16 h. The reaction mixture was quenched with water and extracted using ethyl acetate, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude was isolated with reverse phase (40% acetonitrile in water) to afford tert-butyl 9-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-3- azaspiro[5.5]undecane-3-carboxylate (8) (0.251 g, 0.545 mmol) as white solid. LCMS (ES+): m/z 456.46 [M+H]⁺ Step-5: To the stirred solution of tert-butyl 9-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-3- azaspiro[5.5]undecane-3-carboxylate (8) (0.080 g, 0.175 mmol) in DCM (1 mL) was added HCl (4.0 M in 1,4-dioxane) (4 M, 0.043 mL) at 0 °C and the resulting reaction mixture was allowed to stirred for 1 hour at 25 °C. The reaction mixture was concentrated under reduced pressure to afford crude compound. The crude product was triturated with diethyl ether (10 mL) to afford 3-[4-(3-azaspiro[5.5]undecan-9-yl)anilino]piperidine-2,6-dione (B-57) (0.075 mg, 0.173 mmol, 98.66% yield, 90.53% purity, Hydrochloric acid) as an off white solid. LCMS (ES+): m/z 356.40 [M+H]⁺ Synthesis B26: Synthesis of 3-[4-(2,7-diazaspiro [3.5] nonan-2-yl)anilino]piperidine-2,6- dione (B-58) Step-1: To a stirring solution of 1-fluoro-4-nitro-benzene (1) (8.05 g, 57.08 mmol, 6.06 mL) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (2) (10 g, 38.06 mmol, Hydrochloric acid) in DMSO (50 mL) was added DIPEA (24.59 g, 190.28 mmol, 33.14 mL) under nitrogen atmosphere at room temperature. The resulting reaction mixture was heated at 100 °C and stirred for 16 h. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and quenched with ice cooled water (120 mL). The formed solid precipitate was filtered off and dried under vacuum to afford the crude. The crude was washed with petroleum ether (100 mL) to afford tert-butyl 2-(4-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7- carboxylate (3) (12 g, 33.88 mmol, 89.02% yield, 98.08% purity) as a yellow solid. LCMS (ES+): m/z 348 [M+H]⁺ 292.10 [M-Boc]⁺ Step-2: To a stirred solution of tert-butyl 2-(4-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7- carboxylate (3) (4 g, 11.51 mmol) in water (24.66 mL) and Ethanol (73.97 mL) was added iron powder (2.57 g, 46.06 mmol, 0.32 mL) and ammonium chloride (3.70 g, 69.08 mmol, 2.42 mL) at room temperature. The reaction mixture was stirred at 85 °C for 16 h. After completion of starting material, the reaction mixture was filtered through celite bed and washed with ethyl acetate (200 mL), concentrated under reduced pressure to afford crude. The crude was purified by column chromatography using devisal silica eluted at 50% ethyl acetate in petroleum ether to afford tert-butyl 2-(4-aminophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (4) (2.5 g, 7.64 mmol, 66.35% yield, 97% purity) as white solid. LCMS (ES+): m/z 318.27 [M+H]⁺ Step-3: To a stirred solution of tert-butyl 2-(4-aminophenyl)-2,7-diazaspiro [3.5] nonane-7- carboxylate (4) (1 g, 3.15 mmol) in DMF (4 mL) was added sodium bicarbonate (793.95 mg, 9.45 mmol) and 3-bromopiperidine-2,6-dione (5) (0.604 mg, 3.15 mmol) at 25°C. The reaction mixture was stirred under nitrogen atmosphere at 90 °C for 16 h. The reaction mixture was quenched with water and extracted using ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure to afford crude which was purified by reverse phase column to afford tert-butyl 2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-2,7-diazaspiro[3.5]nonane-7- carboxylate 6 (0.300 g, 626.85 μmol, 19.90% yield, 89.54% purity) as purple solid. LCMS (ES+): m/z 429.46 [M+H] ⁺ Step-4: To the stirred solution of tert-butyl 2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-2,7- diazaspiro[3.5]nonane-7-carboxylate (6) (0.100 g, 0.233.36 mmol) in DCM (2 mL) was added HCl炷4.0 M in 1,4-dioxane炸 (4 M, 1 mL) at 0 °C and the resulting reaction mixture was stirred for 1 hour at 25 °C. The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure afforded crude compound. The crude product was triturated in diethyl ether (20 mL) to afford 3-[4-(2,7-diazaspiro [3.5] nonan-2-yl)anilino]piperidine-2,6- dione (B-58) (0.095 g, 0.185 mmol, 79.53% yield, 71.28% purity, Hydrochloric acid) as a greenish solid. LCMS (ES+): m/z 329.44 [M+H] ⁺ Synthesis of CRBN binders based on reference literature 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (B-59) Compound 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on page 265 of WO2018237026 A1. 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (B-60) Compound 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on page 268 of WO2018237026 A1. 4-((3-(piperidin-4-yl)phenyl)amino)cyclohexane-1,3-dione (B-61) Compound 4-((3-(piperidin-4-yl)phenyl)amino)cyclohexane-1,3-dione was prepared using the method described on page 79-80 of WO2023283610 A1.

Synthesis B27: Synthesis of 3-(1-methyl-7-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6- dione (B-62) Step 1: Into a 20 mL glass vial containing a well-stirred solution of 7-bromo-1-methyl-1H-indole 1 (300 mg, 1.43 mmol) and KOH (296.48 mg, 5.28 mmol) in DMF (2 mL) was added I₂ (724.93 mg, 2.86 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for ten minutes. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with ice-cold water (20 mL) containing ammonia (0.5%) and sodium metabisulphite (0.1%). The aqueous layer was extracted twice with EtOAc (2 x 100 mL). The organic layer was washed with water (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 7-bromo-3-iodo-1-methyl-1H-indole 2 (200 mg, 0.485 mmol, 34% yield) as a brown solid. LC-MS (ES⁺): m/z 336.9 [M+H]⁺. Step 2: Into a 20 mL vial containing a well-stirred solution of 7-bromo-3-iodo-1-methyl-1H- indole 2 (500 mg, 1.19 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine 3 (496.84 mg, 1.19 mmol) in water (0.5 mL) and 1,4-dioxane (5 mL) was added sodium carbonate (378.57 mg, 3.57 mmol) at room temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas for 10 minutes. Subsequently 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (48.61 mg, 0.059 mmol) was added to the reaction mixture and the reaction mixture was heated at 90 ℃ and stirred for 16 hours. After completion of the reaction as indicated by UPLC-MS and TLC, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to get the crude material that was purified by reverse phase column chromatography [Column: Redisep Rf Gold C18-60g, mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile] to afford 3-(2,6- bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indole 4 (400 mg, 0.577 mmol, 48% yield) as a brown solid. LC-MS (ES⁺): m/z 499.0 [M+H]⁺. Step 3: Into a 20 mL glass vial containing a well-stirred solution of 3-(2,6- bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indole 4 (450 mg, 0.648 mmol) and tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 5 (300.91 mg, 0.973 mmol) in dry DMF (5 mL) was added cesium carbonate (528.47 mg, 1.62 mmol) at room temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas for three minutes. Pd(dppf)Cl₂·DCM (52.98 mg, 0.064 mmol) was added to the reaction mixture and stirred at 90 ℃ for 12 hours. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with water (50 mL) and extracted twice with EtOAc (2 x 100 mL). The combined organic phase was dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to get a crude residue, which was purified by column chromatography [Column: Redisep Rf Gold C18-100g, mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile] to afford tert-butyl 4-(3-(2,6- bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indol-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate 6 (350 mg, 0.568 mmol, 87% yield) as a brown sticky solid. LC-MS (ES⁺): m/z 602.2 [M+H]⁺. Step 4: Into a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert- butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indol-7-yl)-3,6-dihydropyridine- 1(2H)-carboxylate 6 (200 mg, 0.322 mmol) in 1,4-dioxane (2 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (226.39 mg, 0.322 mmol) at room temperature and the resultant reaction mixture was stirred under hydrogen bladder pressure at room temperature for 16 hours. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was purged with nitrogen, catalyst was removed by filtration through celite pad and washed with mixture of 1,4 dioxane (100 mL) and ethanol (100 mL). The filtrate was concentrated under reduced pressure to get crude compound which was purified by column chromatography [Column: Redisep Rf Gold C18-60g, mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile] to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indol-7-yl)piperidine-1-carboxylate 7 (30 mg, 0.069 mmol, 21% yield) as a black gummy liquid. LC-MS (ES⁺): m/z 424.1 [M-H]-. Step 5: Into a 25 mL round-bottom flask, containing a well-stirred solution of tert-butyl 4-(3- (2,6-dioxopiperidin-3-yl)-1-methyl-1H-indol-7-yl) piperidine-1-carboxylate 7 (40 mg, 0.092 mmol) in anhydrous DCM (2 mL) was added 4 M HCl in 1,4-dioxane (0.11 mL, 0.460 mmol) at 0 ℃ under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction as indicated by UPLC-MS, the solvent was removed under reduced pressure to get 3-(1-methyl-7-(piperidin-4-yl)-1H-indol-3-yl) piperidine-2,6-dione B-62 (30 mg, 0.066 mmol, 72% yield, HCl salt) as an off-white solid. LC- MS (ES⁺): m/z 326.2 [M+H]⁺.

EXAMPLE 3: SYNTHESIS OF INTERMEDIATES Synthesis C1: Synthesis of 5-(((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2- dihydrobenzo[cd]indol-6-yl)methyl)amino)-5-oxopentanoic acid (C-1) Step-1: To a cooled solution of 5-(tert-butoxy)-5-oxopentanoic acid (1 eq) in DMF (20 mL). The reaction mixture cooled at 0 °C followed by diisopropylethylamine (6 eq.) was added. After 5 minutes 3-(6-(aminomethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (1.3 eq, TFA salt) was added. After 10 minutes PyBOP (1.2 eq.) was added at 0^oc.The reaction mixture stirred at RT for 16 h. The reaction was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture quenched with ice water and extracted with ethyl acetate. The organic layer washed by brine solution and dried over with Na2So4& evaporated to afford tert- butyl 5-(((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)amino)-5- oxopentanoate. Step-2: To a cooled solution of tert-butyl 5-(((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2- dihydrobenzo[cd]indol-6-yl)methyl)amino)-5-oxopentanoate (1 eq.) and DCM (20 mL) was added trifluoro acetic acid (5 eq.). The reaction mixture stirred at 0 °C for 3 hours. The reaction mixture monitored by LCMS, after completion of the reaction the reaction mixture solvent was removed by under vacuum, then the crude was azeotroped with acetonitrile and toluene to afford 5-(((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)amino)-5- oxopentanoic acid (C-1). LCMS (ES⁺): m/z 424.2 [M+H]⁺. The following intermediates were prepared using identical or similar method as described above, with the corresponding CRBN binder and monoprotected diacid as starting materials. Alternative amide coupling (Step-1) conditions used include 1) HATU, DIPEA, DMF or 2) HOBt, EDC, DIPEA, DMF). Other deprotection (Step-2) condition used was 4 M HCl in dioxane, DCM. Synthesis C₂: Synthesis of 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)acetic acid (C-5)

Step-1: Into a 500 mL round bottom flask containing a well-stirred solution of 1-(1-methyl-6- (piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1 eq., HCl salt) in anhydrous DMF (149.91 mL) was added Triethylamine (5 eq) at 0 °C under nitrogen atmosphere. After 10 minutes, tert-butyl 2-bromoacetate (1 eq.) was added and the resulting reaction mixture was stirred at 30 °C for 16 h. After completion of the reaction as indicated by TLC, the reaction mixture was added into ice cold water (1500 ml) to form a solid. The solid was filtered, dried under vacuum to obtain tert-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)acetate. Step-2: Into a 100 mL three-necked round-bottomed flask containing a well-stirred solution of tert-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)acetate in anhydrous DCM was added Hydrogen chloride, 4M in 1,4-dioxane, 99% (4 M) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford a solid. The solid was dissolved in Water: Acetonitrile (3:1) (200 mL) and lyophilized to afford 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)acetic acid (C-5). LCMS (ES⁺): m/z 386.3 [M+H]⁺. The following intermediates were prepared using identical or similar method as described above, with the corresponding CRBN binder as starting materials. Alternative SN2 reaction (Step-1) condition used was DIPEA, DMF. Other deprotection (Step-2) condition used was TFA, DCM.

Synthesis C3: Synthesis of 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-4- oxo-butanoic acid (C-10) Step-1: To a cooled solution of 4-tert-butoxy-4-oxo-butanoic acid (0.5 g, 2.87 mmol) in DMF (20 mL). The reaction mixture cooled at 0 °C followed by diisopropylethylamine (2.23 g, 17.22 mmol, 3.00 mL) was added. After 5minutes 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (1.5 g, 3.74 mmol, TFA salt) was added. After 10 minutes PyBOP (1.79 g, 3.44 mmol) was added at 0^oc.The reaction mixture stirred at RT for 16 h. The reaction confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture quenched with ice water and extracted with ethyl acetate. The organic layer washed by brine solution and dried over with Na2So4& evaporated to afford tert-butyl 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-4- oxo-butanoate (0.8 g, 1.47 mmol, 51.09% yield, 81.31% purity). LCMS (ESI): m/z 444.58 [M+H] ⁺. Step-2: To a cooled solution of tert-butyl 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]-4-oxo-butanoate (0.8 g, 1.80 mmol) and DCM (20 mL) was added trifluoro acetic acid (1.03 g, 9.02 mmol, 694.80 μL). The reaction mixture stirred at 0 °C for 3 hours. The reaction mixture monitored by LCMS, after completion of the reaction the reaction mixture solvent was removed by under vacuum, then the crude was azeotroped with acetonitrile and toluene to afford 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-4-oxo-butanoic acid (1.0 g, 1.43 mmol, 79.27% yield, 88% purity, 062) . LCMS (ESI): m/z 388.34 [M+H] ⁺. The following intermediates were prepared using identical or similar method as described above, with the corresponding CRBN binder and monoprotected diacid as starting materials. Alternative amide coupling (Step-1) conditions used include 1) HATU, DIPEA, DMF or 2) HOBt, EDC, DIPEA, DMF). Other deprotection (Step-2) condition used was 4 M HCl in dioxane, DCM.

Synthesis C₂: Synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]acetic acid (C-18) Step-1: Into a 500 mL round bottom flask containing a well-stirred solution of 3-[4-(4- piperidyl)anilino]piperidine-2,6-dione (24.5 g, 85.26 mmol, HCl salt) in anhydrous DMF (149.91 mL) was added triethylamine (43.14 g, 426.30 mmol, 59.42 mL) at 0 ℃ under nitrogen atmosphere. After 10 minutes, tert-butyl 2-bromoacetate (16.63 g, 85.26 mmol, 12.50 mL) was added and the resulting reaction mixture was stirred at 30 ℃ for 16 hours. After completion of the reaction as indicated by TLC, the reaction mixture was added into ice cold water (1500 ml) to form a solid. The solid was filtered, dried under vacuum to obtain tert-butyl-2-[4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (20.5 g, 50.55 mmol, 59.29% yield, 99% purity, No Salt) tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (20.5 g, 50.55 mmol, 59.29% yield, 99% purity, No Salt) LCMS (ESI): m/z 402.2 [M+ H]⁺ Step-2: Into a 100 mL three-necked round-bottomed flask containing a well-stirred solution of tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (21 g, 51.78 mmol, No Salt) in anhydrous DCM (100 mL) was added Hydrogen chloride, 4M in 1,4-dioxane, 99% (4 M, 129.45 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford a solid. The solid was dissolved in Water: Acetonitrile (3:1) (200 mL) and lyophilized to afford 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetic acid (21.89 g, 51.78 mmol, quantitative yield, 98.95% purity, hydrochloric acid*2) as an off white solid. LCMS (ESI): m/z 346.2 [M+H]⁺ The following intermediates were prepared using identical or similar method as described above, with the corresponding CRBN binder as starting materials. Alternative S_N2 reaction (Step-1) condition used was DIPEA, DMF. Other deprotection (Step-2) condition used was TFA, DCM.

Synthesis C4: Synthesis of 2-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-4-piperidyl]acetic acid (C-28) OBn OBn N N HN O BnO Pd(OH)₂/C BnO O dioxane, H N ₂ N Pd₂(dba)₃, XPhos O Step-2 O Cs₂CO₃, dioxane _{O N} ^N _Br ^N Step-1 O O O HN HN O O TFA, DCM N N O Step-3 O O_N ^N _{O N} ^N O HO Step-1: Into a 20 mL screw capped vial, a well-stirred solution of 5-bromo-1-(2,6-dibenzyloxy- 3-pyridyl)-3-methyl-benzimidazol-2-one (0.5 g, 968.27 μmol) and tert-butyl 2-(4- piperidyl)acetate (578.90 mg, 2.90 mmol) in anhydrous Dioxane (8 mL) was added Cs2CO3 (946.44 mg, 2.90 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 10 minutes. Subsequently, XPhos (92.32 mg, 193.65 μmol) was added to the reaction mixture and was degassed by bubbling nitrogen gas for 2-3 min and later was added Pd2(dba)3 (88.67 mg, 96.83 μmol) and degassed for another 2-3 min and reaction mixture was heated to 90 °C. The reaction mixture was monitored for 16 h by UPLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to afford a crude. The crude was purified using C18 reverse phase 50 gm column in 0.1% ammonium bicarbonate in water/ Acetonitrile the desired compound was collected in 70-90% and was eluted in acetonitrile. The desired compound was lyophilized to afford a product tert-butyl 2-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-5-yl]-4-piperidyl]acetate (0.23 g, 260.89 μmol, 26.94% yield, 72% purity, No Salt) as brown solid. LCMS (ESI) m/z: 635.2 [M+H]+. Step-2: Into a 25 mL single-necked round-bottomed flask containing a well-stirred suspension of tert-butyl 2-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4- piperidyl]acetate (0.22 g, 346.59 μmol) in Dioxane (6 mL) was added Pd(OH)₂炷20% on Carbon (wetted with ca.55% Water)炸 (243.36 mg, 1.73 mmol) at ambient temperature under nitrogen atmosphere. The resulting suspension was stirred at ambient temperature under hydrogen atmosphere (bladder) for 16 h. After complete consumption of the starting material as indicated by TLC and UPLC, reaction mixture was filtered through a pad of Celite and Celite bed was washed with 1,4-dioxane (50 mL) and 1:1 EtOAc/THF (100 mL). Combined filtrate was concentrated under reduced pressure to afford a crude. The crude was purified using C18 reverse phase 30g column using 0.1% ammonium bicarbonate in H₂O/Acetonitrile the desired compound was collected in 40-60 % and was lyophilized to afford desired compound as tert- butyl 2-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]acetate (0.07 g, 146.43 μmol, 42.25% yield, 95.5% purity, No Salt). LCMS (ESI) m/z:457.2 [M+H]⁺. Step-3: Into a 50 mL round bottomed flask containing well-stirred solution of tert-butyl 2-[1-[1- (2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]acetate (0.1 g, 219.04 μmol) in anhydrous DCM (3 mL) as added TFA (199.81 mg, 1.75 mmol, 134.10 μL) was added dropwise manner at 0^oC under nitrogen atmosphere and the reaction was allowed to stir for 3 hours at 0^oC to room temperature. After completion of reaction, the reaction mixture was concentrated under reduced pressure and was triturated 2-3 times with DCM and toluene to afford 2-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]acetic acid (C-28) (0.095 g, 181.32 μmol, 82.78% yield, 98.19% purity, Trifluoroacetic acid) as crude yellow fluid. LCMS (ESI): m/z 401.0 [M+H]⁺. The following intermediates were prepared using identical or similar method as described above, with the corresponding bis benzyloxy pyridine as starting material. Alternative deprotection (Step-3) condition used was 4M HCl in dioxane, DCM. Synthesis C5: Synthesis of 2-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-4-piperidyl]acetic acid (C-30) Step-1: To a stirred solution of 4-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol- 2-one (2 g, 3.87 mmol, No Salt) and ethyl 2-(4-piperidyl)acetate (1.99 g, 11.62 mmol, No Salt) in toluene (30 mL) was added Sodium tert-butoxide (1.12 g, 11.62 mmol, 1.09 mL)t 25°C under nitrogen purging, RuPhos (361.46 mg, 774.62 μmol) and (1E,4E)-1,5-diphenylpenta-1,4-dien- 3-one;palladium (354.66 mg, 387.31 μmol) was added. Then reaction mixture was heated to 90°C for 16 hours. After complete consumption of the starting material, the reaction mixture diluted with ethyl acetate, washed with water and brine solution. Collected organic layer was dried over with sodium sulphate filtered, which was concentrated under reduced pressure to afford crude compound. which was purified by flash column chromatography using 230-400 silica gel, eluted with 30-40% ethyl acetate in petroleum ether to ethyl 2-[1-[1-(2,6-dibenzyloxy- 3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]acetate (1.6 g, 572.27 μmol, 14.78% yield, 21.7% purity, No Salt) as a solid. LCMS (ES+): m/z 607.36 [M+H]⁺ Step-2: To a stirred solution of ethyl 2-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-4-yl]-4-piperidyl]acetate (1.5 g, 2.47 mmol, No Salt) in THF (10 mL)was added Lithium hydroxide monohydrate, 98% (414.99 mg, 9.89 mmol) at 0°C and the reacion mixture was allowed to stirred for 25°C for 16h . After complete consumption of the starting material, the reaction mixture was acidified with citric acid and extracted with ethyl acetate. Collected organic layer was dried over sodium sulphate filtered and concentrated under reduced pressure, to 2-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]acetic acid (0.5 g, 765.39 μmol, 30.96% yield, 88.58% purity, No Salt) as a solid. LCMS (ES+): m/z 579.73 [M+H]⁺ Step-3: To a stirred solution of 2-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-4-yl]-4-piperidyl]acetic acid (0.2 g, 345.63 μmol, No Salt) in Ethyl Acetate (10 mL) and THF (10 mL) was added Palladium, 10% on carbon, Type 487, dry (183.91 mg, 1.73 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred in hydrogen atmosphere under balloon pressure for 16 h. Subsequently, it was filtered through celite bed and washed with ethyl acetate (25 mL). The filtrate was concentrated under reduced pressure to afford 2-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4- piperidyl]acetic acid (C-30) (0.07 g, 169.60 μmol, 49.07% yield, 97.02% purity, No Salt) as colorless gel, which was used for next step without further purification. LCMS (ES+): m/z 401.41 [M+H] ⁺ Synthesis C6: Synthesis of 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)cyclohexyl)acetic acid (C-31) Step-1: To a stirred solution of ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclohex-3-en-1-yl]acetate (2) (478.56 mg, 1.63 mmol) and 5-bromo-1-(2,6-dibenzyloxy-3- pyridyl)-3-methyl-benzimidazol-2-one (1) (0.700 g, 1.36 mmol) in 1,4-Dioxane (10 mL) and Water (2 mL), was added Sodium carbonate (431.03 mg, 4.07 mmol, 170.23 μL) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes before adding Pd(dppf)Cl2 (99.19 mg, 135.56 μmol) and reaction stirred at 100 °C for 16 h. Subsequently, the reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by column chromatography using Davisil silica in 20% ethyl acetate in petroleum ether as eluent to ethyl 2-(4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)cyclohex-3-en-1-yl)acetate (3) (0.550 g, 754.07 μmol, 55.63% yield, 82.77% purity ) as light brown gum. LCMS (ES+): m/z 604.41[M+H] ⁺ Step-2: To a stirred solution of ethyl 2-(4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)cyclohex-3-en-1-yl)acetate (3) (500 mg, 824.12 μmol, No Salt) in Water (5 mL) and THF (20 mL), was added LiOH (78.94 mg, 3.30 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 3hr. After completion the reaction mixture was concentrated under reduced pressure to afford crude residue which was diluted with water (20 mL) and acidified with 4 N HCl and extracted with EtOAC (50 mL), the EtOAC layer was dried over anhydrous sodium sulphate, concentrated under reduced pressure to afford 2-[4- [1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]cyclohex-3-en-1-yl]acetic acid (4) (0.4 g, 459.03 μmol, 55.70% yield, 66.06% purity,) as a gummy. LCMS: m/z 576.44 [M+H] ⁺ Step-3: To a stirred solution of 2-(4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)cyclohex-3-en-1-yl)acetic acid (4) (0.05 g, 86.86 μmol ) in Ethyl acetate (20 mL) and THF (20 mL) then degassed with nitrogen for 10 minutes was added Pd/c (100 mg, 939.67 μmol) at room temperature. The reaction mixture was stirred under hydrogen atmosphere using balloon pressure for 16 h. after completion of starting material the reaction mixture was filtered through celite bed and washed with Ethyl acetate (100 mL).The filtrate was concentrated under reduced pressure to afford the crude product, which was triturated with diethyl ether (20 mL) to afford 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)cyclohexyl)acetic acid C-31 (0.008 g, 17.71 μmol, 20.40% yield, 88.45% purity) as an Off-white solid. LCMS (ESI): m/z 400.42 [M+H]⁺. The following intermediate was prepared substantially following the method described above, using the corresponding bis benzyloxy pyridine as starting material.

Synthesis C7: Synthesis of 3-[3-methyl-2-oxo-5-[1-(4-piperidyl)-4-piperidyl]benzimidazol- 1-yl]piperidine-2,6-dione (C-33) Step-1: Into a 25 mL RB, containing a well stirred solution of 3-[3-methyl-2-oxo-5-(4- piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (200 mg, 516.95 μmol) and tert-butyl 4- oxopiperidine-1-carboxylate (154.50 mg, 775.43 μmol) in DMSO (534.45 μL) was added acetic acid (310.44 mg, 5.17 mmol, 295.94 μL) and Sodium acetate (169.63 mg, 2.07 mmol, 169.63 μL) at ambient temperature . Resulting reaction mixture was allowed to stirred for 3 hours at room temperature under nitrogen atmosphere, then into the reaction mixture was added mp cyanoborohydride (100 mg) and allowed the reaction to stir over night. Progress of reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was concentrated under vacuum. The crude residue was dissolved with water , the aqueous layer was extracted twice with ethyl acetate and washed with brine followed by saturated bicarbonate solution and dried over sodium sulphate, filtered and the filtrate was concentrated under vacuum to afford crude tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]piperidine-1-carboxylate (200 mg, 304.39 μmol, 58.88% yield, 80% purity, No Salt) as a brown solid. LCMS (ESI): m/z 526.2 [M+H]⁺. Step-2: Into a 100 mL round bottom flask, containing a well-stirred solution of tert-butyl 4-[4- [1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]piperidine-1- carboxylate (200 mg, 304.39 μmol) in anhydrous DCM (3.31 mL) was added HCl炷4.0 M in 1,4-dioxane炸 (4 M, 760.98 μL) HCl炷4.0 M in 1,4-dioxane炸 (4 M, 760.98 μL) at 0 °C under N2 atmosphere. The resulting mixture was stirred for 1hr at room temperature. Progress of the reaction was monitored by UPLC-MS. After completion of the reaction solvents were evaporated under reduced pressure to afford 3-[3-methyl-2-oxo-5-[1-(4-piperidyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-33) (120 mg, 215.59 μmol, 70.83% yield, 83% purity, Hydrochloric acid) as a brown fluffy solid. LCMS (ESI): m/z 426.2 [M+H]⁺. The following intermediate was prepared using identical or similar method as described above, with the corresponding CRBN binder and ketone as starting materials. Alternative reductive amination (Step-1) condition was TEA, STAB, THF. Other deprotection (Step-2) condition was TFA, DCM. The following intermediates are prepared using identical or similar method as described above, with the corresponding CRBN binder and ketone as starting materials. Alternative reductive amination (Step-1) condition is TEA, STAB, THF. Other deprotection (Step-2) condition is TFA, DCM.

Synthesis C8: Synthesis of 3-[3-methyl-2-oxo-5-[1-(4-piperidylmethyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-42) Step-1: To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (0.2 g, 584.13 μmol) and tert-butyl 4-formylpiperidine-1-carboxylate (124.58 mg, 584.13 μmol) in DCE (2 mL) and Methanol (2 mL) at RT was added Sodium acetate (191.67 mg, 2.34 mmol, 125.44 μL) and Acetic acid (35.08 mg, 584.13 μmol) at 0 °C. The reaction mixture was stirred at RT for 13 hours. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with water and extracted with DCM and washed with brine the organic layer was dried over sodium sulfate, filtered and then evaporated under reduced pressure to afford Crude which was purified by combi-flash column chromatography to afford tert-butyl 4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]methyl]piperidine-1-carboxylate (0.107 g, 174.28 μmol, 29.84% yield, 87.90% purity). LCMS (ESI): m/z 540.43 [M+H]⁺. Step-2: To the stirred solution of tert-butyl 4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]methyl]piperidine-1-carboxylate (50 mg, 92.65 μmol, No Salt) in DCM (1 mL) was added HCl (4.0 M in 1,4-dioxane ) (4 M, 0.5 mL) at 0°C and the resulting reaction mixture was stirred for 3 hours at 25 °C . The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain crude compound. The crude product was triturated in diethyl ether (5 mL). Diethyl ether layer was decanted and dried under reduced pressure to afford 3-[3-methyl-2-oxo-5-[1-(4-piperidylmethyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-42) (40 mg, 80.67 μmol, 87.07% yield, 96% purity, Hydrochloric acid) as off white solid. LCMS (ESI): m/z 440.62 [M+H]⁺. The following intermediates were prepared using identical or similar method as described above, with the corresponding CRBN binder and aldehyde as starting materials. Alternative reductive amination (Step-1) conditions were 1) TEA, AcOH, NaBH₃CN, DMAc or 2) TEA, STAB, THF. Other deprotection (Step-2) condition was TFA, DCM.

The following intermediates are prepared using identical or similar method as described above, with the corresponding CRBN binder and aldehyde as starting materials. Alternative reductive amination (Step-1) conditions are 1) TEA, AcOH, NaBH₃CN, DMAc or 2) TEA, STAB, THF. Other deprotection (Step-2) condition was or is TFA, DCM.

Synthesis C9: Synthetic schemes for intermediates C-67 to C-70:

Synthesis C10: Synthesis of 3-[4-[1-[2-(4-piperidyl)ethyl]-4-piperidyl]anilino]piperidine- 2,6-dione (C-71) Step-1: To a stirred solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (0.5 g, 1.25 mmol, Trifluoroacetic acid) in THF (3 mL) was added TEA (378.15 mg, 3.74 mmol, 520.87 μL) at 25 °C then added tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (283.15 mg, 1.25 mmol, No Salt) portion wise at 25 °C. The reaction mixture was stirred under nitrogen atmosphere at 25°C for 16 h then added STAB (264.02 mg, 1.25 mmol) at 0°C.The progress of reaction was monitored by TLC/LCMS. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate (200 ml) and filtered through celite bed. Then added water and extracted product using ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure, which was column purified using (davisil silica) with 10% Methanol in DCM as an eluent to afford tert-butyl 4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]ethyl]piperidine-1-carboxylate (0.38 g, 679.67 μmol, 54.56% yield, 89.19% purity) as a pale green solid. LCMS (ESI): m/z 499.40 [M+H] ⁺ Step-2: To the stirred solution of tert-butyl 4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]ethyl]piperidine-1-carboxylate (100 mg, 200.54 μmol, No Salt) in DCM (1 mL) was added Hydrogen chloride 4.0M 1,4-dioxane (4 M, 1 mL) at 0°C and the reaction was stirred for 2 hours at 25 C .The reaction progress was monitored by TLC and LCMS. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure to afford crude product. The crude product was triturated with diethyl ether (30 ml) to afford 3-[4-[1-[2-(4-piperidyl)ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (C-71) (100 mg, 197.70 μmol, 98.58% yield, 86% purity, Hydrochloric acid) as an off-white solid. LCMS (ESI): m/z 399.36 [M+H] ⁺ The following intermediate was prepared using identical or similar method as described above, with the corresponding CRBN binder and aldehyde as starting materials. Alternative reductive amination (Step-1) conditions were 1) NaOAc, AcOH, Si-CBH, MeOH, DCE; 2) NaBH3CN, AcOH The following intermediates are prepared using identical or similar method as described above, with the corresponding CRBN binder and aldehyde as starting materials. Alternative reductive amination (Step-1) conditions are 1) NaOAc, AcOH, Si-CBH, MeOH, DCE; 2) NaBH3CN, AcOH

Synthesis C11: Synthesis of afford 3-[3-methyl-2-oxo-5-[1-(2-piperazin-1-ylethyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-84) Step-1: Into a 20 mL vial containing a well-stirred solution of tert-butyl 4-(2- bromoethyl)piperazine-1-carboxylate (300 mg, 818.55 μmol) were added, DIPEA (317.37 mg, 2.46 mmol, 427.72 μL) , 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6- dione (350.33 mg, 818.55 μmol) at 70°C and stirred at ambient temperature for 16 h. After completion of the reaction indicated by UPLC, the reaction mixture was diluted with water (20 mL) and the product was extracted with ethyl acetate (2 x 40 mL). Combined organic phases were washed with cold water (30 mL), dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure to afford a crude tert-butyl 4-[2-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethyl]piperazine-1-carboxylate (330 mg, 279.62 μmol, 34.16% yield, 47% purity, No Salt) as light brown sticky solid. LC-MS (ESI): m/z 555.4 [M+H]⁺. Step-2: Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl 4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-3H-benzimidazol-5-yl]-1- piperidyl]ethyl]piperazine-1-carboxylate (200 mg, 173.86 μmol) in anhydrous DCM (9.56 mL) was added 4.0 M HCl in 1,4-dioxane (434.66 μL) at 0°C under nitrogen atmosphere. The contents were stirred for 16 h at ambient temperature. After consumption of the starting material as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure to afford a crude mass. The crude product was washed with MTBE (10 mL) to afford 3-[3-methyl-2-oxo-5-[1-(2-piperazin-1-ylethyl)-4-piperidyl]benzimidazol-1-yl]piperidine-2,6- dione (C-84) (70 mg, 150.91 μmol, 86.80% yield, 98% purity) as a grey solid. LCMS (ESI): m/z 455.3 [M+H]⁺. The following intermediates were prepared substantially following the method described above, using the corresponding CRBN binder and bromide as starting materials. Synthesis C12: Synthesis of 3-[3-methyl-2-oxo-5-[1-(piperazine-1-carbonyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-87)

Step-1: Into a 20mL vial containing a well stirred solution of 3-[3-methyl-2-oxo-5-(4- piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (250 mg, 730.16 μmol) in DCM (4.24 mL) and DMA (1mL) were added TEA (369.42 mg, 3.65 mmol, 508.85 μL) and 4-nitrophenyl) carbonochloridate (17.66 mg, 87.62 μmol) at 0°C.The reaction mixture was stirred at room temperature for 16 h. Thereafter, the mixture was diluted water (150 mL) and extracted with DCM (2 X 70 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude was co-distilled with Toluene (7 mL) and washed with MTBE (10mL) to afford (4-nitrophenyl) 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2- oxo-benzimidazol-5-yl]piperidine-1-carboxylate (200 mg, 326.27 μmol, 44.68% yield, 82.79% purity, No Salt) as a pale yellow solid. LC-MS (ESI):m/z 508.2 [M+H]⁺. Step-2: Into a 20mL vial containing a well stirred solution of (4-nitrophenyl) 4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (200 mg, 346.80 μmol) in DMF (4 mL) was added DIPEA (224.10 mg, 1.73 mmol, 302.03 μL) and tert-butyl piperazine- 1-carboxylate (71.05 mg, 381.48 μmol) The reaction mixture was stirred at 90°C for 4 hours. The reaction was monitored by UPLC/TLC. The solvent was removed from the reaction mixture to afford crude was purified by reverse phase [Redisef-RF C18 column 120g, mobile phase: 0.1% HCOOH in water : MeCN] to afford tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl- 2-oxo-benzimidazol-5-yl]piperidine-1-carbonyl]piperazine-1-carboxylate (140 mg, 252.42 μmol, 72.78% yield, No Salt) a pale yellow solid. LCMS (ESI): m/z 455.2 [M-Boc+H]^{+ .} Step-3: Into a 50 mL single-necked round-bottomed flask containing a well stirred solution of tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1- carbonyl]piperazine-1-carboxylate (120 mg, 214.19 μmol) in DIOXNE (3.46 mL) was added HCl炷4.0 M in 1,4-dioxane炸 (4 M, 535.49 μL) under at 0°C and the resultant solution was stirred at room temperature for 2h, monitored by LCMS. Thereafter, the reaction mixture was concentrated under reduced pressure get the residue and triturated with MTBE (5mL) to afford 3-[3-methyl-2-oxo-5-[1-(piperazine-1-carbonyl)-4-piperidyl]benzimidazol-1-yl]piperidine-2,6- dione (C-87) (100 mg, 203.51 μmol, 95.01% yield, 99.92% purity, Hydrochloric acid) as a pale yellow solid. LCMS (ESI): m/z 455.2 [M+H]⁺. Synthesis C13: Synthesis of 3-[4-[1-(piperazine-1-carbonyl)-4- piperidyl]anilino]piperidine-2,6-dione (C-88) Step-1: To a stirred solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (250 mg, 870.00 μmol) in DCM was added triphosgene (258.17 mg, 870.00 μmol) and DIPEA (449.76 mg, 3.48 mmol, 606.15 μL) and the reaction mixture was stirred for 1 hour at 0 °C. 1-Boc-piperazine (162.04 mg, 870.00 μmol) was added and the reaction mixture was stirred for 16 h at room temperature. The progress of the reaction was monitored by LCMS. On completion, the solvent was evaporated in vacuo and the residue was purified by column chromatography using 5% methanol in DCM as eluent to provide tert-butyl 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperidine-1-carbonyl]piperazine-1-carboxylate (180 mg, 347.43 μmol, 39.93% yield, 96.43% purity) as off white solid. LCMS (ESI): m/z 498.39 [M-H]-. Step-2: To a stirred solution of tert-butyl 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperidine-1-carbonyl]piperazine-1-carboxylate (100 mg, 200.16 μmol) in DCM (2 mL) was added 4.0 M HCl in 1,4-dioxane (0.5 mL) dropwise at 0°C under nitrogen atmosphere. The reaction mixture was stirred at RT for 1h. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure to afford crude, which was triturated with diethyl ether (3 mL x 2) to afford 3- [4-[1-(piperazine-1-carbonyl)-4-piperidyl]anilino]piperidine-2,6-dione (C-88) (90 mg, 176.16 μmol, 88.01% yield, 85.33% purity, Hydrochloric acid) as a off white solid. LCMS (ESI): m/z 400.49 [M+H]⁺. Synthesis C14: Synthesis of 3-[3-methyl-2-oxo-5-[1-(2-piperazin-1-ylacetyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-89) Step-1: To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (0.250 g, 547.75 μmol, Trifluoroacetic acid) and 2-(4-tert-butoxycarbonylpiperazin- 1-yl)acetic acid (93.67 mg, 383.42 μmol) in DMF (5 mL) was added DIPEA (176.98 mg, 1.37 mmol, 238.52 μL) at 0 °C and stirred it for 0°C to rt for 10 minutes. then added HATU (312.40 mg, 821.62 μmol) and continue the stirring at RT for 2 hours. The progress of the reaction was monitored by LCMS and TLC. After completion the reaction mixture was directly evaporated under reduced pressure to afford Crude which was purified by Prep- HPLC purification to afford tert-butyl 4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]- 2-oxo-ethyl]piperazine-1-carboxylate (0.18 g, 305.93 μmol, 55.85% yield, 96.65% purity) as a white solid. LCMS (ES+): m/z 569.47 [M+H]⁺. Step-2: To the stirred solution of tert-butyl 4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-2-oxo-ethyl]piperazine-1-carboxylate (100 mg, 175.85 μmol, No Salt) in DCM (1 mL) was added 4.0 M HCl in 1,4-dioxane (1 mL) at 0°C and the resulting reaction mixture was stirred for 1 hour at 25 °C . The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtained crude compound. The crude product was triturated in diethyl ether (5 mL). Diethyl ether layer was decanted and dried under reduced pressure to afford 3-[3-methyl-2-oxo-5-[1-(2-piperazin-1-ylacetyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-89) (90 mg, 168.23 μmol, 95.67% yield, 94.40% purity, Hydrochloric acid) as off white solid. LCMS (ES+): m/z 469.32 [M+H]⁺. The following intermediates were prepared using identical or similar method as described above, with the corresponding CRBN binder and carboxylic acid as starting material. Alternative amide coupling (Step-1) conditions included 1) triphosgene, DIPEA, MeCN, DCM. Other deprotection (Step-2) condition used was TFA, DCM. Synthesis C15: Synthesis of 3-[3-methyl-5-[1-[2-(methylamino)ethyl]-4-piperidyl]-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (C-95) Step-1: Into a 20 ml glass containing a solution of tert-butyl N-methyl-N-(2-oxoethyl)carbamate (116.86 mg, 674.67 μmol) and 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (200mg, 449.78 μmol) in anhydrous DMSO (2 mL) were added Sodium acetate, anhydrous (110.69 mg, 1.35 mmol, 72.44 μL) and Acetic acid (270.10 mg, 4.50 mmol, 259.71 μL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 hours at room temperature. After that, MP-Cyanoborohydride; 2mmol/g (250 mg, 899.56 μmol) was added to the resultant reaction mixture and stirring was continued for 16 hours at 70°C temperature. After the completion of reaction as per UPLC, the reaction mixture was filtered through celite bed and filtrate was concentrated under reduced pressure to afford the crude purified column chromatography [Purification method: Column : RediSep C 18-30g, Mobile phase: A: 0.1% Ammonium bicarbonate in water, B:Acetonitrile fractions were lyophilized to afford tert-butyl N-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]ethyl]-N-methyl-carbamate (80 mg, 150.52 μmol, 33.47% yield, 94% purity) as an off- white solid. LCMS (ESI): m/z 500.2 [M+H]⁺. Step-2: Into a 25 mL round bottom flask, containing a well-stirred solution of tert-butyl N-[2-[4- [1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethyl]-N-methyl- carbamate (80 mg, 150.52 μmol) in anhydrous DCM (1.78 mL) was added 4M hydrogen chloride in 1,4-dioxane, 99% (376.30 μL) at 0 °C under N2 atmosphere. The resulting mixture was stirred for 1 h at room temperature. After completion of the reaction solvents were evaporated under reduced pressure to afford the crude 3-[3-methyl-5-[1-[2-(methylamino)ethyl]-4-piperidyl]-2- oxo-benzimidazol-1-yl]piperidine-2,6-dione (C-95) (50 mg, 107.81 μmol, 71.63% yield, 94% purity, Hydrochloric acid) as an off-white fluffy solid. LCMS (ESI): m/z 400.3 [M+H]⁺. The following intermediates were prepared using identical or similar method as described above, with the corresponding CRBN binder and aldehyde as starting material. Alternative reductive amination (Step-1) condition includes NaOAc, AcOH, Si-CBH, DCE, MeOH.

Synthesis C16: Synthesis of 3-[3-methyl-5-[1-[5-(methylamino)pentyl]-4-piperidyl]-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (C-101)

Step-1: To a stirred solution of tert-butyl N-(5-hydroxypentyl)-N-methyl-carbamate (0.5 g, 2.30 mmol, No Salt) in DCM (15 mL) was added dropwise TEA (465.66 mg, 4.60 mmol, 641.41 μL) and methanesulfonyl chloride (316.29 mg, 2.76 mmol, 214.14 μL, No Salt) at 0 °C under N2 atmosphere.The reaction mixture was stirred atroom temperature for 4 hours. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 15 mL). The combined organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product 5-[tert-butoxycarbonyl(methyl)amino]pentyl methanesulfonate (0.55 g, 1.58 mmol, 68.78% yield, 85% purity, No Salt) as a yellow gummy solid. Step-2: To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (0.5 g, 1.46 mmol, No Salt) in ACN (10 mL) was added DIPEA (943.67 mg, 7.30 mmol, 1.27 mL) at 25 °C then added 5-[tert-butoxycarbonyl(methyl)amino]pentyl methanesulfonate (560.78 mg, 1.90 mmol, No Salt) portion wise at 25 °C. The reaction mixture was stirred under nitrogen atmosphere. The reaction mixture was stirred at 70°C for 16 h. The progress of reaction was monitored by TLC and LCMS. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed with water and brine. Collected organic layer was dried over with sodium sulphate, filtered and then concentrated under reduced pressure to afford crude compound. which was purified by column chromatography using (Davisil silica) with 70% Ethyl acetate in Petroleum ether as an eluent to afford tert-butyl N-[5-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]pentyl]-N-methyl-carbamate (0.15 g, 238.15 μmol, 16.31% yield, 86% purity, No Salt) as an off white solid. LCMS (ES+): m/z 542.52 [M+H]⁺. Step-3: To the stirred solution of tert-butyl N-[5-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]pentyl]-N-methyl-carbamate (50 mg, 92.31 μmol, No Salt)in DCM (1 mL) was added 4.0 M HCl in 1,4-dioxane (500.00 μL) at 0°C and the resulting reaction mixture was stirred for 1 h at 25 °C . The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain crude compound. The crude product was triturated in diethyl ether (5 mL). Diethyl ether layer was decanted and dried under reduced pressure to afford 3-[3-methyl-5-[1-[5-(methylamino)pentyl]-4-piperidyl]-2-oxo-benzimidazol- 1-yl]piperidine-2,6-dione (C-101) (50 mg, 65.76 μmol, 71.24% yield, 62.87% purity, Hydrochloric acid) as an off white solid. LCMS (ES+): m/z 442.48 [M+H]⁺. The following intermediate was prepared substantially following the method as described above, using the corresponding CRBN binder and alcohol as starting material. Synthesis C17: Synthesis of 3-(2-oxo-5-(1-(2-(piperazin-1-yl)ethyl)piperidin-4- yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (C-103) Step 1: Into a 50 mL two-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate 1 (1 g, 4.34 mmol) in DCM (20 mL) was added triphenylphosphine (1.71 g, 6.51 mmol) and carbon tetrabromide (2.16 g, 6.51 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by TLC, the reaction mixture was quenched by adding aqueous NaOH solution (10 mL). The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure to afford the crude material that was purified by a flash silica-gel (230-400 mesh 50 g SNAP) column with 0-100% EtOAc/petroleum ether while desired compound eluting at 30% to afford tert-butyl 4-(2- bromoethyl)piperazine-1-carboxylate 2 (500 mg, 1.71 mmol, 39% yield) as a white solid. LC- MS (ES⁺): m/z 213.2 [M+H]⁺. Step 2: Into a 20 mL screw-capped vial containing a well-stirred solution of 3-(2-oxo-5- (piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione B-6 (100 mg, 0.272 mmol) in anhydrous DMF (2 mL) were added DIPEA (0.23 mL, 1.36 mmol) and tert-butyl 4-(2- bromoethyl)piperazine-1-carboxylate 2 (119.81 mg, 0.408 mmol). The resultant reaction mixture was stirred at 110 °C for 4 hours. After completion of the reaction as indicated by UPLC- MS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude residue that was purified by a reverse-phase column chromatography [Column: Redisep RF gold C18-60 g; Mobile phase A: 0.1% Ammonium bicarbonate in Water and Mobile Phase B: Acetonitrile] to afford tert-butyl 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-2- oxo-1,2-dihydrobenzo[cd]indol-5-yl)piperidin-1-yl)ethyl)piperazine-1-carboxylate 3 (80 mg, 0.129 mmol, 47% yield) as an off-white solid. LC-MS (ES⁺): m/z 576.3 [M+H]⁺. Step 3: Into a 10 mL single-neck round-bottom flask containing a well-stirred solution of tert- butyl 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)piperidin-1- yl)ethyl)piperazine-1-carboxylate 4 (80 mg, 0.129 mmol) in anhydrous DCM (2 mL) was added 4 M HCl in 1,4-dioxane (0.32 mL, 1.29 mmol) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude material was triturated with MTBE (10 mL) to afford 3-(2-oxo-5-(1-(2-(piperazin-1-yl) ethyl)piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione C-103 (80 mg, 0.122 mmol, 95% yield, HCl salt) as an off-white solid. LC-MS (ES⁺): m/z 476.3 [M+H]⁺. Synthesis C18: Synthesis of 3-(7-([1,4'-bipiperidin]-4-yl)-1-methyl-1H-indol-3- yl)piperidine-2,6-dione (C-104) Step 1: Into a 8 mL vial containing a well-stirred solution of tert-butyl 4-oxopiperidine-1- carboxylate 1 (29.63 mg, 0.148 mmol) and 3-(1-methyl-7-(piperidin-4-yl)-1H-indol-3- yl)piperidine-2,6-dione 2 (40.33 mg, 0.099 mmol) in dry DMSO (1.5 mL) were added sodium acetate, anhydrous (65.06 mg, 0.793 mmol) followed by acetic acid (8.93 mg, 0.148 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. MP-cyanoborohydride 2.0 mmol/g (80 mg, 0.16 mmol) was added to the reaction mixture and stirred at 70 °C for 3 hours. After completion of the reaction as indicated by LC-MS, the reaction mixture was filtered through Celite bed and washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure to get crude compound that was purified by reverse phase column chromatography [Column: Redisep Rf Gold C18- 60g, Mobile phase A: 0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile] to afford tert- butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indol-7-yl)-[1,4'-bipiperidine]-1'-carboxylate 3 (30 mg, 0.058 mmol, 59% yield) as an off-white solid. LC-MS (ES⁺): m/z 509.9 [M+H] ⁺. Step 2: Into a 25 mL round-bottom flask, containing a well-stirred solution of tert-butyl 4-(3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indol-7-yl)-[1,4'-bipiperidine]-1'-carboxylate 3 (40 mg, 0.077 mmol) in anhydrous DCM (2 mL) was added 4M HCl in 1,4-dioxane ( 0.097 mL, 0.389 mmol) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction as indicated by UPLC-MS, the solvent was removed under reduced pressure to get 3-(7-([1,4'-bipiperidin]-4-yl)-1-methyl-1H- indol-3-yl)piperidine-2,6-dione C-104 (25 mg, 0.055 mmol, 71% yield; HCl salt) as an off- white solid. LC-MS (ES⁺): m/z 409.2 [M+H] ⁺. EXAMPLE 4: SYNTHESIS OF DEGRADER COMPOUNDS Synthesis 1: Synthesis of N1-(2-((S)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-N10-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2- dihydrobenzo[cd]indol-6-yl)methyl)decanediamide (Compound 1) and N¹-(2-((S)-2-(((4- ((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-N¹²-((1-(2,6- dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)dodecanediamide (Compound 2):

CRBN acid intermediates used General protocol for Amides (Step 1). Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl 3-[2-[[(2S)-1-(2-aminoethyl)pyrrolidin-2-yl]methoxy]-7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (A-1; Scaffold amine; 1.0 eq.) and carboxylic acid (C- 3 or C-4; 1-1.2 eq) in anhydrous DMF (6 mL/mmol) were added HATU (1.2 eq.) and DIPEA (5 eq.) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred for 1- 2 hours. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by reversed-phase column chromatography following a method: C18 Redisep Rf Gold (30g HP C18) ; Mobile phase A : 0.1% ammonium bicarbonate in MQ-water and B: acetonitrile; Flow rate: 10 mL/minutes while the desired compound was eluting at ~ 50% of the mobile phase to give the amides (Compound 1A or Compound 2A; Table 3). Table 3. Amides from Acid-amine coupling (Step 1)

General protocol for Both Boc & MOM deprotection of Compound 1A and 2A (Step-2) Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of Compound 1A or 2A (1.0 eq.) in anhydrous DCM (10 mL/0.1 mmol) was added 4N HCl in 1,4- dioxane (10.0 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 hour. After completion of the starting material as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure to afford a crude residue. The crude residue was purified by two methods – Method A: reverse phase preparatory HPLC [Purification method: [Column: XBRIDGE C8(150x19) mm, 5 microns; Mobile phase: A:10mM NH4HCO3 in MQ-water; B: Acetonitrile Method B: reverse phase preparatory HPLC [Purification method: X-Select C18(250x19) 5micron; Mobile phase A: 0.1% FORMIC ACID in MQ Water and Mobile phase B: Acetonitrile; to afford Compound 1 or 2 (Table 4). Table 4. Both Boc & MOM deprotection of 1A and 2A (Step 2) Synthesis 2: Synthesis of compound 3- compound 6:

CR.BN adds used.

General protocol for Amides (Step-1):

Into a 25 niL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R , 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-

((triisopropylsilyl)ethynyl)naphthalen-1 -yl)-2-(( 1 -(piperazin- 1 - ylmethyI)cycIopropyl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabic.yclo[3.2.1]octane-8- carboxylate (A-2; Scaffold amine; 1.0 eq.) and Acid (C-1 to C-4; 1-1.2 eq) in anhydrous DMF (6 mL/mmol) were added HATU (1.2 eq.) and DIPEA (5 eq.) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred for 1-2 hours. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by reverse phase column chromatography following a method: C18 Redisep Rf Gold (30g HP C18) ; Mobile phase A : 0.1% Ammonium bicarbonate in MQ-water and B: Acetonitrile; Flow rate: 10 mL/min while the desired compound was eluting at ~ 50% of the mobile phase to give the Amides (3A-6A; Amides; Table 5). Table 5. Amides (3A-6A) from Acid-amine coupling (Step 1)

General protocol for TIPS deprotection (Step 2). Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of amides (3A-6A; Table 5; 1.0 eq.) in anhydrous THF (6 mL/mmol) was added 1M TBAF in THF (3.0 eq.) at 0 °C under nitrogen atmosphere and the reaction mixture was stirred at ambient temperature for 2 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was cooled to 0 °C and quenched with ammonium chloride solution (20 mL) and aqueous phase was extracted twice with EtOAc (2 x 50 mL). Combined organic phase was washed with water (60 mL) followed by brine (40 mL) and then dried (anhydrous Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to afford a crude mass. The crude mass was purified by reverse phase HPLC following a method : C18 Redisep Rf Gold (30g HP C18) ; Mobile phase A : 0.1% formic acid in MQ-water and B: Acetonitrile; Flow rate: 10 mL/min while the desired compound was eluting at 60% of the mobile phase to afford 3B-6B (Table 6). Table 6. TIPS deprotection of amides (Step 2) General protocol for both Boc and MOM deprotection (Step 3) Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of 3B-6B (Table 6; 1.0 eq.) in anhydrous 1,4-dioxane (10 mL/mmol) was added 4N HCl in 1,4- dioxane (10.0 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 hour. After completion of the starting material as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure to afford a crude residue. The crude residue was purified by reverse phase preparatory HPLC [Purification method: [Column: XBRIDGE C8(150*19) mm 5 microns; Mobile phase: A:10mM NH₄HCO₃ in MQ-water; B: Acetonitrile to afford Compounds 3-6 (Table 7). Table 7. Both Boc & MOM deprotection of 3B-6B (Step-3)

Synthesis 3: Synthesis of Compounds 7-10

CRBN acids (C1-C4) used General protocol for Amides 14a-d (Step-1). Into a 10 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- ((1-methyl-5-(piperazin-1-ylmethyl)pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (A-3; Scaffold amine; 1.0 eq.) and Acids (C1-C4; 1- 1.2 eq ) in anhydrous DMF (2 ml/ mmol) were added HATU (1.2 eq.) and DIPEA (5.0 eq.) at ambient temperature under nitrogen atmosphere and resulting mixture was stirred for 1 hour. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was concentrated in vacuo to afford a crude residue, which was purified by reverse phase column chromatography using C18 Redisep Rf Gold (30g HP C18) ; Mobile phase A : 0.1% ammonium bicarbonate in MQ-water and B: acetonitrile; Flow rate: 10 mL/minutes while the compound was eluting at 49% of the mobile phase to afford amides 7A- 10A; Table 8). Table 8. Amides 7A-10A from Acid-amine coupling (Step 1)

General protocol for both Boc and MOM deprotection of 7A-10A (Step 2) Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of 7A-10A (1.0 eq.) in anhydrous 1,4-dioxane (10 mL/mmol) was added 4N HCl in 1,4-dioxane (10.0 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 hour. After completion of the starting material as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure to afford a crude residue. The crude residue was purified by two methods – Method A: reverse phase preparatory HPLC [Purification method: [Column: XBRIDGE C8(150x19) mm, 5 microns; Mobile phase: A: 10 mM NH4HCO3 in MQ-water; B: Acetonitrile Method B: reverse phase preparatory HPLC [Purification method: X-Select C18 (250x19)mm, 5 micron; Mobile phase A: 0.1% FORMIC ACID in MQ Water and Mobile phase B: Acetonitrile; to afford Compounds 7-10 (Table 9). Table 9. Both Boc & MOM deprotection of 7A-10A (Step 2)

Synthesis 4: Synthesis of Compounds 11-13: General protocol for Amides (Step-1). Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (A-4; Scaffold amine; 1.0 eq.) and Acids (C-5, C-7, C- 8; 1-1.2 eq) in anhydrous DMF (6 mL/mmol) were added HATU (1.2 eq.) and DIPEA (5 eq.) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred for 1-2 hours. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by reverse phase column chromatography following a method : C18 Redisep Rf Gold (30g HP C18) ; Mobile phase A : 0.1% ammonium bicarbonate in MQ-water and B: acetonitrile; Flow rate: 10 mL/min while the desired compound was eluting at ~ 50% of the mobile phase to give the Amides (11A-13A). CRBN acids

Table 10. Amides (11A-13A) from Acid-amine coupling (Step 1) id ( ) d

General protocol for both Boc and MOM deprotection (Step 2) Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of 11A-13A (Table 10; 1.0 eq.) in anhydrous 1,4-dioxane (10 mL/mmol) was added 4N HCl in 1,4-dioxane (10.0 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 hour. After completion of the starting material as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure to afford a crude residue. The crude residue was purified by reverse phase preparatory HPLC [Purification method: [Column: XBRIDGE C8(150x19) mm, 5 microns; Mobile phase: A: 10 mM NH4HCO3 in MQ- water; B: acetonitrile to afford Compounds 11-13 (Table 11). Table 11. Both Boc & MOM deprotection of 11A-13A (Step-2) Synthesis 5: Synthesis of 5-(4-((3S,5S)-5-(((4-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)-1-methylpyrrolidin-3-yl)piperazin-1-yl)-N-((1-(2,6-dioxopiperidin-3-yl)-2- oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-5-oxopentanamide (Compound 14)

Step 1: Into a 1000 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1; 20 g, 92.06 mmol) in dry DCM (100 mL) were added TEA (101.26 mmol, 14.11 mL), DMAP (449.84 mg, 3.68 mmol) and tert-butyl dimethyl silyl chloride (15.26 g, 101.26 mmol) at 0 ^oC under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 16 h. The reaction was monitored by ELSD. The reaction mixture was quenched with ice-cold water (250 mL) and extracted with DCM (3 x 200 mL). Combined organic phase was dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by flash silica-gel (230-400 mesh; 25 g SNAP) column with 0-100% EtOAc/petroleum ether while desired compound was eluting at 20-25% of the mobile phase to afford tert-butyl (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1- carboxylate (2; 28 g, 82.7 mmol, 98% purity) as a yellow liquid. Yield-89.9%; LCMS (ESI): [M+H-100]⁺ m/z Calculated: 232.22. Found: 232.2. Step 2: Into a 1000 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1- carboxylate (2; 28 g, 83.61 mmol) in dry DCM (250 mL) was added TEA (94.65 mmol, 13.19 mL) and the resulting mixture was stirred at ambient temperature for 15 minutes. Mesyl chloride (73.86 mmol, 5.73 mL) was added at 0 °C under nitrogen atmosphere and the reaction mixture was stirred at ambient temperature for 1 hour. After completion of the reaction as indicated by LCMS, the reaction mixture was quenched with ice-cold water (200 mL) and extracted with EtOAc (3 x 200 mL). Combined organic phase was dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl (2S,4R)-2-(((tert- butyldimethylsilyl)oxy)methyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (3; 34 g, 81.35 mmol, 98% purity) as a brown solid. The latter was used in the next step without further purification. Yield-97.3%; LCMS (ESI): [M+H-isobutene]⁺ m/z Calculated: 354.2. Found: 354.2. Step 3: Into a 1000 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4- ((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (3; 12 g, 29.00 mmol) and piperazine (4; 12.49 g, 145.02 mmol) in anhydrous MeCN (120 mL) was added cesium carbonate (47.25 g, 145.02 mmol). The reaction mixture was kept for stirring at 80 °C for 16 h. The reaction progress was monitored by TLC and ELSD. After the completion of the reaction, the reaction mixture was quenched with water and extracted with 1:4 MeOH/DCM (100 mL). The organic layer was then washed with brine (30 mL), dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by flash silica- gel (230-400 mesh) column with 0-25% DCM/MeOH while desired compound eluting at 20- 25% of the mobile phase to afford tert-butyl (2S,4S)-2-(((tert-butyldimethylsilyl)oxy)methyl)- 4-(piperazin-1-yl)pyrrolidine-1-carboxylate (5; 3.4 g, 8.5 mmol, 99.9% purity) as a brown gum. Yield-29.3%; LCMS (ESI): [M+H]⁺ m/z Calculated: 400.3. Found:400.2. Step 4: Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (2S,4S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(piperazin-1-yl)pyrrolidine-1- carboxylate (5; 2 g, 4.95 mmol) in MeCN (10 mL) were added K2CO3 (1.37 g, 9.91 mmol) and benzyloxy carbonyl chloride (1.01 g, 5.95 mmol) at ambient temperature under nitrogen atmosphere. The reaction was stirred at ambient temperature for 30 minutes. After completion of the reaction as indicated by UPLC, the reaction mixture was diluted with water (100 mL) and the aqueous layer was further extracted with EtOAc (150 mL). The organic phase was washed with brine (20 mL), dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure to afford benzyl 4-((3S,5S)-1-(tert-butoxycarbonyl)-5-(((tert- butyldimethylsilyl)oxy)methyl)pyrrolidin-3-yl)piperazine-1-carboxylate (6; 1.7 g, 3.01 mmol, 94.5% purity) as a yellow oil and it was used in the next step without further purification. Yield- 60.7%; LCMS (ESI): [M+H]⁺ m/z Calculated: 534.3. Found: 534.2. Step 5: Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of benzyl 4-((3S,5S)-1-(tert-butoxycarbonyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin- 3-yl)piperazine-1-carboxylate (6; 1.7 g, 3.18 mmol) in anhydrous DCM (10 mL) was added TFA (39.20 mmol, 3 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 3 hours. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure to afford benzyl 4-((3S,5S)-5- (hydroxymethyl)pyrrolidin-3-yl)piperazine-1-carboxylate (7; 1.02 g, 3.13 mmol, 98.1% purity) as a yellow sticky solid and it was used in the next step without further purification. Yield-98.4%; LCMS (ESI): [M+H]⁺ m/z Calculated: 320.2. Found: 320.2. Step 6: Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of benzyl 4-((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)piperazine-1-carboxylate (7; 1 g, 2.31 mmol) in water (1 mL) was added dropwise Formaldehyde, 37% w/w aq. soln., stab. with 7-8% MeOH (10.38 mmol, 0.287 mL) and the resulting mixture was stirred at ambient temperature for 10 minutes. MP-Cyanoborohydride (2 g, 31.83 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. After completion of the reaction as indicated by LCMS(ELSD), the reaction mixture was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by neutral alumina Glass column with 0-10% MeOH/DCM while the desired product eluting at 8-10% of the mobile phase to afford benzyl 4-((3S,5S)-5- (hydroxymethyl)-1-methylpyrrolidin-3-yl)piperazine-1-carboxylate (8; 600 mg, 1.78 mmol, 98.5% purity) as a colorless gum. Yield-77.1%; LCMS (ESI): [M+H]⁺ m/z Calculated: 334.2. Found: 334.2. Step 7: Into a 500 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (9; 8.98 g, 20.56 mmol) in anhydrous toluene (60 mL) were added benzyl 4- ((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)piperazine-1-carboxylate (8; 7 g, 20.68 mmol) and cesium carbonate (16.84 g, 51.70 mmol) at ambient temperature. The resulting mixture was heated to 100 °C for 4 hours. After completion of the reaction as indicated by LCMS, the solvent was removed in vacuo to afford a crude residue. The crude residue was purified by reverse phase column chromatography (Column: RediSep C 18-30g, mobile phase: 0.1% HCOOH: MeCN) and fractions were lyophilized to afford tert-butyl (1R,5S)-3-(2- (((2S,4S)-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-1-methylpyrrolidin-2-yl)methoxy)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10; 4.3 g, 5.27 mmol, 94.6% purity) as a yellow solid. Yield-25.5%; LCMS (ESI): [M+H]⁺ m/z Calculated: 725.3. Found: 725.2. Step 8: Into a 250 mL sealed tube containing a well-stirred solution of tert-butyl (1R,5S)-3-(2- (((2S,4S)-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-1-methylpyrrolidin-2-yl)methoxy)-7- chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10; 3.49 g, 4.55 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (11; 1.64 g, 4.55 mmol) in a mixture of dry 1,4-dioxane (20 mL) and water (5 mL) was added potassium phosphate tribasic (44.98 mg, 0.21 mmol) ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas for 5 minutes. CataCXium A Pd G3 (331.37 mg, 0.45 mmol) was added and the mixture was degassed for additional 5 minutes. The resulting mixture was heated to 90 °C and stirred for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was diluted with water (200 mL) and the product was extracted with EtOAc (3 x 100 mL). Combined organic phase was dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by flash silica-gel (230-400 mesh) column with 0-10% MeOH/DCM while desired compound eluting at 7% of the mobile phase to afford tert-butyl (1R,5S)-3-(2-(((2S,4S)-4-(4-((benzyloxy)carbonyl)piperazin-1- yl)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (12; 2.01 g, 2.02 mmol, 92.8% purity) as a yellow solid. Yield-44.4%; LCMS (ESI): [M+H]⁺ m/z Calculated: 923.5. Found: 923.2. Step 9: Into a 250 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R,5S)-3-(2-(((2S,4S)-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-1- methylpyrrolidin-2-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (12; 2.01 g, 1.98 mmol) in dry MeOH (5 mL) was charged Palladium hydroxide on carbon, 20 wt.% 50% water (1.79 g, 12.72 mmol) and the mixture was saturated with hydrogen by bubbling hydrogen gas for 10 minutes and the mixture was hydrogenated through bladder (1 atm) of hydrogen ags at room temperature for 2 hours. After completion of the reaction as indicated by LCMS, the reaction mixture was purged with nitrogen, catalyst was removed by filtration through a pad of Celite and the Celite bed was washed with MeOH (120 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2S,4S)-1-methyl-4-(piperazin-1- yl)pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (13; 1.54 g, 1.78 mmol, 91% purity)as a brown sticky solid and it was used in the next step without further purification. Yield-89.6%; LCMS (ESI): [M+H]⁺ m/z Calculated: 789.4. Found: 789.2. Step 10: Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2S,4S)-1-methyl-4-(piperazin-1-yl)pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (13; 89 mg, 0.101 mmol) and 5-(((1-(2,6- dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)amino)-5-oxopentanoic acid (14; 52.5 mg, 0.111 mmol) in anhydrous DMF (1 mL) were added HATU (57.8 mg, 0.152 mmol) and DIPEA (0.088 mL, 0.507 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 hour. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by reverse phase column chromatography following a method: C18 Redisep Rf Gold (30g HP C18) ; Mobile phase A : 0.1% ammonium bicarbonate in MQ- water and B: acetonitrile; Flow rate: 10 mL/minutes while the desired compound was eluting at 50% of the mobile phase to afford tert-butyl (1R,5S)-3-(2-(((2S,4S)-4-(4-(5-(((1-(2,6- dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)amino)-5- oxopentanoyl)piperazin-1-yl)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (15; 40 mg, 0.0307 mmol, 91.8% purity) as an off- white solid. Yield-30.3%; LCMS (ESI): [M+H]⁺ m/z Calculated: 1194.5. Found: 1194.4. Step 11: Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R,5S)-3-(2-(((2S,4S)-4-(4-(5-(((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2- dihydrobenzo[cd]indol-6-yl)methyl)amino)-5-oxopentanoyl)piperazin-1-yl)-1- methylpyrrolidin-2-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15; 40 mg, 0.0304 mmol) in anhydrous 1,4-dioxane (4 mL) was added 4N HCl in 1,4-dioxane (0.15 mL, 0.609 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 hour. After completion of the reaction as indicated by UPLC, excess solvent was removed from the reaction mixture in vacuo to afford a crude residue. The crude residue was purified by reverse phase preparatory HPLC [Purification method: [Column: XBRIDGE C8(150x19) mm, 5 microns; Mobile phase: A:10 mM NH4HCO3 in MQ-water; B: acetonitrile to afford 5-(4-((3S,5S)-5-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro- 3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1- methylpyrrolidin-3-yl)piperazin-1-yl)-N-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2- dihydrobenzo[cd]indol-6-yl)methyl)-5-oxopentanamide (16; 8 mg, 0.007 mmol, 97 purity) as an off-white solid.. Yield-30.3%; ¹H NMR (400 MHz, DMSO-d₆). δ11.14 (s, 1H), 10.02 (s, 1H), 9.16 (s, 1H), 8.39 (m, 2H), 8.14-8.11 (m, 1H), 7.88-7.84 (m, 1H), 7.8-7.76 (m, 1H), 7.41-7.34 (m, 3H), 7.1 (d, J = 7.6 Hz, 1H), 7.02-7.02 (m, 1H), 5.45 (m, 1H), 4.68-4.57 (m, 6H), 4.2 (m, 2H), 3.95-3.8 (m, 2H), 3.28 (m, 2H), 3.05-2.9 (m, 3H), 2.8 (m, 2H), 2.6 (m, 2H), 2.5 (m, 3H), 2.4 (m, 7H), 2.3 (m, 3H), 2.1 (m, 5H), 2.01-1.95 (m, 4H), 1.6 (m, 3H) and 0.75 (m, 3H). LCMS (ESI): [M+H]⁺ m/z Calculated: 1050.5. Found: 1050.3. Synthesis 6: Synthesis of Compounds 15-18

CRBN-Acids (C-5 to C-8) used. General protocol for Amides (Step-1). Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((R)-2-methyl- 3-(piperazin-1-yl)propoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (A-5; Scaffold amine; 1.0 eq.) and Acid (C-5 to C-8; 1-1.2 eq) in anhydrous DMF (6 mL/mmol) were added HATU (1.2 eq.) and DIPEA (5 eq.) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred for 1-2 hours. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by reverse phase column chromatography following a method : C18 Redisep Rf Gold (30g HP C18) ; Mobile phase A : 0.1% ammonium bicarbonate in MQ-water and B: acetonitrile; Flow rate: 10 mL/min while the desired compound was eluting at ~ 50% of the mobile phase to give Amides (15A-18A; Table 12).

Table 12. Amides from Acid-amine coupling (Step 1)

General protocol for both Boc and MOM deprotection (Step 2) Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of 15A-18A(1.0 eq.) in anhydrous 1,4-dioxane (10 mL/mmol) was added 4N HCl in 1,4-dioxane (10.0 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 hour. After completion of the starting material as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure to afford a crude residue. The crude residue was purified by two methods – Method A: reverse phase preparatory HPLC [Purification method: [Column: XBRIDGE C8(150x19) mm, 5 microns; Mobile phase: A: 10 mM NH₄HCO₃ in MQ-water; B: Acetonitrile Method B: reverse phase preparatory HPLC [Purification method: X-Select C18(250x19) 5micron; Mobile phase A: 0.1% FORMIC ACID in MQ Water and Mobile phase B: Acetonitrile; to afford Compounds 15-18 (Table 13). Table 13. Both Boc & MOM deprotection of 15A-18A (Step-2)

Synthesis 7: Synthesis of Compounds 19-22:

General protocol for Amides (Step-1). Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(piperazin- 1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (A-6; Scaffold amine; 1.0 eq.) and Acids (C-1 to C-4; 1-1.2 eq) in anhydrous DMF (6 mL/mmol) were added HATU (1.2 eq.) and DIPEA (5 eq.) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred for 1-2 hours. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by reverse phase column chromatography following a method : C18 Redisep Rf Gold (30g HP C18) ; Mobile phase A : 0.1% Ammonium bicarbonate in MQ-water and B: Acetonitrile; Flow rate: 10 mL/min while the desired compound was eluting at ~ 50% of the mobile phase to give the Amides (19A-22A; Table 14). Table 14. Amides from Acid-amine coupling (Step 1) General protocol for MOM deprotection (Step 2). Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of 19A-22A (Table 14; 1.0 eq.) in anhydrous 1,4-dioxane (10 mL/mmol) was added 4N HCl in 1,4- dioxane (10.0 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 hour. After completion of the starting material as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure to afford a crude residue. The crude residue was purified by two methods – Method A: reverse phase preparatory HPLC [Purification method: [Column: XBRIDGE C8(150x19) mm; 5 microns; Mobile phase: A:10 mM NH4HCO3 in MQ-water; B: Acetonitrile Method B: reverse phase preparatory HPLC [Purification method: X-Select C18(250x19)mm; 5 micron; Mobile phase A: 0.1% FORMIC ACID in MQ Water and Mobile phase B: Acetonitrile; to afford Compounds 19-22 (Table 15). Table 15. MOM deprotection of 19A-22A (Step 2)

Synthesis 8: Synthesis of Compounds 23-27

CRBN-Acids (C-5 to C-8) used General protocol for Amides (Step-1). Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(piperazin-1- ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (A-7; Scaffold amine; 1.0 eq.) and Acids (C-5 to C-8; 1-1.2 eq) in anhydrous DMF (6 mL/mmol) were added HATU (1.2 eq.) and DIPEA (5 eq.) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred for 1-2 hours. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by reverse phase column chromatography following a method : C18 Redisep Rf Gold (30g HP C18) ; Mobile phase A : 0.1% ammonium bicarbonate in MQ-water and B: acetonitrile; Flow rate: 10 mL/minutes while the desired compound was eluting at ~ 50% of the mobile phase to give the Amides (23A-27A; Table 14). Table 14. Amides from Acid-amine coupling (Step 1)

General protocol for both Boc and MOM deprotection of 23A-27A (Step 2) Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of 23A-27A (Table 14; 1.0 eq.) in anhydrous 1,4-dioxane (10 mL/mmol) was added 4N HCl in 1,4- dioxane (10.0 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 hour. After completion of the starting material as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure to afford a crude residue. The crude residue was purified by reverse phase preparatory HPLC [Purification method: [Column: XBRIDGE C8(150x19) mm, 5 microns; Mobile phase: A:10 mM NH₄HCO₃ in MQ-water; B: acetonitrile to afford Compounds 23-27 (Table 15). Table 15. Both Boc & MOM deprotection of 23A-27A (Step-2)

Synthesis 9: Synthesis of 3-(6-(1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)- yl)piperidine-2,6-dione (Compound 28)

Step 1: Into a 100 mL two-necked round-bottomed flask containing a well-stirred solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (650 mg, 1.03 mmol) in dry DCM (5 mL) was added Dess-Martin Periodinane (1.31 g, 3.08 mmol) at 0 °C and the reaction mixture was stirred at ambient temperature for 16 h under nitrogen atmosphere. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with DCM (100 mL), the filtrate was washed with saturated sodium bicarbonate solution (40 mL) followed by brine (40 mL) and dried (anhydrous Na₂SO₄), filtered and the filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while the desired product eluting at 78-85% of the mobile phase to afford (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropane-1-carbaldehyde (8; 420 mg, 0.65 mmol, 91% purity) as a brown solid. Yield-62.8%; LCMS (ESI): [M+ H]⁺ m/z Calculated:593.25. Found: 593.2. Step 2: Into a 20mL glass vial, containing a well stirred solution of 1-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde (100 mg, 127.25 μmol) and 3-[2-oxo- 6-(4-piperidyl)benzo[cd]indol-1-yl]piperidine-2,6-dione (72.64 mg, 190.87 μmol) in dry DMSO (507.26 μL) was added acetic acid (22.92 mg, 381.74 μmol, 22.26 μL) followed by NaBH3CN (175 mg, 254.49 μmol) at ambient temperature. The resulting reaction mixture was allowed to stir for 1 hour at 70°C. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (3 × 100ml) and the combined organic layers was concentrated under reduced pressure to afford a crude product, which was further purified by reverse phase preparatory HPLC [Purification method:[Column:X Bridge C8(250*19)mm 5microns; Mobile phase:A:0.1% ammonium bicarbonate in MQ-water; B: Acetonitrile to afford 3-[6-[1-[[1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6- dione (25 mg, 25.85 μmol, 20.32% yield, 97.211% purity) as white solid. LCMS (ESI):m/z 940.04[M+H]⁺. Found: 940.3. Step 3: Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of 3- [6-[1-[[1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy- 3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4- piperidyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione (25.00 mg, 26.59 μmol) in anhydrous DCM (5 mL) was added HCl ^4.0 M in 1,4-dioxane ^ (4.85 mg, 132.97 μmol) at 0°C under nitrogen atmosphere. The contents were stirred for 1 hour at ambient temperature. After completion of the starting material as indicated by UPLC, the reaction mixture was concentrated under nitrogen atmosphere to afford crude compound. The crude was purified by reverse phase column chromatography preparatory HPLC [Purification method :[Column: XBRIDGE C8(250*19)mm 5 microns; Mobile phase: A: 0.1% ammonium bicarbonate, B: ACN) and fractions were lyophilized to afford 3-[6-[1-[[1-[[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6- dione (9 mg, 9.82 μmol, 36.94% yield, 97.80% purity) as white solid. LCMS (ES+): m/z 896.39 [M+H]⁺. Found 896.4. The following compounds were synthesized following a similar experimental procedure.

The following compounds are synthesized following a similar experimental procedure.

Synthesis 10: Synthesis of 3-(5-(1-((1-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-4-((R)-3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin- 2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2- oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 88) Into a 25 mL single-necked round-bottomed flask containing a well-stirred solution of 3- (5-(1-((1-((1-(((8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 4-((R)-3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-oxobenzo[cd]indol- 1(2H)-yl)piperidine-2,6-dione (1.0 eq.) in anhydrous THF is added 1M TBAF in THF (3.0 – 10.0 eq.) at 0 °C under nitrogen atmosphere and the reaction mixture is stirred at ambient temperature for 2 hours. After completion of the reaction as indicated by UPLC, the reaction mixture is subjected to standard work-up procedure to afford 3-(5-(1-((1-((1-(((7-(8-ethynyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-(trifluoromethyl)piperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione. The following compounds are synthesized following a similar experimental procedure.

Synthesis 11: Synthesis of 3-(5-(1'-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-bipiperidin]-4-yl)-2-oxobenzo[cd]indol-1(2H)- yl)piperidine-2,6-dione (Compound 49)

Step 1: Into a 20 mL screw-cap vial containing a well-stirred solution of (R)-1-(((7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (90 mg, 0.131 mmol, No Salt), 3-(5-([1,4'-bipiperidin]-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6- dione C-40 (65.11 mg, 0.131 mmol, HCl salt) in anhydrous DMSO (4 mL) were added sodium acetate (21.61 mg, 0.263 mmol), acetic acid (79.11 mg, 1.32 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. MP-cyanoborohydride; 2mmol\g (22 mg, 0.04 mmol) was added to the reaction mixture and stirred at 70 °C 16 h. After completion of the reaction as indicated by LCMS, the mixture was passed through a sintered funnel and concentrated under reduced pressure to get crude compound. The crude compound was purified by reverse phase column chromatography [Column: Redisep Rf Gold C18- 50 g; Mobile phase A: 0.1% Ammonium bicarbonate in water and Mobile phase B: Acetonitrile] to afford 3-(5-(1'-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4- ((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-bipiperidin]-4-yl)-2-oxobenzo[cd]indol-1(2H)- yl)piperidine-2,6-dione 2 (100 mg, 0.076 mmol, 58% yield) as an off-white solid. LC-MS (ES⁺): m/z 1023.4 [M+H] ⁺. Step 2: Into a 25 mL single-neck round-bottom flask containing well-stirred solution of 3-(5-(1'- ((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'- bipiperidin]-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 2 (100 mg, 0.076 mmol) in DCM (2 mL) was added 4N HCl in 1,4-dioxane (0.3 mL, 1.20 mmol) at 0 ℃. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure to get crude compound, which was purified by a reverse-phase prep HPLC to afford 3- (5-(1'-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'- bipiperidin]-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione Compound 49 (43 mg, 0.043 mmol, 57% yield) as an off-white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C8 (19*250mm); Mobile phase A: 0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile; Flow rate: 5 microns/minutes. LC-MS (ES⁺): m/z 979.3 [M+H] ⁺.¹H NMR (400 MHz, DMSO-d₆) δ = 11.12 (s, 1H), 9.93 (br s, 1H), 9.22 (d, J = 1.4 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.76 (dd, J = 9.1, 6.1 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.55-7.49 (m, 1H), 7.37-7.31 (m, 2H), 7.15 (d, J = 7.3 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 5.48- 5.42 (m, 1H), 4.74 (br d, J = 4.9 Hz, 1H), 4.42-4.27 (m, 3H), 4.10-4.00 (m, 1H), 3.67-3.61 (m, 1H), 3.56-3.51 (m, 1H), 3.47-3.40 (m, 1H), 3.38-3.35 (m, 3H), 3.07-2.92 (m, 5H), 2.82-2.74 (m, 1H), 2.65-2.60 (m, 1H), 2.47-2.36 (m, 3H), 2.32-2.25 (m, 2H), 1.91-1.77 (m, 6H), 1.75-1.66 (m, 5H), 1.49-1.39 (m, 2H), 1.26-1.23 (m, 1H), 1.20-1.16 (m, 3H), 0.78-0.73 (m, 3H), 0.67 (s, 2H), 0.42 (s, 2H). Synthesis 12: Synthesis of 3-[7-[1-[[1-[[1-[[5-cyclopropyl-7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3- yl]piperidine-2,6-dione (Compound 63):

Step-1: To a stirred solution of (3R)-1-[5-cyclopropyl-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)- 1-naphthyl]-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-3-methyl-piperidin-3-ol A-125 (40 mg, 63.02 μmol) in dichloromethane (0.1 mL) and acetonitrile (0.1 mL) was cooled to 0 °C. Dess-martin Periodinane (213.84 mg, 504.17 μmol) was added portion wise over a period of 5 minutes. The resulting reaction mixture was allowed to stir at room temperature for 24 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution(10 mL) and extracted with dichloromethane(30 mL), the organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude 1-[[5-cyclopropyl-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropanecarbaldehyde 1 (32 mg, 56 % yield) as brown solid, LCMS (ESI): m/z 633.27 [M+H]⁺. Step-2: To a stirred solution of 1-[[5-cyclopropyl-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropanecarbaldehyde 1 (30 mg, 47.42 μmol) and 3-[1-methyl-7-[1-(4- piperidylmethyl)-4-piperidyl]indazol-3-yl]piperidine-2,6-dione C-47 (21.81 mg, 47.42 μmol, Hydrochloric acid salt) in DMSO (0.3 mL) was added anhydrous sodium acetate (3.89 mg, 47.42 μmol) and Acetic acid (2.85 mg, 47.42 μmol). The resulting reaction mixture was heated to stir at 70 °C for 3 hours then MP-Cyano borohydride (50 mg, 47.42 μmol) was added and continue the reaction at 70 °C for 12 hours. The reaction mixture was lyophilized to get crude which was purified by Prep-HPLC to afford 3-[7-[1-[[1-[[1-[[5-cyclopropyl-7-[8-ethyl-7-fluoro- 3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1- piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4- piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione 2 (7 mg,14 % yield) as an off white solid, LCMS [ES+]: m/z 1040.86 [M+H] ⁺. Prep-HPLC method: Column/dimensions: X BRIDGE C8 (10 x 250 x 5um) Mobile phase A: 10mM ammonium bicarbonate in water+0.1% Ammonia and Mobile phase B: 0.1% ammonia with acetonitrile. Gradient (Time/%B): 0/70, 3/70, 7/90, 9/90 Flow rate: 18 mL/minutes. Solubility: THF+ water+ acetonitrile. Step-3: To a stirred solution of 3-[7-[1-[[1-[[1-[[5-cyclopropyl-7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1-methyl- indazol-3-yl]piperidine-2,6-dione 3 (6.00 mg, 5.77 μmol) 3-[7-[1-[[1in DCM (0.5 mL) was added 4M HCl in 1,4-dioxane (0.05 mL) by drop wise at 0 °C under nitrogen atmosphere and allowed to stir at room temperature for 15 minutes. the resulting reaction mixture was concentrated under reduced pressure to get crude which was triturated with diethyl ether to afford 3-[7-[1-[[1-[[1-[[5-cyclopropyl-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-[(3R)-3- hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dion Compound 63 (4.7 mg, 71 % yield, Hydrochloric acid salt) as an off white solid. LCMS (ESI): m/z 996.58[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6):δ 10.90 (s, 1H), 10.20-10.02 (m, 2H), 9.10 (s, 1H), 7.77 – 7.73 (m, 1H), 7.60 (d, J= 8 Hz, 1H), 7.33 – 7.28 (m, 2H), 7.22 (d, J= 7.2 Hz, 1H), 7.14-7.11 (m, 1H), 7.08 – 7.05 (m,1H), 6.98 – 6.96 (m, 1H),4.39 – 4.35 (m, 1H), 4.30 – 4.24 (m, 6H), 3.74 – 3.66 (m, 6H), 3.35 –3.02(m,8H), 2.96 – 2.93 (m, 4H), 2.27 – 2.20 (m, 2H), 2.15-2.10 (m, 9H), 1.68- 1.63 (m, 5H), 1.10 – 1.05 (m, 1H), 0.89 – 0.84 (m, 5H), 0.76 – 0.69 (m, 5H), 0.68 – 0.64 (m, 3H) ppm. Synthesis 13: Synthesis of 3-(7-(1-((1-((1-(((2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 1-fluoro-6-hydroxy-6-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12- tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (Compound 75) Step 1: Into a 25 mL single-neck round-bottom flask containing a well-stirred solution of 2-(8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-11-((1- (hydroxymethyl)cyclopropyl)methoxy)-6-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12- tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-6-ol A-134 (40 mg, 0.054 mmol) in DCM (2 mL) was added DMP (69.48 mg, 0.163 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1.5 hours. After completion of the reaction as indicated by LCMS, the reaction mixture was quenched with a mixture of aqueous sodium bicarbonate solution (10 mL) and aqueous sodium thiosulphate solution (10 mL) and extracted with DCM (50 mL). The organic layer was dried over anhydrous Na₂SO_4, filtered and concentrated under reduced pressure to get 1-(((2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-6- hydroxy-6-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12- tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-yl)oxy)methyl)cyclopropane-1- carbaldehyde 1 (38 mg, 0.053 mmol, 97.55% yield) as an off-white solid. UPLC-MS (ES⁺): m/z 621.4 [M+H]⁺. Step 2: Into a 20 mL screw-capped vial containing well-stirred solution of 1-(((2-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-6-hydroxy-6-methyl-5,5a,6,7,8,9- hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11- yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (38 mg, 53.27 μmol), 3-(1-methyl-7-(1- (piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione C-47 (40.84 mg, 0.079 mmol; HCl salt) in anhydrous DMSO (3 mL) were added sodium acetate (21.85 mg, 0.266 mmol) and acetic acid (3.20 mg, 0.053 mmol, 0.5 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. MP-cyanoborohydride; 2mmol/g (80 mg, 0.16 mmol) was added to the reaction mixture and stirred at 70 °C for 6 h. After completion of the reaction as indicated by LCMS, the reaction mixture was filtered and filtrate was concentrated under reduced pressure to get crude compound, which was purified by reverse phase column chromatography [column: Redisep Rf Gold C18- 50g; mobile phase A: 0.1% Ammonium bicarbonate in water and mobile phase B: Acetonitrile] to afford 3-(7-(1-((1-((1- (((2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-6-hydroxy-6-methyl- 5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen- 11-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione 3 (35 mg, 0.016 mmol, 30% yield) as an off-white solid. LC- MS (ES⁺): m/z 1028.4 [M+H]⁺. Step 3: Into a 25 mL single-neck round-bottom flask containing well-stirred solution of 3-(7-(1- ((1-((1-(((2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-6-hydroxy-6- methyl-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3- de]naphthalen-11-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione 2 (35 mg, 0.016 mmol) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (0.1 mL, 0.400 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure to get crude compound, which was purified by reverse phase PREP HPLC to furnish 3-(7-(1-((1-((1-(((2-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-1-fluoro-6-hydroxy-6-methyl-5,5a,6,7,8,9-hexahydro-4-oxa- 3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione Compound 75 (6 mg, 0.006 mmol, 37% yield) as an off-white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C18 (19*250mm); Mobile phase A: 0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile; Flow rate: 5 microns/minutes. LC-MS (ES⁺): m/z 984.5 [M+H] ⁺.¹H NMR (400 MHz, DMSO-d6) δ: 10.89 (br s, 1H), 7.76-7.68 (m, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.37-7.22 (m, 3H), 7.10-6.94 (m, 2H), 5.36-5.14 (m, 2H), 4.94-4.83 (m, 1H), 4.51-4.40 (m, 1H), 4.38-4.32 (m, 2H), 4.31-4.26 (m, 2H), 4.20 (s, 3H), 3.64-3.56 (m, 1H), 3.03-2.91 (m, 5H), 2.65-2.56 (m, 3H), 2.31-2.23 (m, 2H), 2.20- 2.04 (m, 6H), 1.88-1.74 (m, 9H), 1.70-1.61 (m, 3H), 1.54-1.43 (m, 1H), 1.25-1.17 (m, 4H), 1.09- 1.00 (m, 2H), 0.86-0.75 (m, 3H), 0.65 ( s, 2H) and 0.41 (s, 2H). Synthesis 14: Synthesis of 3-(7-(1-((1-((1-((((S)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-1-fluoro-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8- ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)- 1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound 78)

Step 1: Into a 50 mL round bottom flask containing a well stirred solution of (S)-(1-(((2-(8-ethyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,9,10-tetrahydro-5H,8H-4,7- dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methanol A-136 (60 mg, 0.093 mmol) in anhydrous DCM (3 mL) was added dropwise DMP (119.17 mg, 0.280 mmol) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of reaction as indicated by UPLC-MS, the reaction mixture was quenched with sodium thiosulphate (10mL) solution and extracted with DCM (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get crude compound, which was purified by reverse phase column chromatography [Column: Redisep Rf Gold C18-30g, Mobile phase A: 0.1%Ammonium bicarbonate in water, Mobile phase B: Acetonitrile] to afford (S)-1-(((2-(8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,9,10-tetrahydro-5H,8H-4,7- dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropane-1- carbaldehyde 1 (50 mg, 0.028 mmol, 30% yield) as a yellow fluid. LC-MS (ES⁺): m/z 607.2 [M+H] ⁺. Step 2: Into a 20 mL glass vial containing a well-stirred solution of (S)-1-(((2-(8-ethyl-7-fluoro- 3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa- 3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (40 mg, 0.023 mmol) in DMSO (3 mL) was added 3-(1-methyl-7-(1-(piperidin-4- ylmethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione C-47 (15.92 mg, 0.034 mmol, HCl salt) and sodium acetate, anhydrous (9.47 mg, 0.115 mmol) and acetic acid (168.39 mg, 2.80 mmol) stirred at room temperature for 2 hours. MP-Cyanoborohydride 2.0 mmol/g (80 mg, 0.16 mmol) was added to the reaction mixture and stirred at 70 °C for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered and washed with DCM (10 mL) and the filtrate was concentrated under reduced pressure to get the crude residue which was purified by reverse phase column chromatography [Column: Redisep Rf Gold C18-30g, Mobile phase A: 0.1%Ammonium bicarbonate in water, Mobile phase B: Acetonitrile] to afford 3-(7- (1-((1-((1-((((S)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,9,10- tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-12- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione 2 (40 mg, 0.026 mmol, 100% yield) as a pale-yellow solid. LC-MS (ES⁺): m/z 1014.3 [M+H] ⁺. Step 3: Into a 50 mL single-neck containing a well-stirred solution of 3-(7-(1-((1-((1-((((S)-2-(8- ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl)-1-fluoro-5a,6,9,10-tetrahydro-5H,8H- 4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-12- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione 2 (40 mg, 0.026 mmol) in dry DCM (3.03 mL) was added 4M HCl in 1,4-dioxane (0.065 mL, 0.260 mmol) at 0 °C. The resulting reaction mixture stirred at room temperature for 1 hour. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure to get crude residue, which was purified by prep-HPLC to furnish 3-(7-(1-((1-((1-((((S)-2-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-1-fluoro-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13- tetraazanaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione Compound 78 (3 mg, 0.003 mmol, 11% yield) as an off white solid. Preparative HPLC Method: Column/dimensions: XSELECT C18 (19*250mm); Mobile phase A :10mM ammonium bicarbonate in water, Mobile phase B: ACN (100%); Flow rate: 5 microns/minutes.¹H NMR (400 MHz, DMSO-d6) δ = 10.90 (s, 1H), 9.95 ( s, 1H), 7.75 (dd, J = 6.1, 8.5 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.38-7.29 (m, 2H), 7.25 (d, J = 7.1 Hz, 1H), 7.08-7.05 (m, 1H), 7.04-7.02 (m, 1H), 4.84-4.74 (m, 1H), 4.71-4.63 (m, 2H), 4.35 (dd, J = 5.1, 9.9 Hz, 1H), 4.32-4.29 (m, 1H), 4.28-4.22 (m, 1H), 4.20 (s, 3H), 4.13-4.06 (m, 1H), 3.86-3.80 (m, 1H), 3.67-3.59 (m, 1H), 3.01- 2.86 (m, 4H), 2.66-2.58 (m, 2H), 2.54-2.53 (m, 2H), 2.39-2.35 (m, 1H), 2.27-2.21 (m, 1H), 2.21- 2.12 (m, 3H), 2.12-2.02 (m, 3H), 1.88-1.82 (m, 3H), 1.78-1.69 (m, 3H), 1.68-1.60 (m, 3H), 1.48- 1.48 (m, 1H), 1.51-1.42 (m, 1H), 1.26-1.23 (m, 2H), 1.10-0.95 (m, 2H), 0.89-0.83 (m, 2H), 0.79- 0.72 (m, 2H), 0.67-0.63 (m, 2H), 0.54-0.54 (m, 1H) and 0.42-0.38 (m, 2H). LCMS (ESI): m/z 970.3 [M+H] ⁺. Synthesis 15: Synthesis of 3-(7-(1-((1-((1-((((S)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8- ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)- 1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound 82): Step 1: Into a 50 mL single-neck round-bottom flask containing well stirred solution of (S)-(1- (((2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro- 5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-12- yl)oxy)methyl)cyclopropyl)methanol A-139 (90 mg, 0.132 mmol) in anhydrous DCM (3 mL) was added Dess-Martin periodinane (168.0 mg, 0.396 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction as indicated by UPLC-MS and TLC, the reaction mixture was quenched with NaHCO₃ solution (15 mL), Na2S2O3 solution (15 mL) and extracted with DCM (2 X 20 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), dried (anhydrous Na₂SO₄), filtered and concentrated under reduced pressure to afford (S)-1-(((2-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13- tetraazanaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (50 mg, 0.070 mmol, 53% yield) as a white solid. LC-MS (ES⁺): m/z 605.2 [M+H]⁺. Step 2: Into a 20 mL screw-capped vial containing a well-stirred solution of (S)-1-(((2-(8-ethyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa- 3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (90 mg, 0.127 mmol), 3-(1-methyl-7-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3- yl)piperidine-2,6-dione HCl salt C-47 (74.66 mg, 0.152 mmol) in anhydrous DMSO (4 mL) were added sodium acetate (52.15 mg, 0.635 mmol), acetic acid (76.34 mg, 1.27 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. Then MP-cyanoborohydride; 2mmol\g (180 mg, 0.360 mmol) was added and stirring was continued for another 16 h at 70 °C. After completion of the reaction as indicated by UPLC-MS and TLC, the reaction mixture was passed through a sintered funnel and concentrated under reduced pressure to get the crude compound which was purified by reverse phase column chromatography by using redisep C18 column; mobile phase: 10 mM ammonium bicarbonate in water and ACN to afford 3-(7-(1-((1-((1-((((S)-2-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13- tetraazanaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 2 (60 mg, 0.045 mmol, 36% yield) as an off-white solid. LC-MS (ES⁺): m/z 1012.3 [M+H]⁺. Step 3: Into a 25 mL single-neck round-bottom flask containing a well-stirred solution of 3-(7- (1-((1-((1-((((S)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro- 5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-12- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione 2 (55 mg, 0.041 mmol) in anhydrous DCM (3 mL) was added TFA (0.12 mL, 0.167 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour. After completion of the starting material as indicated by UPLC, the solvent was removed under reduced pressure to get a crude residue which was purified by reverse phase preparatory HPLC to furnish 3-(7-(1-((1-((1-((((S)-2-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13- tetraazanaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione HCOOH salt Compound 82 (5 mg, 0.004 mmol, 11% yield) as an off-white solid. LC-MS (ES+): m/z 968.4 [M+H]⁺. Preparative HPLC Method: Column/dimensions: XSLECT C18 (19*250mm); Mobile phase A :0.1% HCOOH in water, Mobile phase B: ACN (100%); Flow rate: 5 microns/min; Solubility: WATER+CAN.¹H NMR (400 MHz, DMSO-d6) δ = 10.89 (s, 1H), 9.92 (br d, J = 18.0 Hz, 1H), 8.25 (s, 1H), 7.75 (dd, J = 5.9, 9.2 Hz, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.38-7.28 (m, 2H), 7.25 (d, J = 7.3 Hz, 1H), 7.09-7.05 (m, 1H), 7.05-6.97 (m, 1H), 4.97-4.85 (m, 1H), 4.62-4.54 (m, 1H), 4.52-4.43 (m, 1H), 4.39-4.32 (m, 2H), 4.32-4.24 (m, 2H), 4.20 (s, 3H), 3.45- 3.41 (m, 1H), 2.99-2.88 (m, 5H), 2.66-2.63 (m, 2H), 2.62-2.60 (m, 2H), 2.47-2.44 (m, 2H), 2.38- 2.35 (m, 1H), 2.31-2.28 (m, 1H), 2.28-2.23 (m, 1H), 2.19-2.16 (m, 1H), 2.16-2.11 (m, 2H), 2.11- 2.03 (m, 2H), 1.89-1.82 (m, 4H), 1.78-1.72 (m, 3H), 1.70-1.62 (m, 4H), 1.55-1.44 (m, 2H), 1.26- 1.23 (m, 2H), 1.09-1.02 (m, 2H), 0.89-0.83 (m, 2H), 0.83-0.77 (m, 2H), 0.66-0.62 (m, 2H) and 0.45-0.37 (m, 2H). Synthesis 16: Synthesis of 3-(7-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-1,6-naphthyridin-2-yl) oxy) methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (Compound 83)

Step 1: Into a 50 mL round bottom flask containing a well stirred solution of (R)-1-(7-(8-ethyl- 7-fluoro-3-(methoxymethoxy) naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl) cyclopropyl) methoxy)-1,6-naphthyridin-4-yl)-3-methylpiperidin-3-ol A-140 (100 mg, 0.168 mmol) in DCM (4 mL) was added DMP (142.89 mg, 0.336 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by UPLC-MS and TLC, the reaction mixture was quenched with saturated solution of sodium bicarbonate (30 mL) and sodium thiosulphate (30 mL) and extracted with DCM (100 mL). The organic layer was dried over sodium sulphate, filtered and concentrated the filtrate under reduced pressure to afford (R)-1-(((7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)- 1,6-naphthyridin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (90 mg, 0.136 mmol, 81% yield) as a white solid. LC-MS (ES⁺): m/z 592.2 [M+H]⁺. Step 2: Into a 20 mL vial containing a well stirred solution of (R)-1-(((7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-1,6- naphthyridin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (100 mg, 0.152 mmol) and 3- (1-methyl-7-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione C- 47 (81.76 mg, 0.152 mmol) in dry DMSO (1 mL) was added sodium acetate (37.44 mg, 0.456 mmol) and followed by acetic acid (91.35 mg, 1.52 mmol) was stirred at room temperature for 2 hours. MP-CNBH3 (200 mg, 0.400 mmol) was added to the reaction mixture and stirred at 70 °C for 16 h. After completion of the reaction as indicated by LC-MS, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to get a crude residue that was purified by reverse phase [column: C18 Redisep Rf Gold (60 g HP C18); Mobile phase A: 0.1% ammonium acetate in MQ-water; Mobile phase B: Acetonitrile] to afford 3-(7-(1-((1-((1- (((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)-1,6-naphthyridin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 2 (100 mg, 0.081 mmol, 53% yield) as a white solid. LC-MS (ES⁺): m/z 999.4 [M+H] ⁺. Step 3: Into a 25 mL single-neck round-bottom flask containing well-stirred solution of 3-(7-(1- ((1-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)-1,6-naphthyridin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione 3 (100 mg, 0.081 mmol) in DCM (2 mL) was added 4 M HCl in 1,4-dioxane (0.20 mL, 0.810) at 0 °C. The resulting reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction the reaction as indicated by LC- MS, the reaction mixture was concentrated under reduced pressure to get crude compound, which was purified by a reverse-phase prep HPLC to furnish 3-(7-(1-((1-((1-(((7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-1,6- naphthyridin-2-yl) oxy) methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione Compound 83 (15 mg, 0.015 mmol, 19% yield) as an off-white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C18 (19*250mm); Mobile phase A: 0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile; Flow rate: 5 microns/minutes.¹H NMR (400 MHz, DMSO-d6) δ = 10.88 (s, 1H), 9.90 (d, J = 2.5 Hz, 1H), 9.23 (d, J = 11.0 Hz, 1H), 7.76 (dd, J = 6.0, 9.1 Hz, 1H), 7.74-7.66 (m, 1H), 7.55-7.51 (m, 1H), 7.38-7.31 (m, 2H), 7.24 (d, J = 7.0 Hz, 1H), 7.09-7.01 (m, 2H), 6.52 (d, J = 2.0 Hz, 1H), 4.76 (d, J = 7.5 Hz, 1H), 4.43-4.32 (m, 3H), 4.20 (s, 3H), 4.14 (dd, J = 3.4, 5.7 Hz, 1H), 3.46-3.36 (m, 1H), 3.20-3.02 (m, 2H), 3.02-2.97 (m, 1H), 2.96-2.90 (m, 3H), 2.66-2.56 (m, 2H), 2.35-2.27 (m, 4H), 2.19-2.11 (m, 3H), 2.10-2.00 (m, 3H), 1.90-1.78 (m, 4H), 1.78-1.61 (m, 6H), 1.59 (br d, J = 4.8 Hz, 1H), 1.41-1.31 (m, 1H), 1.31-1.25 (m, 2H), 1.12-0.98 (m, 2H), 0.92-0.83 (m, 2H), 0.75-0.64 (m, 5H) and 0.44-0.37 (m, 2H). LC-MS (ES⁺): m/z 955.4 [M+H]⁺. Synthesis 17: Synthesis of 3-[6-[1-[[1-[[1-[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione (Compound 92): Step-1: To a stirred solution of 1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropanecarbaldehyde 1 (0.1 g, 0.168 mmol) and 3-[6-[1-(4- piperidylmethyl)-4-piperidyl]-1,2-benzoxazol-3-yl]piperidine-2,6-dione 2 (0.091 g, 0.202 mmol, Hydrochloric acid salt) in DMSO (0.5 mL) was added anhydrous Sodium acetate (0.055 g, 0.674 mmol ) and acetic acid (0.101 g, 1.69 mmol), the resulting reaction mixture was heated to stir at 70 ^°C for 1 hour. MP-Cyano borohydride (0.021 g, 0.337 mmol) was added and continue the reaction at 70 ^°C for 16 h. The Reaction mixture filtered and lyophilized to get crude which was purified by prep-HPLC to afford 3-[6-[1-[[1-[[1-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1,2- benzoxazol-3-yl]piperidine-2,6-dione 3 (0.030 g, 17 % yield,) as an off white solid, LCMS [ESI]: m/z 987.9 [M+H]⁺. Prep HPLC method: Column: X Bridge C18 (10*250mm*5um), Mobile phase A: 10mM Ammonium bicarbonate in water+0.1 % Ammonia, Mobile phase B: 100% Acetonitrile+0.1 % Ammonia, Gradient (Time / % B): 0.1/60, 9/90, 11/90, 11.10/100 Flow Rate: 7 mL/minutes. Solubility: Acetonitrile+THF+Water. Step-2: To a stirred solution of 3-[6-[1-[[1-[[1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione 3 (30 mg, 0.0303 mmol) in DCM (2 mL) was added 4M HCL in 1,4 dioxane (0.05 mL, 0.030 mmol) at 0 ιC. The reaction mixture was allowed to stir at room temperature for 1 hour and concentrated under reduced pressure to get crude which was triturated with pentane and lyophilized to afford 3-[6-[1-[[1-[[1-[[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione Compound 92 (0.028 g, 84 % yield, Hydrochloric acid salt) as an off white solid. LCMS (ESI): m/z 943.82 [M+H] ⁺.¹H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 10.12 (bs, 1H), 9.98 (bs, 1H), 9.26 (s, 1H), 7.84-7.75 (m, 2H), 7.61 (bs, 1H), 7.37-7.31 (m, 3H), 7.04-7.03 (m, 1H), 4.59-4.56 (m, 2H), 4.34 (bs, 3H), 4.25-4.01 (m, 1H), 3.73-3.41 (m, 5H), 3.24-3.22 (m, 3H), 3.04 – 2.93 (m, 6H), 2.82-2.71 (m, 1H), 2.65-2.60 (m, 1H), 2.41-2.32 (m, 1H), 2.25-2.21 (m, 6H), 2.15-2.02 (m, 3H), 1.92-1.90 (m, 1H), 1.80-1.60 (m, 6H), 1.23 (s, 1H), 1.18 (d, J = 9.6 Hz, 3H), 0.89 (bs, 2H), 0.80 (bs, 2H), 0.76-0.71 (m, 3H). Synthesis 18: Synthesis of 3-[7-[1-[[1-[[1-[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione (Compound 93): Step-1: To a stirred solution of 1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]- cyclopropanecarbaldehyde 1 (100 mg, 0.168 mmol) and 3-[7-[1-(4-piperidylmethyl)-4- piperidyl]-1,2-benzoxazol-3-yl]piperidine-2,6-dione 2 (90.51 mg, 0.202 mmol, Hydrochloric acid salt ) in DMSO (1 mL) was added Sodium acetate anhydrous (55.37 mg, 0.674 mmol ), acetic acid (101.33 mg, 1.69 mmol) followed by addition of MP-Cyano borohydride (21.26 mg, 0.337 mmol). The resulting reaction mixture was heated to stir at 70 °C for 16 h. The reaction mixture was filtered and lyophilized to afford crude 3-[7-[1-[[1-[[1-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1,2- benzoxazol-3-yl]piperidine-2,6-dione 3 (0.150 g, 67% yield) as an off white solid, LCMS [ESI]: m/z 988.37 [M+H]⁺. Note: The crude material was directly proceeded for next step without purification. Step-2: To a stirred solution of 3-[7-[1-[[1-[[1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione 3 (150 mg, 0.151 mmol) in DCM (2 mL) was added 4 M HCl in 1,4 dioxane (0.056 mL, 0.227 mmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to get crude which was purified by prep-HPLC Method to afford 3-[7-[1-[[1-[[1-[[7-(8-ethyl-7-fluoro- 3-hydroxy-1-naphthyl)-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1,2- benzoxazol-3-yl]piperidine-2,6-dione Compound 93 (19 mg, 12% yield) as an off white solid LCMS (ESI): m/z 943.75 [M+H] ⁺. Prep HPLC method: Column: X Bridge C18 (10*250*5um) Mobile phase A: 10mM Ammonium bicarbonate in Water. Mobile phase B: 100% Acetonitrile, Gradient (Time / % B): 0/20, 2/25, 10/85, 14/85, 14.10/98, 16.50/20, 19/20, Flow Rate: 18 mL/minutes. Solubility: Acetonitrile+ THF+ water.¹H NMR (400 MHz, DMSO-d6): δ 11.10 (bs, 1H), 9.92 (s, 1H), 9.21 (s, 1H), 7.77 – 7.74 (m, 1H), 7.66 (d, J = 7.6Hz, 1H), 7.50 (d, J = 7.2 Hz,1H) ,7.38 – 7.31 (m, 3H), 7.05 (bs, 1H), 4.41-3.98 (m, 5H), 3.63-3.52 (m, 1H), 3.50-3.35 (m, 1H), 2.94-2.75 (m, 7H), 2.66-2.61 (m, 1H), 2.33-2.20 (m, 4H), 2.18-2.13 (m, 2H), 2.11-1.98 (m, 3H), 1.88-1.84 (m, 6H), 1.76-1.60 (m, 6H), 1.52-1.41 (m, 1H), 1.23 (s, 1H), 1.17 (d, J = 11.2Hz, 3H), 1.07-1.03 (m, 2H), 0.77-0.73 (m, 3H), 0.64 (s, 2H), 0.42 (bs, 2H). Synthesis 19: Synthesis of 3-[7-[1-[1-[[1-[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]-4-piperidyl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione (Compound 94): Step-1: To a stirred solution of 1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclo- propanecarbaldehyde 1 (100 mg, 0.168 mmol) and 3-[7-[1-(4-piperidyl)-4-piperidyl]-1,2- benzoxazol-3-yl]piperidine-2,6-dione 2 (87.67 mg, 0.202 mmol, Hydrochloric acid salt) in DMSO (0.467 mL) was added Sodium acetate (55.37 mg, 0.674 mmol), Acetic acid (101.33 mg, 1.69 mmol) followed by addition of MP-Cyano borohydride (0.674 mg, 0.337 mmol). The resulting reaction mixture was heated to stir at 70 °C for 16 h. The reaction mixture filtered and lyophilized to get crude which was purified by prep-HPLC method to afford 3-[7-[1-[1-[[1-[[7- [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1- piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]-4- piperidyl]-1,2-benzoxazol-3-yl]piperidine-2,6-dione 3 (20 mg, 12% yield) as an off white solid, LCMS [ESI]: m/z 973.82 [M+H]⁺. Prep HPLC method: Column: X Bridge C18 (10*250mm) 5um, Mobile phase A: 10mM Ammonium bicarbonate in Water, Mobile phase B: 100% Acetonitrile, Gradient (Time / % B): 0/45, 2/45, 6/64, 13.3/64, 13.31/100. Flow Rate: 7 mL/minutes. Solubility: Acetonitrile+ THF+ water. Step-2: To a stirred solution of 3-[7-[1-[1-[[1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]-4-piperidyl]-1,2-benzoxazol-3-yl]piperidine- 2,6-dione 3 (20 mg, 0.205 mmol ) in DCM (1.99 mL) was added 4 M HCl in 1,4 dioxane (0.051 mL,0.205 mmol) at 0 °C . The reaction mixture was allowed to stir at room temperature for 1 hour and concentrated under reduced pressure to get crude which was triturated with pentane and lyophilized to afford 3-[7-[1-[1-[[1-[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl] methyl]-4-piperidyl]-4-piperidyl]-1,2-benzoxazol-3-yl]piperidine-2,6-dione Compound 94 (19 mg, 88% yield, Hydrochloric acid salt) as a white solid. LCMS (ESI): m/z 929.67 [M+H] ⁺.¹H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 10.85 (s, 1H), 9.96 (bs, 1H), 9.56 (bs, 1H), 9.25 (s, 1H), 7.77-7.35 (m, 2H), 7.47-7.46 (m, 1H), 7.40 (t, J =7.6 Hz,1H), 7.34 (t, J = 9.2 Hz, 2H), 7.04 (m, 1H), 4.64-4.60 (m, 2H), 4.36 (m, 3H), 4.17-4.02 (m, 1H), 3.88-3.86 (m, 2H), 3.65-3.56 (m, 5H), 3.25 (bs, 4H), 3.05-3.03 (m, 2H), 2.82-2.72 (m, 1H), 2.67-2.60 (m, 2H), 2.44-2.84 (m, 4H), 2.21-2.08 (m, 8H), 1.72-1.66 (m, 3H), 1.19-1.17 (m, 3H), 0.76-0.71 (m, 7H). Synthesis 20: Synthesis of 3-[6-[1-[1-[[1-[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-

yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]-4-piperidyl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione (Compound 95): Step-1: To a stirred solution of 1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclo- propanecarbaldehyde 1 (100 mg, 168.74 μmol) and 3-[6-[1-(4-piperidyl)-4-piperidyl]-1,2- benzoxazol-3-yl]piperidine-2,6-dione 2 (87.67 mg, 202.49 μmol, Hydrochloric acid salt ) in DMSO (0.5 mL) was added Sodium acetate, anhydrous (55.37 mg, 0.674 mmol), acetic acid (101.33 mg, 1.69 mmol) followed by addition of MP-Cyanoborohydride (21.26 mg, 337.48 μmol). The resulting reaction mixture was heated to stir at 70 °C for 16 h. The reaction mixture was filtered and lyophilized to get crude which was purified by prep-HPLC to afford 3-[6-[1-[1- [[1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3- methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]- 4-piperidyl]-1,2-benzoxazol-3-yl]piperidine-2,6-dione 3 (25 mg) as an off white solid, LCMS [ESI]: m/z 974.74 [M+H] ⁺. Prep HPLC method: Column: X Bridge C18 (10*250mm) 5um, Mobile phase A: 10mM Ammonium bicarbonate in Water, Mobile phase B: 100% Acetonitrile, Gradient (Time / %B): 0/65, 3/65, 7/75, 11/75, 11.31/100 Flow Rate: 7mL/minutes. Solubility: Acetonitrile+ THF+ water. Step-2: To a stirred solution of 3-[6-[1-[1-[[1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]-cyclopropyl]methyl]-4-piperidyl]-4-piperidyl]-1,2-benzoxazol-3-yl]piperidine- 2,6-dione 3 (25 mg, 25.69 μmol) in DCM (2 mL) was added 4M HCL in 1,4 dioxane (0.064 mL, 0.256 mmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 1 hour and concentrated under reduced pressure to get crude product which was triturated with pentane and lyophilized to afford 3-[6-[1-[1-[[1-[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]-4-piperidyl]-1,2-benzoxazol-3-yl]piperidine- 2,6-dione Compound 95 (22 mg, 77% yield, Hydrochloric acid salt) as an yellow solid, LCMS (ESI): m/z 929.80 [M+H] ⁺.¹H NMR (400 MHz, DMSO-d6): δ 11.10 (bs, 2H), 9.96 (s, 1H), 9.96 (s, 1H), 9.26(s, 1H), 7.84 – 7.82 (m, 1H), 7.78-7.74 (m, 1H), 7.59(s, 1H), 7.37-7.28 (m, 3H), 7.04 (m, 1H), 4.60-4.57 (m, 1H), 4.22-4.05 (m, 1H), 4.36 (m, 3H), 3.88-3.85 (m, 2H), 3.56- 3.53 (m, 4H), 3.24 (bs, 2H), 3.16-3.01 (m, 5H), 2.85-2.72 (m, 1H), 2.59-2.50 (m, 1H), 2.41 (m, 4H), 2.28-2.06 (m, 10H), 1.72-1.67 (m, 3H), 1.19-1.15 (m, 3H), 0.90-0.76 (m, 4H), 0.74-0.71 (m, 3H). Synthesis 21: Synthesis of 3-(4-(1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)phenoxy)piperidine-2,6-dione (Compound 96)

Step 1: Into a 20 mL vial containing a well-stirred solution of (R)-1-(((7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (100 mg, 0.148 mmol) and 3-(4- (piperidin-4-yl)phenoxy)piperidine-2,6-dione 2 (51.90 mg, 0.178 mmol) in DMSO (3 mL) were added acetic acid (89.17 mg, 1.48 mmol) and sodium acetate, anhydrous (36.54 mg, 0.445 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere. MP-Cyanoborohydride; 2mmol/g (200 mg, 0.400 mmol) was added and the reaction mixture was heated at 70 °C for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered and concentrated under vacuum to get crude, which was purified by reverse phase column chromatography [Column: [RediSep-RF Gold C18- 60g, Mobile phase A: 0.1% ammonium bicarbonate in MQ-water; Mobile phase B: Acetonitrile and fractions were lyophilized to afford 3-(4-(1-((1-(((7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4- yl)phenoxy)piperidine-2,6-dione 3 (60 mg, 0.063 mmol, 43% yield) as an off-white fluffy solid. LC-MS (ES⁺): m/z 865.3 [M+H] ⁺ Step 2: Into a 50 mL single neck-round bottom flask a well-stirred solution of 3-(4-(1-((1-(((7- (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4- yl)phenoxy)piperidine-2,6-dione 3 (60 mg, 0.066 mmol) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (0.33 mL, 1.33 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get a crude residue, which was purified by prep HPLC to furnish 3-(4-(1-((1-(((7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)phenoxy)piperidine-2,6-dione Compound 96; 10 mg, 0.011 mmol, 18% yield) as an off white fluffy solid. Preparative HPLC Method: Column/dimensions: X SELECT C18 (19*250mm); Mobile phase A :0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile; Flow rate: 5 microns/minutes. LC-MS (ES⁺): m/z 821.3 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d6) δ = 10.92 (s, 1H), 9.99 ( s, 1H), 9.22 (s, 1H), 7.77 (dd, J = 6.0, 9.0 Hz, 1H), 7.39-7.32 (m, 2H), 7.13-7.08 (m, 2H), 7.03 (d, J = 2.5 Hz, 1H), 6.93-6.88 (m, 2H), 5.13 (dd, J = 5.1, 10.6 Hz, 1H), 4.77 ( d, J = 7.8 Hz, 1H), 4.42-4.28 (m, 3H), 4.10-3.99 (m, 1H), 3.66-3.61 (m, 1H), 3.56-3.50 (m, 2H), 3.11-3.01 (m, 2H), 2.75-2.65 (m, 1H), 2.64-2.55 (m, 1H), 2.42-2.35 (m, 2H), 2.35-2.32 (m, 1H), 2.21-2.13 (m, 2H), 2.13-2.06 (m, 2H), 1.99-1.90 (m, 2H), 1.74-1.62 (m, 5H), 1.60-1.49 (m, 2H), 1.20-1.14 (m, 3H), 0.73 (q, J = 7.1 Hz, 3H), 0.69-0.65 (m, 2H), 0.46-0.41 (m, 2H) Synthesis 22: Synthesis of 3-(5-(1-((1-(((7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-2- oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 97)

Step 1: Into a 20 mL vial containing a well-stirred solution of (R)-1-(((7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (100 mg, 168.74 μmol) and 3-(2- oxo-5-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione B-6 (61.32 mg, 168 mmol) in dry MeOH (3 mL) was added acetic acid (20.27 mg, 0.337 mmol) at room temperature and stirred under nitrogen atmosphere for 3 hours. MP-CNBH₃ (150 mg, 0.3 mmol) was added to the reaction and stirred for 14 hours. After completion of the reaction as indicated by UPLC- MS, the reaction mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to get a crude residue that was purified by a reversed-phase column chromatography [Column: RediSep Rf Gold C18-50g; Mobile phase: A: 0.1% Formic acid in water, Mobile phase B: Acetonitrile] to afford 3-(5-(1-((1-(((7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-2- oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 3 (40 mg, 0.028 mmol, 17% yield) as a yellow solid. LCMS (ES⁺): m/z 940.2 [M+H]⁺. Step 2: Into a 10 mL single-necked round-bottomed flask containing a well-stirred solution of 3- (5-(1-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine- 2,6-dione 2 (40 mg, 0.028 mmol) in anhydrous DCM (2 mL) was added 4M HCl in 1,4-dioxane (0.2 mL, 0.8 mmol) under nitrogen atmosphere. The contents were stirred at ambient temperature for 3 hours. After completion of the starting material as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get crude residue. The crude residue was purified by preparative HPLC to afford 3-(5-(1-((1-(((7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-2- oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 3 (Compound 97; 16 mg, 0.0176 mmol, 41% yield) as an off-white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C18 (19*150mm); Mobile phase A :0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile; Flow rate: 5 microns/minutes. LCMS (ES+): m/z 896.3 [M+H]⁺ and ¹H NMR (400 MHz, DMSO-d6) δ = 11.20-11.02 (m, 1H), 10.12-9.81 (m, 1H), 9.24 (s, 1H), 8.01 (d, J = 7.3 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.76 (dd, J = 6.1, 8.9 Hz, 1H), 7.66 (dd, J = 2.1, 7.1 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.38-7.31 (m, 2H), 7.14 (d, J = 7.3 Hz, 1H), 7.05-7.00 (m, 1H), 5.48-5.38 (m, 1H), 4.75 ( d, J = 11.0 Hz, 1H), 4.47-4.29 (m, 3H), 4.13-4.00 (m, 1H), 3.65 ( d, J = 13.1 Hz, 1H), 3.54 ( d, J = 13.3 Hz, 1H), 3.43-3.40 (m, 1H), 3.39-3.37 (m, 1H), 3.21-3.10 (m, 2H), 2.97- 2.89 (m, 1H), 2.82-2.72 (m, 1H), 2.65-2.61 (m, 1H), 2.46-2.39 (m, 2H), 2.22-2.12 (m, 3H), 2.11- 2.04 (m, 2H), 1.88-1.74 (m, 4H), 1.74-1.61 (m, 3H), 1.22-1.14 (m, 3H), 0.78-0.67 (m, 5H), 0.54- 0.42 (m, 2H). Synthesis 23: Synthesis of 3-(5-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3- d]pyrimidyl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2- oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 99) Step 1: Into a 20 mL screw-capped vial containing well-stirred solution of (R)-1-(((7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (90 mg, 0.131 mmol), 3-(2-oxo-5-(1-(piperidin-4-ylmethyl)piperidin-4-yl)benzo[cd]indol-1(2H)- yl)piperidine-2,6-dione C-50 (63 mg, 0.124 mmol, HCl salt) in anhydrous DMSO (4 mL) were added sodium acetate (32.42 mg, 0.395 μmol), acetic acid (197.78 mg, 3.29 μmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. MP- cyanoborohydride; 2mmol\g (22 mg, 0.044 mmol) was added to the reaction mixture and stirred at 70 °C for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was passed through a sintered funnel and concentrated under reduced pressure to get the crude compound that was purified by reverse phase column chromatography [Column: Redisep RF Gold C18–50 g; mobile phase A: 0.1% ammonium bicarbonate in water, Mobile phase B: Acetonitrile to afford 3-(5-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-oxobenzo[cd]indol- 1(2H)-yl)piperidine-2,6-dione 2 (100 mg, 0.094 mmol, 72% yield) as an off-white solid. LC- MS (ES⁺): m/z 1037.3 [M+H]⁺. Step 2: Into a 25 mL single-neck round-bottom flask containing well-stirred solution of 3-(5-(1- ((1-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-oxobenzo[cd]indol- 1(2H)-yl)piperidine-2,6-dione 2 (100 mg, 0.094 mmol) in DCM (2 mL) was added 4N HCl in 1,4-dioxane (0.3 mL, 1.20 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get crude compound that was purified by a reversed-phase PREP HPLC to furnish 3-(5-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2- oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 99) (30 mg, 0.029 mmol, 31% yield) as off white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C8 (19*250mm); Mobile phase A: 0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile; Flow rate: 5 microns/minutes. LC-MS (ES⁺): m/z 993.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ = 11.11 (s, 1H), 9.94 (d, J = 3.3 Hz, 1H), 9.23 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.82 (s, 1H), 7.77 (dd, J = 9.1, 6.1 Hz, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.57-7.51 (m, 1H), 7.38-7.32 (m, 2H), 7.15 (d, J = 7.3 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 5.48-5.41 (m, 1H), 4.75 (d, J = 4.9 Hz, 1H), 4.38-4.27 (m, 3H), 4.10-3.99 (m, 1H), 3.70-3.62 (m, 1H), 3.44- 3.37 (m, 2H), 3.01-2.91 (m, 5H), 2.83-2.73 (m, 1H), 2.65-2.55 (m, 2H), 2.47-2.44 (m, 1H), 2.40- 2.35 (m, 1H), 2.31-2.28 (m, 1H), 2.20-2.09 (m, 6H), 2.05-1.98 (m, 1H), 1.92-1.80 (m, 6H), 1.73- 1.63 (m, 5H), 1.55-1.45 (m, 1H), 1.21-1.16 (m, 3H), 1.12-1.02 (m, 2H), 0.80-0.72 (m, 3H), 0.65 (s, 2H), 0.41 (s, 2H). Synthesis 24: Synthesis of 3-[7-[9-[[1-[[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione (Compound 100): To a stirred solution of (3R)-1-[2-[[1-[[tert-butyl(dimethyl)silyl]oxymethyl]- cyclopropyl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol 1 (500 mg, 978.28 μmol) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane 2 (752.10 mg, 1.47 mmol) in a mixture of THF (2 mL) and Water (0.5 mL) was added K3PO4 (622.97 mg, 2.93 mmol). The reaction mixture was degassed with argon for 5 minutes. Catacxium® A Pd G3 (142.49 mg, 195.66 μmol) was added and resulting reaction mixture was heated to stirred at 110 °C for 1 hour in microwave. The reaction mixture was concentrated under reduced pressure to get crude, which was purified by flash column chromatography (100-200 silica gel) using 20-30% ethyl acetate in petroleum ether as an eluent to afford (3R)-1-[2-[[1-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclopropyl]methoxy]-8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3- methyl-piperidin-3-ol 3 (500 mg, 55% yield) as brown solid, LCMS (ESI): m/z 861.77 [M+H]⁺. Step-2: To a stirred solution of (3R)-1-[2-[[1-[[tert-butyl(dimethyl)silyl]oxy- methyl]cyclopropyl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol 3 (500 mg, 580.57 μmol) in DCM (3 mL) was added TBAF (1.0 M in THF, 3.75 mL) at 0 °C. The resulting reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was quenched with cold water concentrated under reduced pressure to get crude which was purified by flash column chromatography (100-200 silica gel) using 60-70% ethyl acetate in petroleum ether as an eluent to afford (3R)-1-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 3-methyl-piperidin-3-ol 4 (300 mg, 84% yield) as yellow solid, LCMS (ESI): m/z 591.40 [M+H]⁺. Step-3: To a stirred solution of (3R)-1-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl- piperidin-3-ol 4 (300 mg, 507.94 μmol) in a mixture of Acetonitrile (2 mL) and Dichloromethane (2 mL) at 0 °C. Dess-Martin Periodinane (430.88 mg, 1.02 mmol) was added portion wise over a period of 5 minutes. The resulting reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution and concentrated under reduced pressure to get crude compound which was purified by column chromatography using (100-200 silica gel) 40-50% ethyl acetate in petroleum ether as an eluent to afford 1-[[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropanecarbaldehyde 5 (200 mg, 62 % yield) as brown solid. LCMS (ESI): m/z 589.57 [M+H]⁺. Step-4: To a stirred solution of 1-[[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropanecarbaldehyde 5 (100 mg, 169.89 μmol) and 3-[7-(3,9- diazaspiro[5.5]undecan-3-yl)-1,2-benzoxazol-3-yl]piperidine-2,6-dione 6 (92.52 mg, 220.86 μmol, Hydrochloric acid salt) in DMSO (4 mL) was added Sodium acetate, anhydrous (55.75 mg, 679.58 μmol), acetic acid (102.02 mg, 1.70 mmol) and stirred the reaction mixture at room temperature for 2 hours. MP-Cyano borohydride (200 mg, 339.79 μmol) was added and the resulting reaction mixture was heated to stir at 70 °C for 12 hours. The reaction mixture was quenched with ice cold water to get precipitated solid, which was filtered to get crude which was purified by Prep-HPLC Method to afford 3-[7-[9-[[1-[[7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido-[4,3- d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]-1,2- benzoxazol-3-yl]piperidine-2,6-dione 7 (30 mg, 19 % yield) as an off white solid, LCMS [ESI]: m/z 955.96 [M+H]⁺. Prep-HPLC method: Mobile Phase A: 10 mm Ammonium bicarbonate spiked with 0.1% Ammonia, Mobile phase B: Acetonitrile, Gradient: 0/40, 1/40, 8/75, 13/75, 13.10/100, 15/100, 15.10/40, 18/40, Flow Rate: 16 mL/min, Solubility: Acetonitrile+ water+ THF+ DMSO. Step-5: To a stirred solution of 3-[7-[9-[[1-[[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]-cyclopropyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione 7 (20 mg, 20.94 μmol) in DCM (0.5 mL) was added 4M HCl in 1,4- dioxan (0.01 mL) at 0 °C. The resulting reaction mixture was allowed to stir at room temperature for 30 min and concentrated under reduced pressure to get crude which was triturated with diethyl ether and lyophilized to afford 3-[7-[9-[[1-[[7-(8-ethynyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]-methyl]-3,9-diazaspiro[5.5]undecan-3-yl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione Compound 100 (18 mg, 95 % yield, Hydrochloric acid salt) as a yellow solid, LCMS (ESI): m/z 911.70 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 10.20 (bs, 1H), 9.26-9.10 (m, 1H), 8.00-7.96 (m, 1H), 7.49-7.40 (m, 2H), 7.29-7.17 (m, 3H), 7.03-6.98 (m, 1H), 4.92-4.51 (m, 2H), 4.50-4.01 (m, 4H), 3.96-3.75 (m, 1H), 3.62-3.52 (m, 3H), 3.33-3.25 (m, 5H), 3.20-3.02 (m,4H), 2.81-2.70 (m, 1H), 2.66-2.54 (m, 2H), 2.30-2.15 (m, 1H), 2.13 (m, 1H), 2.0-1.90 (m, 2H), 1.87-1.79 (m, 2H), 1.77-1.45 (m, 7H), 1.30-1.08 (m, 3H), 0.88-0.79 (m, 4H). Synthesis 25: Synthesis of 3-(7-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyrido[4,3-d]pyrimidin- 2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (Compound 101) Step 1: Into a 100 mL single-neck round-bottom flask containing a well-stirred solution of (R)- 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol A-130 (180 mg, 0.276 mmol) in DCM (7 mL) was added Dess-Martin Periodinane (351.98 mg, 0.829 mmol) at 0 ºC and stirred at ambient temperature for 3 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was quenched with aqueous sodium bicarbonate solution (30 mL) and extracted with DCM (2 X 70 mL). The combined organic layers were dried over anhydrous sodium sulphate_, filtered and the filtrate was concentrated under reduced pressure to get crude residue. The crude residue was purified by flash silica gel (230-400 mesh) column chromatography with 0-100% ethyl acetate/petroleum ether while desired compound eluting at 60% of the mobile phase to afford (R)-1-(((7-(8-ethyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)- 5-methoxypyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (100 mg, 0.156 mmol, 56% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 622.7 [M+H] ⁺. Step 2: Into a 20 mL glass vial containing a well-stirred solution of (R)-1-(((7-(8-ethyl-7-fluoro- 3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-5- methoxypyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (90 mg, 0.144 mmol) in DMSO (4 mL) was added 3-[1-methyl-7-[1-(4-piperidylmethyl)-4- piperidyl]indazol-3-yl]piperidine-2,6-dione C-47 (61.22 mg, 0.144 mmol, HCl salt) and sodium acetate, anhydrous (59.28 mg, 0.722 mmol) and acetic acid (168.39 mg, 2.80 mmol) and stirred at ambient temperature for 2 hours. MP-Cyanoborohydride; 2mmol\g (160 mg, 0.320 mmol) was added to the reaction mixture and stirred at 70 ºC for 16 h. After completion of the reaction as indicated by LCMS, the reaction mixture was filtered and washed with DCM (20 mL) and concentrated under reduced pressure to get the crude residue. The crude residue was purified by reverse-phase column using C18 column, mobile phase: A:0.1% NH₄CO₃ in water; B: Acetonitrile, Flow rate: 25 mL/minutes; while desired compound eluting at methanol to afford 3-(7-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)-5-methoxypyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione 2 (70 mg, 0.057 mmol, 40% yield) as a pale yellow solid. LC- MS (ES⁺): m/z 1031.3 [M+H]⁺. Step 3: Into a 50 mL single-neck round-bottom flask containing a well-stirred solution of 3-(7- (1-((1-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)-5-methoxypyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione 2 (70 mg, 0.057 mmol) in DCM (4 mL) was added 4M HCL in 1,4-dioxane (0.557 mmol, 0.14 mL) and stirred at ambient temperature for 2 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get crude residue. The crude residue was purified by reverse phase preparatory HPLC to furnish 3-(7-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione Compound 101 (17 mg, 0.017 mmol, 30% yield) as an off- white solid. Preparative HPLC Method: Column/dimensions: X Select C18(250*19)mm, Mobile phase A: 0.1% Ammonium bicarbonate B:Acetonitrile (100%); Gradient (Time/%B): 0/10,3/10,10/30,14/30,15/95,20/95,20.10/10,22/10; Flow rate: 5 microns/min; Solubility: WATER+THF+CAN.¹H NMR (400 MHz, DMSO-d6) δ = 10.88 (s, 1H), 10.04 (br dd, J = 3.0, 4.9 Hz, 1H), 7.79-7.72 (m, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.38-7.31 (m, 2H), 7.25 (d, J = 7.3 Hz, 1H), 7.10-7.04 (m, 2H), 4.58-4.40 (m, 1H), 4.38-4.25 (m, 3H), 4.20 (s, 3H), 3.93-3.89 (m, 3H), 3.65-3.52 (m, 2H), 3.45-3.36 (m, 1H), 3.30-3.23 (m, 2H), 2.99-2.86 (m, 4H), 2.67-2.60 (m, 1H), 2.56-2.52 (m, 3H), 2.47-2.42 (m, 1H), 2.38-2.34 (m, 1H), 2.32-2.26 (m, 2H), 2.25-2.03 (m, 6H), 1.88-1.72 (m, 6H), 1.69-1.60 (m, 5H), 1.52-1.41 (m, 1H), 1.11-1.00 (m, 4H), 0.86-0.77 (m, 3H), 0.64 (s, 2H), 0.40 (s, 2H). LC-MS (ES⁺): m/z 986.4 [M+H]⁺. Synthesis 26: Synthesis of 3-(7-(1-((1-((1-(((5-ethoxy-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound 102)

Step-1: Into a 20 mL vial containing well-stirred solution of 7-chloro-5-ethoxy-8-fluoro-2- methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one A-156 (500 mg, 1.69 mmol) in DMF (5 mL) were added PyBOP (1.15 g, 2.20 mmol), DIPEA (1.09 g, 8.47 mmol, 1.48 mL) and (3R)-3- methylpiperidin-3-ol 1 (308.29 mg, 2.03 mmol, HCl salt) at 0 ºC and stirred at ambient temperature for 3 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get the crude material that was purified by reversed-phase column chromatography [Redisep C18 column; Mobile phase: 0.1% Formic acid in water and ACN], to afford (3R)-1-(7-chloro-5-ethoxy-8-fluoro-2-methylsulfanyl-pyrido[4,3- d]pyrimidin-4-yl)-3-methyl-piperidin-3-ol 2 (0.55 g, 1.37 mmol, 81% yield) as off-white solid. LC-MS (ES⁺): m/z 387.1 [M+H]⁺. Step 2: Into a 40 mL vial containing well stirred solution of (3R)-1-(7-chloro-5-ethoxy-8-fluoro-2- methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-3-methyl-piperidin-3-ol 2 (400 mg, 0.994 mmol), 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 3 (1.07 g, 2.98 mmol) in 1,4-dioxane (9 mL) and water (1 mL) was added cesium carbonate (1.30 g, 3.98 mmol) at room temperature. Nitrogen gas was purged through a reaction mixture for 10 minutes. Then PdCl2(dppf).CH₂Cl2 (243.61 mg, 0.298 mmol) was added to the reaction mixture and stirred at 110 °C for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was passed through a pad of Celite and concentrated the filtrate under reduced pressure to get crude residue. The crude material was purified by flash silica gel (230- 400 mesh) column chromatography (50% EtOAc in petroleum ether) and re-purified by reverse phase column chromatography by using redisep C18 column; mobile phase: 10 mM NH4HCO3 in water and MeCN to afford (3R)-1-[5-ethoxy-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol 4 (430 mg, 0.718 mmol, 72% yield) as off-white solid. LC-MS (ES⁺): m/z 585.3 [M+H]⁺. Step 3: Into a 25 mL single-neck round-bottom flask containing well-stirred solution of (3R)-1- [5-ethoxy-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-methylsulfanyl- pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol 4 (330 mg, 0.551 mmol) in anhydrous DCM (12 mL) was added m-CPBA (292.77 mg, 1.10 mmol, 65% purity) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1.5 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was diluted with EtOAc (100 mL), washed with aqueous NaHCO₃ solution (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to get (3R)-1-[5-ethoxy-7-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-methylsulfonyl-pyrido[4,3-d]pyrimidin-4- yl]-3-methyl-piperidin-3-ol 5 (350 mg, 0.357 mmol, 65% yield) as off white solid. LC-MS (ES⁺): m/z 617.4 [M+H]⁺. Step 4: Into a 50 mL single-neck round-bottom flask containing well stirred solution of (R)-1- (5-ethoxy-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 7 (350 mg, 0.357 mmol), [1-(hydroxymethyl)cyclopropyl]methanol 5 (109.56 mg, 1.07 mmol) in anhydrous THF (5 mL) was added 1M LHMDS in THF (2.5 mL, 2.5 mmol) at 0 ºC. The resulting reaction mixture was stirred at room temperature for 1.5 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was quenched with aqueous 1.5N HCl solution and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na₂SO_4, filtered and filtrate was concentrated under reduced pressure to get crude residue. The crude residue was purified by reverse phase column chromatography by using RediSep C18 column; mobile phase: 10 mM NH4HCO3 in water and ACN to afford (3R)-1-[5-ethoxy-7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1- (hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol 6 (0.21 g, 0.324 mmol, 91% yield) as off white solid. LC-MS (ES⁺): m/z 638.7 [M+H]⁺. Step-5: Into a 50 mL single-neck round-bottom flask containing well stirred solution of (3R)-1- [5-ethoxy-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1- (hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol 6 (200 mg, 0.308 mmol) in DCM (10 mL) was added Dess-Martin Periodinane (392.59 mg, 0.925 mmol) at 0 ºC and stirred at ambient temperature for 4 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was quenched with aqueous sodium bicarbonate solution (30 mL) and aqueous sodium thiosulphate solution (30 mL). Aqueous layer was extracted with DCM (3 X 30 mL). Combined organic layers were dried over anhydrous Na2SO4, filtered and filtrate was concentrated under reduced pressure to get crude compound. This reaction crude was purified by flash silica gel (230-400 mesh) column chromatography (60% EtOAc in petroleum ether) to get 1-[[5-ethoxy-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropanecarbaldehyde 7 (150 mg, 0.233 mmol, 76% yield) as off-white solid. LC-MS (ES⁺): m/z 636.6 [M+H]⁺. Step 6: Into a 20 mL screw cap vial containing well stirred solution of 1-[[5-ethoxy-7-[8-ethyl- 7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1- piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde 7 (100 mg, 0.155 mmol), 3-[1-methyl-7-[1-(4-piperidylmethyl)-4-piperidyl]indazol-3-yl]piperidine-2,6-dione C- 47 (100 mg, 0.195 mmol, HCl salt) in anhydrous DMSO (3 mL) were added sodium acetate (50 mg, 0.609 mmol) and acetic acid (467.40 mg, 7.78 mmol) at 0 ºC and allowed to stir at ambient temperature for 2 hours. Then MP-cyanoborohydride; 2mmol\g (155 mg, 0.311 mmol) was added to the reaction mixture and stirred at 70 ºC for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get crude material. The crude material was purified by reverse phase column chromatography by using RediSep C18 column; Mobile phase: 10 mM NH₄HCO₃ in water and MeCN to afford 3-[7-[1- [[1-[[1-[[5-ethoxy-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3- hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione 8 (100 mg, 0.086 mmol, 56% yield) as an off-white solid. LC-MS (ES⁺): m/z 1044.4 [M+H] ⁺. Step 7: Into a 25 mL single-neck round-bottom flask containing well stirred solution of 3-[7-[1- [[1-[[1-[[5-ethoxy-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3- hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione 9 (100.00 mg, 0.086 mmol) in DCM (2 mL) was added 4N HCl in 1,4-dioxane (0.215 mL, 0.86 mmol) at 0 ºC and stirred at same reaction condition for 30 minutes. After completion of the reaction as indicated by UPLC the reaction mixture was concentrated under reduced pressure to get crude. The crude material was purified by reverse-phase PREP HPLC to afford 3-[7-[1-[[1-[[1-[[5-ethoxy-7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1- piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4- piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 102 (37 mg, 0.0356 mmol, 41% yield) as off- white solid. Preparative HPLC Method: Column/dimensions: [X-bridge C8 (250 X 19)mm 5 microns, Mobile phase A: 0.1% Ammonium bicarbonate B:Acetonitrile (100%); Gradient (Time/%B): 0/10,3/10,10/30,14/30,15/95,20/95,20.10/10,22/10 Solubility: Water+ THF+ acetonitrile.¹H NMR (400 MHz, DMSO-d6) δ = 10.76 (br s, 1H), 7.74-7.68 (m, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.34-7.23 (m, 3H), 7.09-7.03 (m, 2H), 4.43-4.27 (m, 6H), 4.20 (s, 3H), 4.16-4.00 (m, 1H), 3.62-3.52 (m, 2H), 2.97-2.88 (m, 4H), 2.70-2.63 (m, 2H), 2.37-2.23 (m, 5H), 2.19-2.04 (m, 5H), 1.88-1.76 (m, 6H), 1.68-1.61 (m, 5H), 1.51-1.43 (m, 1H), 1.37-1.31 (m, 4H), 1.10-0.99 (m, 6H), 0.92-0.86 (m, 1H), 0.85-0.77 (m, 3H), 0.64 (br s, 2H), 0.40 (br s, 2H). LC-MS (ES⁺): m/z 1000.3 [M+H]⁺. Synthesis 27: Synthesis of 3-(7-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-5-isopropoxypyrido[4,3-d]pyrimidin- 2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (Compound 103) Step 1: Into a 50 mL single-neck round-bottom flask containing well stirred solution of (3R)-1- [7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1- (hydroxymethyl)cyclopropyl]methoxy]-5-isopropoxy-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl- piperidin-3-ol A-132 (200 mg, 0.299 mmol) in DCM (10 mL) was added Dess-Martin periodinane (380.87 mg, 0.898 mmol) at 0 ºC and stirred at ambient temperature for 4 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was quenched with aqueous sodium bicarbonate solution (20 mL) and aqueous sodium thiosulphate solution (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were dried over anhydrous Na₂SO_4, filtered and the filtrate was concentrated under reduced pressure to get crude residue. The crude residue was purified by flash silica gel (230-400 mesh) column chromatography (55% EtOAc in petroleum ether) to get 1-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]-5- isopropoxy-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde 1 (155 mg, 0.235 mmol, 79% yield) as off-white solid. LC-MS (ES⁺): m/z 650.7 [M+H] ⁺. Step 2: Into a 20 mL screw cap vial containing well-stirred solution of 1-[[7-[8-ethyl-7-fluoro- 3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidyl]-5- isopropoxy-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde 1 (100 mg, 0.152 mmol), 3-[1-methyl-7-[1-(4-piperidylmethyl)-4-piperidyl]indazol-3-yl]piperidine-2,6- dione C-47 (100 mg, 0.195 mmol, HCl salt) in anhydrous DMSO (3 mL) were added sodium acetate (50 mg, 0.609 mmol) and acetic acid (456.71 mg, 7.61 mmol) and stirred at ambient temperature for 2 hours. Then MP-cyanoborohydride; 2mmol\g (152 mg, 0.304 mmol) was added to the reaction mixture and stirred at 70 ºC for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get crude. The crude material was purified by reverse phase column chromatography by using Redisep C18 column; mobile phase: A: 0.1%Ammonium bicarbonate in water and B: Acetonitrile, Flow rate: 25 mL/minutes; while desired compound eluting at 60% of the mobile phase to afford 3-[7-[1- [[1-[[1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3- methyl-1-piperidyl]-5-isopropoxy-pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3- yl]piperidine-2,6-dione 2 (110 mg, 0.099 mmol, 66% yield) as off white solid. LC-MS (ES⁺): m/z 1058.4 [M+H]⁺. Step 3: Into a 25 mL single-neck round-bottom flask containing well-stirred solution of 3-[7-[1- [[1-[[1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3- methyl-1-piperidyl]-5-isopropoxy-pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3- yl]piperidine-2,6-dione 2 (110.00 mg, 0.099 mmol) in DCM (2 mL) was added 4N HCl in 1,4- dioxane (0.247 mL, 0.99 mmol) at 0 ºC and stirred at same reaction condition for 30 minutes. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get crude. The crude material was purified by a reverse-phase prep HPLC to afford 3-[7-[1-[[1-[[1-[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-[(3R)- 3-hydroxy-3-methyl-1-piperidyl]-5-isopropoxy-pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3- yl]piperidine-2,6-dione Compound 103 (15 mg, 0.014 mmol, 15% yield) as off white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C8 (19*250mm); Mobile phase A :0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile (100%); Gradient (Time/%B): 0/10,3/10,10/30,14/30,15/95,20/95,20.10/10,22/10; Flow rate: 5 microns/min; Solubility: WATER+THF+CAN.¹H NMR (400 MHz, DMSO-d₆) δ = 10.88 (br s, 1H), 10.06 (br s, 1H), 7.78-7.72 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.37-7.30 (m, 2H), 7.25 (d, J = 7.1 Hz, 1H), 7.11-7.04 (m, 2H), 5.40-5.32 (m, 1H), 4.57-4.32 (m, 3H), 4.31-4.25 (m, 2H), 4.20 (s, 3H), 3.79-3.62 (m, 2H), 3.60-3.51 (m, 1H), 3.46-3.39 (m, 1H), 2.98-2.85 (m, 4H), 2.72-2.61 (m, 2H), 2.40-2.18 (m, 6H), 2.14-2.04 (m, 4H), 1.88-1.73 (m, 7H), 1.70-1.61 (m, 5H), 1.37-1.27 (m, 7H), 1.07-0.98 (m, 5H), 0.82-0.75 (m, 3H), 0.63 (br s, 2H), 0.40 (br s, 2H). LC-MS (ES⁺): m/z 1014.4 [M+H]⁺. Synthesis 28: Synthesis of 3-(7-(1-((1-((1-(((5-cyclopropoxy-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl) pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound 104)

Step 1: Into a 40 mL screw-capped vial containing a stirred solution of 7-chloro-5-cyclopropoxy- 8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one A-35 (1.1 g, 2.81 mmol) in anhydrous DMF (8 mL) were added DIPEA (1.81 g, 14.04 mmol, 2.44 mL), PyBOP (1.90 g, 3.65 mmol) and (R)-3-methylpiperidin-3-ol HCl salt 1 (553.37 mg, 3.65 mmol). The resultant mixture was stirred at room temperature for 3 hours. After completion of the reaction as indicated LCMS, the mixture was concentrated under reduced pressure to afford the crude material which was purified by a reverse-phase HPLC [Column: Redisep Rf Gold C18- 120 g; Mobile phase A: 0.1% Formic acid in water and Mobile Phase B: CH₃CN; Flow rate: 25 mL/min] to afford (R)- 1-(7-chloro-5-cyclopropoxy-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol 2 (1 g, 2.50 mmol, 89% yield) as a white solid. LC-MS (ES⁺): m/z 399.1 [M+H]⁺. Step 2: Into a 40 mL vial containing well stirred solution of (R)-1-(7-chloro-5-cyclopropoxy-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 2 (500 mg, 1.24 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane 3 (1.34 g, 3.72 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added cesium carbonate (1.62 g, 4.96 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 3 minutes. PdCl2(dppf).CH₂Cl₂ (304.03 mg, 0.372 mmol) was added to the reaction mixture and stirred at 110 °C for 16 h. After completion of the reaction as indicated by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to get the crude material that was purified by a reverse-phase HPLC [Column: Redisep Rf Gold C18-120 g; Mobile phase A: 0.1% Formic acid in water and Mobile Phase B: Acetonitrile] to afford (R)-1-(5-cyclopropoxy-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol 4 (350 mg, 0.566 mmol, 45% yield) as a white solid. LC-MS (ES⁺): m/z 597.2 [M+H] ⁺. Step 3: Into a 50 mL single-neck round-bottom flask containing a well stirred solution of (R)-1- (5-cyclopropoxy-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 4 (350 mg, 0.580 mmol) in anhydrous DCM (10 mL) was added m-CPBA (308.35 mg, 1.16 mmol, 65% purity) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by LCMS, the reaction mixture was diluted with NaHCO₃ solution (20 mL) and extracted with DCM (2 X 25 mL). The combined organic phase was washed with water (15 mL), brine (15 mL), dried (anhydrous Na₂SO₄), filtered and concentrated under reduced pressure to afford (R)-1-(5-cyclopropoxy-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 5 (400 mg, 0.408 mmol, 70% yield) as a brown gummy liquid. UPLC-MS (ES⁺): m/z 629.5 [M+H] ⁺. Step 4: Into a 25 mL single-neck round-bottom flask containing a well stirred solution of (R)-1- (5-cyclopropoxy-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 5 (400 mg, 0.413 mmol) and cyclopropane-1,1-diyldimethanol 6 (126.71 mg, 1.24 mmol) in anhydrous THF (15 mL) was added 1M LiHMDS in THF (2.48 mL, 2.48 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by UPLC- MS, the reaction mixture was quenched with aqueous 1.5N HCl solution (20 mL) and extracted with EtOAc (3 X 100 mL). The combined organic phase was washed with water (20 mL), brine (20 mL), dried (anhydrous Na₂SO₄), filtered and concentrated under reduced pressure to get the crude material, which was purified by a reverse-phase column chromatography [Column: Redisep Rf Gold C18- 120 g; Mobile phase A: 0.1% Formic acid in water and Mobile Phase B: Acetonitrile] to afford (R)-1-(5-cyclopropoxy-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 7 (150 mg, 0.219 mmol, 53% yield) as a white solid. LC-MS (ES⁺): m/z 651.8 [M+H]⁺. Step 5: Into a 50 mL single-neck round-bottom flask containing a well-stirred solution of (R)-1- (5-cyclopropoxy-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 7 (130 mg, 0.189 mmol) in anhydrous DCM (10 mL) was added DMP (241.50 mg, 0.569 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was diluted with sodium bicarbonate solution (15 mL) and Na2S2O3 solution (15 mL) and extracted with DCM (2 X 50 mL). The combined organic phase was washed with water (10 mL), brine (10 mL), dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure to afford (R)-1-(((5- cyclopropoxy-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1- carbaldehyde 8 (110 mg, 0.149 mmol, 79% yield) as a white solid. LC-MS (ES⁺): m/z 649.0 [M+H] ⁺. Step 6: Into a 20 mL screw-capped vial containing a well stirred solution of (R)-1-(((5- cyclopropoxy-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1- carbaldehyde 8 (110 mg, 0.149 mmol), 3-(1-methyl-7-(1-(piperidin-4-ylmethyl)piperidin-4-yl)- 1H-indazol-3-yl)piperidine-2,6-dione C-47 (83.90 mg, 0.164 mmol, HCl salt) in anhydrous DMSO (3 mL) were added sodium acetate, anhydrous (61.20 mg, 0.746 mmol) and acetic acid (0.086 mL, 1.49 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. MP-Cyanoborohydride (2mmol\g) (150 mg, 0.298 mmol) was added to the reaction mixture and stirred at 70 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered and concentrated under reduced pressure to afford the crude material, which was purified by a reverse-phase preparatory HPLC [Column: Redisep Rf Gold C18- 60 g; Mobile phase A: 0.1% Ammonium bicarbonate in water and Mobile Phase B: Acetonitrile] to afford 3-(7-(1-((1-((1-(((5-cyclopropoxy-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 9 (100 mg, 0.088 mmol, 59% yield) as a white solid. LC-MS (ES⁺): m/z 1056.4 [M+H] ⁺. Step 7: Into a 10 mL single-neck round-bottom flask containing a well-stirred solution of 3-(7- (1-((1-((1-(((5-cyclopropoxy-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione 9 (100 mg, 0.088 mmol) in anhydrous DCM (2 mL) was added 4M HCl in 1,4-dioxane (0.22 mL, 0.889 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure to get the crude residue. The crude residue was purified by a reverse-phase preparative HPLC to furnish 3-(7-(1-((1-((1-(((5-cyclopropoxy-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl) pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin- 4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione Compound 104 (28 mg, 0.026 mmol, 29% yield, HCOOH salt) as an off-white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C18 (19*150mm); Mobile phase A: 0.1% HCOOH in water, Mobile phase B: ACN (100%); Flow rate: 5 microns/minutes.¹H NMR (400 MHz, DMSO-d6) δ = 10.88 (s, 1H), 8.19 (s, 1H), 7.79-7.72 (m, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.38-7.30 (m, 3H), 7.25 (d, J = 7.1 Hz, 1H), 7.12-7.04 (m, 2H), 4.57-4.47 (m, 1H), 4.40-4.24 (m, 5H), 4.20 (s, 3H), 4.06-3.87 (m, 1H), 3.80- 3.62 (m, 2H), 3.52-3.42 (m, 3H), 3.01-2.90 (m, 4H), 2.66-2.58 (m, 2H), 2.40-2.35 (m, 2H), 2.30- 2.22 (m, 1H), 2.20-2.11 (m, 4H), 2.11-2.01 (m, 2H), 1.94-1.82 (m, 5H), 1.80-1.72 (m, 1H), 1.67- 1.60 (m, 5H), 1.49-1.49 (m, 1H), 1.51-1.43 (m, 1H), 1.07-0.97 (m, 5H), 0.88-0.79 (m, 4H), 0.77- 0.70 (m, 3H), 0.67-0.62 (m, 2H) and 0.44-0.38 (m, 2H). LC-MS (ES⁺): m/z 1012.4 [M+H]⁺. Synthesis 29: Synthesis of 3-(7-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-5-(methylamino)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound 105)

Step 1: Into a 40 mL screw-capped vial containing a well-stirred solution of 5,7-dichloro-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one 1 (1.5 g, 5.36 mmol) in anhydrous DMA (10 mL) were added DIPEA (3.73 mL, 21.42 mmol, 3.73 mL) and methanamine (1.08 g, 16.07 mmol, HCl salt). The resultant mixture was stirred at 90 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude material, which was purified by a reverse-phase HPLC [Column: Redisep Rf Gold C18-120 g; Mobile phase A: 0.1% Formic acid in water, Mobile phase B: Acetonitrile] to afford 7-chloro-8-fluoro-5-(methylamino)-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one 2 (650 mg, 1.83 mmol, 34% yield) as an off- white solid. LC-MS (ES⁺): m/z 275.0 [M+H] ⁺. Step 2: Into a 20 mL screw-capped vial containing a well-stirred solution of 7-chloro-8-fluoro- 5-(methylamino)-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one 2 (700 mg, 1.96 mmol) in anhydrous DMF (8 mL) were added PyBOP (2.04 g, 3.92 mmol), DBU (0.88 mL, 5.89 mmol) and (R)-3-methylpiperidin-3-ol 3 (595.05 mg, 3.92 mmol, HCl salt). The resultant reaction mixture was stirred at 70 °C for 16 h. After completion of the reaction as indicated by UPLC- MS, the reaction mixture was concentrated under reduced pressure to get the crude residue which was purified by a reverse-phase HPLC [Column: Redisep Rf Gold C18-120 g; Mobile phase A: 0.1% Formic acid in water, Mobile Phase B: Acetonitrile] to afford (R)-1-(7-chloro-8-fluoro-5- (methylamino)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 4 (450 mg, 1.05 mmol, 53% yield; HCOOH salt) as a white solid. LC-MS (ES⁺): m/z 371.9 [M+H] ⁺. Step 3: Into a 40 mL vial containing well stirred solution of (R)-1-(7-chloro-8-fluoro-5- (methylamino)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 4 (430 mg, 0.998 mmol, HCOOH salt), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane 5 (1.08 g, 2.99 mmol) in 1,4-dioxane (8 mL) and water (1 mL) was added cesium carbonate (1.30 g, 3.99 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 3 minutes. PdCl₂(dppf).CH₂Cl₂ (244.53 mg, 0.299 mmol) was added to the reaction mixture and stirred at 110 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude material that was purified by a reversed-phase HPLC [Column: Redisep Rf Gold C18-120 g; Mobile phase A: 0.1% Formic acid in water and Mobile Phase B: Acetonitrile] to afford (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoro-5-(methylamino)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin- 3-ol 6 (380 mg, 0.665 mmol, 66% yield) as a white solid. LC-MS (ES⁺): m/z 570.2 [M+H]⁺. Step 4: Into a 50 mL single-neck round-bottom flask containing well stirred solution of (R)-1- (7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-(methylamino)-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 6 (360 mg, 0.625 mmol) in anhydrous DCM (6 mL) was added m-CPBA (332.20 mg, 1.25 mmol, 65% purity) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was diluted with sodium bicarbonate solution (20 mL) and extracted with DCM (2 X 50 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), dried (anhydrous Na2SO4), filtered and concentrated the filtrate under reduced pressure to afford (R)-1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-(methylamino)-2-(methylsulfonyl)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 7 (400 mg, 0.412 mmol, 66% yield) as an off-white solid. UPLC-MS (ES⁺): m/z 602.5 [M+H] ⁺. Step 5: Into a 50 mL single-neck round-bottom flask containing a well-stirred solution of (R)-1- (7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-(methylamino)-2- (methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol 7 (400 mg, 0.412 mmol) and cyclopropane-1,1-diyldimethanol 8 (126.29 mg, 1.24 mmol) in anhydrous THF (15 mL) was added 1M LiHMDS in THF (2.47 mL, 2.47 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by UPLC- MS, the reaction mixture was quenched with aqueous 1.5N HCl solution (30 mL) and extracted with EtOAc (3 X 50 mL). The combined organic phase was washed with water (20 mL), brine (20 mL), dried (anhydrous Na₂SO₄), filtered and concentrated under reduced pressure to get the crude material, which was purified by a reverse-phase HPLC [Column: Redisep Rf Gold C18- 120 g; Mobile phase A: 0.1% Formic acid in water and Mobile Phase B: Acetonitrile] to afford (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)-5-(methylamino)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol 9 (130 mg, 0.184 mmol, 44% yield) as a white solid. LC-MS (ES⁺): m/z 624.2 [M+H] ⁺. Step 6: Into a 50 mL single-neck round-bottom flask containing well-stirred solution of (R)-1- (7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)-5-(methylamino)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol 9 (110 mg, 0.167 mmol) in anhydrous DCM (10 mL) was added DMP (213.20 mg, 0.502 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was diluted with sodium bicarbonate solution (15 mL) and Na2S2O3 solution (15 mL) and extracted with DCM (2 X 50 mL). The combined organic phase was washed with water (20 mL), brine (20 mL), dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure to afford (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3- hydroxy-3-methylpiperidin-1-yl)-5-(methylamino)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropane-1-carbaldehyde 10 (100 mg, 0.152 mmol, 90% yield) as a white solid. UPLC-MS (ES⁺): m/z 622.4 [M+H] ⁺. Step 7: Into a 20 mL screw-capped vial containing a well stirred solution of (R)-1-(((7-(8-ethyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)- 5-(methylamino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 10 (100 mg, 0.152 mmol), 3-(1-methyl-7-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3- yl)piperidine-2,6-dione C-47 (85.92 mg, 0.168 mmol, HCl salt) in anhydrous DMSO (3 mL) were added sodium acetate, anhydrous (62.68 mg, 0.764 mmol), acetic acid (91.76 mg, 1.53 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. MP-cyanoborohydride (2mmol\g) (153 mg, 0.305 mmol) was added to the reaction mixture and stirred at 70 °C for 16 h. After completion of the reaction as indicated by UPLC- MS, the reaction mixture was filtered and concentrated under reduced pressure to get the crude material that was purified by a reverse-phase column chromatography [Column: Redisep Rf Gold C18-120 g; Mobile phase A: 0.1% Ammonium bicarbonate in water and Mobile Phase B: Acetonitrile] to afford 3-(7-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-5-(methylamino)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione 11 (100 mg, 0.089 mmol, 58% yield) as a white solid. LC-MS (ES⁺): m/z 1029.3 [M+H] ⁺. Step 8: Into a 25 mL single-neck round-bottom flask containing a well-stirred solution of 3-(7- (1-((1-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)-5-(methylamino)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione 11 (100 mg, 0.089 mmol) in anhydrous DCM (2 mL) was added 4M HCl in 1,4-dioxane (0.22 mL, 0.893 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure to get the crude compound. The crude compound was purified by a reverse-phase preparatory HPLC to furnish 3-(7-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)-5-(methylamino)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione Compound 105 (29 mg, 0.029 mmol, 32% yield) as a white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C18 (19*250mm); Mobile phase A :0.1% Ammonium bicarbonate in water, Mobile phase B: ACN (100%); Flow rate: 5 microns/min; Solubility: WATER+CAN. ¹H NMR (400 MHz, DMSO-d6) δ = 10.99 (s, 1H), 7.72 (dd, J = 6.1, 9.3 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.35-7.22 (m, 4H), 7.10-7.00 (m, 2H), 4.44-4.28 (m, 3H), 4.20 (s, 3H), 3.68-3.60 (m, 1H), 3.50-3.40 (m, 2H), 3.10-3.00 (m, 1H), 2.99- 2.91 (m, 4H), 2.89-2.84 (m, 4H), 2.72-2.68 (m, 1H), 2.66-2.59 (m, 2H), 2.46-2.41 (m, 1H), 2.28- 2.22 (m, 1H), 2.17-2.02 (m, 6H), 1.88-1.78 (m, 5H), 1.71-1.61 (m, 4H), 1.58-1.55 (m, 1H), 1.50- 1.39 (m, 2H), 1.27-1.20 (m, 1H), 1.16-0.94 (m, 7H), 0.87-0.81 (m, 4H), 0.70-0.62 (m, 2H) and 0.43-0.35 (m, 2H). LC-MS (ES⁺): m/z 985.4 [M+H] ⁺. Synthesis 30: Synthesis of 3-(7-(1-((1-((1-((((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-6,8-difluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (Compound 106)

Step 1: Into a 10 mL single-neck round-bottom flask containing a well-stirred solution of (R)-1- ((S)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol A-127a (35 mg, 0.056 mmol) in DCM (1 mL) was added Dess-Martin Periodinane (72.08 mg, 0.169 mmol) at 0° C under nitrogen atmosphere and stirred at ambient temperature for 4h. After completion of the reaction as indicated by LCMS, the reaction mixture was filtered through celite bed and washed with DCM (50 mL). The filtrate was washed with saturated bicarbonate solution (30 mL) followed by brine (30 ml), dried over anhydrous Na2SO4, filtered and filtrate was concentrated under reduced pressure to get compound 1-((((S)-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)quinazolin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (40 mg, 0.043 mmol, 75% yield) as an off white solid. LCMS (ES⁺): m/z 610.2 [M+H] ⁺. Step 2: Into a 8 mL screw-capped vial containing a well stirred solution of 1-((((S)-7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)quinazolin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (40 mg, 0.065 mmol) , 3-(1-methyl-7-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3- yl)piperidine-2,6-dione C-47 (27.79 mg, 0.065 mmol) in anhydrous methanol (1 mL) were added sodium acetate, anhydrous (16.15 mg, 0.196 mmol), acetic acid (39.40 mg, 0.656 mmol) and followed by MP-Cyan borohydride (65 mg, 0.131 mmol) was added at room temperature. The resulting reaction mixture was stirred at 70 °C for 16h. After completion of the reaction as indicated by LCMS, the reaction mixture concentrated under reduced pressure to get a crude. The crude was purified by preparatory HPLC to afford 3-(7-(1-((1-((1-((((S)-7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 2 (28 mg, 0.024 mmol, 37% yield )as an off white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C8 (19*250mm); Mobile phase A :0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile (100%); Gradient (Time/%B): 0/10,3/10,10/30,14/30,15/95,20/95,20.10/10,22/10; Flow rate: 5 microns/min; Solubility: Water+ THF+ acetonitrile. LCMS (ES⁺): m/z 1017.4 [M+H]⁺ _. Step 3: Into a 10 mL single-neck round-bottom flask containing a well-stirred solution of 3-(7- (1-((1-((1-((((S)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-4-((R)- 3-hydroxy-3-methylpiperidin-1-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin- 4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 2 (28 mg, 0.027 mmol) in anhydrous DCM (1 mL) was added 4M HCl in 1,4-dioxane (0.034 mL, 0.137 mmol) under nitrogen atmosphere. The contents were stirred at ambient temperature for 3h. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get crude. The crude material was purified by column chromatography preparatory HPLC to furnish 3-(7-(1-((1-((1-((((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-6,8-difluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (Compound 106) (3.0 mg, 0.003 mmol, 11% yield) as off- white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C8 (19*150mm); Mobile phase A :0.1% Ammonium bicarbonate in water, Mobile phase B: ACN (100%); Gradient (Time/%B): 0/10,3/10,10/30,14/30,15/95,20/95,20.10/10,22/10; Flow rate: 5 microns/min; Solubility: Water+ THF+ acetonitrile. LC-MS (ES⁺): m/z 973.3 [M+H] ⁺. Synthesis 31: Synthesis of 3-(7-(1-((1-((1-((((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-6,8-difluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (Compound 107) Step 1: Into a 10 mL single-neck round-bottom flask containing a well-stirred solution of (R)-1- ((R)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol A-127b (30.61 mg, 0.049 mmol)in DCM (1 mL) was added Dess-Martin Periodinane (62.41 mg, 0.147 mmol) at 0° C under nitrogen atmosphere and stirred at ambient temperature for 4h. After completion of the reaction as indicated by LCMS, the reaction mixture was filtered through celite bed and washed with DCM (50 mL), the filtrate was washed with saturated bicarbonate solution (20 mL) followed by brine (20 mL) and dried over anhydrous Na₂SO₄, filtered and filtrate was concentrated under reduced pressure to get compound 1-((((R)-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)quinazolin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (38 mg, 0.024 mmol, 50% yield) as an off white solid. LC-MS (ES⁺): m/z 610.2 M+H] ⁺. Step 2: Into a 8 mL vial containing a well-stirred solution of 1-((((R)-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)quinazolin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 1 (75.00 mg, 0.049 mmol), 3-(1- methyl-7-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione C-47 (20.84 mg, 0.049 mmol) in anhydrous DMSO (1 mL) were added sodium acetate, anhydrous (12.11 mg, 0.147 mmol), acetic acid (29.55 mg, 0.492 mmol) and stirred at ambient temperature for 2h. Then MP-Cyanoborohydride (40 mg, 0.123. mmol) was added to the reaction mixture and stirred at 70 ºC for 16 h. After completion of the reaction as indicated by LCMS, the mixture was concentrated under reduced pressure to get crude. The crude was purified by preparatory HPLC [Purification method:[Column:X Bridge C8(250*19)mm 5microns; Mobile phase:A:0.1% Formic acid in MQ-water; B: Acetonitrile) to fractions containing compound was lyophilized to afford 3-(7-(1-((1-((1-((((R)-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione 2 (20 mg, 0.019 mmol, 39% yield) as an off white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C8(250*19)mm Mobile phase A :0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile (100%); Gradient (Time/%B): 0/10,3/10,10/30,14/30,15/95,20/95,20.10/10,22/10; Flow rate: 5 microns/min; Solubility: water+ THF+ acetonitrile. LC-MS (ES⁺): m/z 1017.3 M+H]⁺. Step 3: Into a 10 mL single-neck round-bottom flask containing a well-stirred solution of 3-(7- (1-((1-((1-((((R)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-4-((R)- 3-hydroxy-3-methylpiperidin-1-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin- 4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 2 (20 mg, 0.019 mmol) in anhydrous DCM (1 mL) was added 4M HCl in 1,4-dioxane (0.024 mL, 0.097 mmol) under nitrogen atmosphere. The contents were stirred at ambient temperature for 3h. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by column chromatography preparatory HPLC to furnish 3-(7-(1-((1-((1-((((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-6,8-difluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione 3 (Compound 107; 5.5 mg, 0.005 mmol, 28% yield) as off- white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C8 (19*150mm); Mobile phase A :0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile (100%); Gradient (Time/%B): 0/10,3/10,10/30,14/30,15/95,20/95,20.10/10,22/10; Flow rate: 5 microns/min; Solubility: water+ THF+ acetonitrile. LC-MS (ES⁺): m/z 973.4 [M+H]⁺. Synthesis 32: Synthesis of 3-(5-(1-(2-(4-((1-(((4-(azocan-1-yl)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)-2- oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 108)

Step 1: Into 8 mL vial containing a well stirred solution of tert-butyl 4-((1-(((7-(8-ethyl-7-fluoro- 3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperazine-1-carboxylate 1 (100 mg, 0.15 mmol) in anhydrous DMF (1 mL) were added DIPEA (0.13 mL 0.751 mmol), PyBOP (85.99 mg, 0.165 mmol) at 0 °C. Azocane 2 (25.51 mg, 0.225 mmol) was added to the reaction mixture and stirred at 0 °C for 15 minutes. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get crude residue that was purified by reversed-phase chromatography [Column: Redisep Rf Gold C18- 30 g, mobile phase A: 0.1% Ammonium bicarbonate in water, mobile phase B: Acetonitrile] to afford tert-butyl 4-((1-(((4- (azocan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazine-1-carboxylate 3 (90 mg, 0.117 mmol, 78% yield) as a colourless sticky solid. LCMS (ESI): m/z 761.8 [M+H] ⁺. Step 2: Into 10 mL round-bottom flask containing a well-stirred solution of tert-butyl 4-((1-(((4- (azocan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazine-1-carboxylate 3 (100 mg, 0.131 mmol) in anhydrous DCM (3 mL) was added 4M HCl in 1,4-dioxane (0.32 mL, 1.31 mmol). The resulting mixture was stirred at 0 °C for 30 minutes. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to afford tert- butyl 4-((1-(((4-(azocan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazine-1-carboxylate 4 (85 mg, 0.114 mmol, 87% yield, HCl salt) as a yellow solid. LCMS (ESI): m/z:617.7 [M+H] ⁺ Step 3: Into a 8 mL vial containing a well-stirred solution of 4-[4-(azocan-1-yl)-8-fluoro-2-[[1- (piperazin-1-ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6-fluoro- naphthalen-2-ol 4 (80 mg, 0.129 mmol) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo- benzo[cd]indol-5-yl]-1-piperidyl]acetic acid C-9 (82.00 mg, 0.194 mmol) in anhydrous DMF (1.52 mL) were added HATU (59.19 mg, 0.155 mmol) and DIPEA (0.07 mL, 0.389 mmol) at room temperature under nitrogen atmosphere. The contents were stirred at room temperature for 1 hour. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to get crude residue that was purified by reversed-phase column chromatography (Column: RediSep C 18-30g, Mobile phase: A: 0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile) to afford 3-(5-(1-(2-(4-((1-(((4-(azocan-1- yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)-2- oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 108; 7.0 mg, 6.73 μmol, 5.19% yield, 98.075% purity, No Salt) as an off white solid. LCMS (ES+): m/z 1020.20 [M+H] ⁺.¹H NMR (400 MHz, DMSO-d₆) δ = 11.12 (s, 1H), 9.90 (s, 1H), 8.95 (s, 1H), 8.02 (d, J = 7.4 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.75 (dd, J = 5.9, 9.2 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.54 (dd, J = 7.3, 8.6 Hz, 1H), 7.36-7.29 (m, 2H), 7.15 (d, J = 7.3 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 5.49- 5.39 (m, 1H), 4.73-4.66 (m, 1H), 4.57-4.49 (m, 1H), 3.96-3.84 (m, 2H), 3.81-3.70 (m, 2H), 3.52- 3.46 (m, 2H), 3.38-3.35 (m, 2H), 3.19 (s, 2H), 3.01-2.90 (m, 3H), 2.81-2.73 (m, 1H), 2.70-2.69 (m, 1H), 2.69-2.66 (m, 1H), 2.58-2.54 (m, 2H), 2.42-2.23 (m, 6H), 2.17-2.03 (m, 2H), 1.91-1.78 (m, 8H), 1.60-1.48 (m, 5H), 1.48-1.40 (m, 2H), 0.82-0.69 (m, 5H), 0.57-0.47 (m, 2H). Synthesis 33: Synthesis of 3-(5-(1-(2-(4-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)piperidin-4-yl)-2- oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 109) Step 1: Into a 20 mL screw-capped vial containing a well-stirred solution of 3-(2-oxo-5-(1-(2- (piperazin-1-yl)ethyl)piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 1 (70 mg, 0.116 mmol) and (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro- 4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane- 1-carbaldehyde 2 (80.13 mg, 0.116 mmol) in anhydrous DMSO (2 mL) were added sodium acetate, anhydrous (19.08 mg, 0.232 mmol), acetic acid (34.91 mg, 0.581 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. MP- Cyanoborohydride (2mmol\g) (116 mg, 0.232 mmol) was added to the reaction mixture and stirred at 70 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered and concentrated the filtrate under reduced pressure to afford the crude material that was purified by a reversed-phase column chromatography [Column: Redisep C18, 60 g gold; Mobile phase A: 0.1% Ammonium bicarbonate in Water and Mobile Phase B: Acetonitrile] to afford 3-(5-(1-(2-(4-((1-(((7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)piperidin- 4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 3 (70 mg, 0.062 mmol, 53% yield) as a white solid. LC-MS (ES⁺): m/z 1052.4 [M+H]⁺. Step 2: Into a 10 mL single-neck round-bottom flask containing a well-stirred solution of 3-(5- (1-(2-(4-((1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3- hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)piperidin-4-yl)-2-oxobenzo[cd]indol- 1(2H)-yl)piperidine-2,6-dione 3 (65.53 mg, 0.058 mmol) in anhydrous DCM (1 mL) was added 4M HCl in 1,4-dioxane (0.14 mL, 0.585 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure to get crude material that was purified by a reverse- phase preparatory HPLC to furnish 3-(5-(1-(2-(4-((1-(((7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)ethyl)piperidin-4-yl)-2- oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 109; 28 mg, 0.02768 mmol, 47% yield) as an off-white solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C8 (19*150mm); Mobile phase A: 0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile; Flow rate: 5 microns/minutes. LC-MS (ES⁺): m/z 1008.4 [M+H] ⁺.¹H NMR (400 MHz, DMSO-d₆) δ = 11.12 (s, 1H), 9.22 (s, 1H), 8.18 (s, 1H), 8.04 (d, J = 7.4 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.77 (dd, J = 6.0, 9.0 Hz, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.54 (dd, J = 7.3, 8.4 Hz, 1H), 7.39-7.32 (m, 2H), 7.15 (d, J = 7.1 Hz, 1H), 7.04 (d, J = 2.6 Hz, 1H), 5.49-5.41 (m, 1H), 4.81-4.67 (m, 1H), 4.39-4.24 (m, 4H), 4.10-3.96 (m, 1H), 3.70-3.51 (m, 4H), 3.12-3.03 (m, 3H), 3.01-2.89 (m, 2H), 2.79-2.72 (m, 1H), 2.65-2.62 (m, 1H), 2.47-2.35 (m, 10H), 2.32-2.28 (m, 2H), 2.28-2.21 (m, 3H), 2.13-2.08 (m, 1H), 1.88-1.79 (m, 4H), 1.73-1.63 (m, 3H), 1.21-1.15 (m, 3H), 0.79-0.71 (m, 3H), 0.69-0.62 (m, 2H), 0.46-0.37 (m, 2H). Synthesis 34: Synthesis of 3-(7-(1'-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-bipiperidin]-4-yl)-1-methyl-1H-indol-3- yl)piperidine-2,6-dione (Compound 110) Step 1: Into a 8 mL glass vial containing a well-stirred solution of (R)-1-(((7-(8-ethyl-7-fluoro- 3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde 2 (36.64 mg, 0.060 mmol) and 3-(7-([1,4'-bipiperidin]-4-yl)-1-methyl-1H-indol-3-yl)piperidine-2,6-dione 1 (25 mg, 0.055 mmol; HCl salt) in dry DMSO (1.5 mL) were added sodium acetate, anhydrous (4.97 mg, 0.060 mmol), acetic acid (3.64 mg, 0.060 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. MP-Cyanoborohydride 2.0 mmol/g (60 mg, 0.12 mmol) was added to the reaction mixture and stirred at 70 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered and filtrate was concentrated under reduced pressure to get crude residue that was purified by column chromatography [Column: Redisep Rf Gold C18-30g, Mobile phase A: 0.1%Ammonium bicarbonate in water, Mobile phase B: Acetonitrile] to afford 3-(7-(1'-((1-(((7-(8-ethyl-7-fluoro- 3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-bipiperidin]-4-yl)-1- methyl-1H-indol-3-yl)piperidine-2,6-dione 3 (20 mg, 0.014 mmol, 24% yield) as brown gummy solid. LC-MS (ES⁺): m/z 985.3 [M+H] ⁺. Step 2: Into a 25 mL round bottom flask, containing a well-stirred solution of 3-(7-(1'-((1-(((7- (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'- bipiperidin]-4-yl)-1-methyl-1H-indol-3-yl)piperidine-2,6-dione 3 (27.78 mg, 0.020 mmol) in anhydrous DCM (2 mL) was added 4 M HCl in 1,4-dioxane (0.05 mL, 0.20 mmol) under nitrogen atmosphere at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure to get the crude compound that was purified preparatory HPLC to furnish 3-(7-(1'-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4- ((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-bipiperidin]-4-yl)-1-methyl-1H-indol-3- yl)piperidine-2,6-dione (Compound 110; 1.5 mg, 0.015 mmol, 7% yield; HCOOH salt) as an off-white fluffy solid. Preparative HPLC Method: Column/dimensions: XBRIDGE C18 (19*150mm); Mobile phase A :0.1% HCOOH in water, Mobile phase B: ACN (100%); Flow rate: 5 microns/minutes. LC-MS (ES⁺): m/z 941.3 [M+H] ⁺. Synthesis 35: Synthesis of 3-(7-(1-((1-((1-(((4-(2-oxa-6-azabicyclo [5.1.0] octan-6-yl)-7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) piperidin-4-yl) methyl) piperidin-4-yl)-1-methyl-1H-indazol- 3-yl) piperidine-2,6-dione (Compound 111):

Step-1: To a stirred solution of 6-(2,7-dichloro-8-fluoro-pyrido[4,3-d] pyrimidin-4-yl)-2-oxa-6- azabicyclo [5.1.0] octane A-12 (0.75 g, 2.28 mmol) and [1-[[tert-butyl(dimethyl)silyl] oxymethyl] cyclopropyl] methanol 1 (591.67 mg, 2.73 mmol) in Tetrahydrofuran (15 mL) was added sodium hydride (109.37 mg, 4.56 mmol) at 0 ^oC and allowed to stir at room temperature for 3 hours. The reaction mixture was quenched with ice-cold water, the solid precipitate was filtered, dried and purified by flash column chromatography using (devisal silica) with 80% Ethyl acetate in Petroleum ether as an eluent to afforded tert-butyl- [[1- [[7-chloro-8-fluoro-4- (2-oxa-6-azabicyclo [5.1.0] octan-6-yl) pyrido[4,3-d] pyrimidin-2-yl] oxymethyl] cyclopropyl] methoxide]-dimethyl-silane 2 (0.7 g, 42% yield) as an off white solid. LCMS (ESI): m/z 509.73 [M+H] ⁺. Step-2: To a stirred solution of tert-butyl-[[1-[[7-chloro-8-fluoro-4-(2-oxa-6- azabicyclo[5.1.0]octan-6-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methoxy]- dimethyl-silane 2 (0.5 g, 0.98 mmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane 3 (707 mg, 1.96 mmol) in the mixture of Tetrahydrofuran (15 mL) and Water (2 mL) was added Potassium phosphate tribasic (625 mg, 2.95 mmol) and degassed with nitrogen for 10 minutes. Catacxium Pd G3 (143 mg, 0.19 mmol) was added and the resulting reaction mixture was irradiated under microwave at 130 ιC for 1 hour. The reaction mixture was diluted with water and then extracted with Ethyl acetate. The combined organic layer was dried over anhydrous Sodium sulphate and concentrated under reduced pressure to get crude which was purified by flash column chromatography over silica gel (100-200 mesh) using 50-60% of ethyl acetate in Petroleum ether to afford tert-butyl-[[1-[[7- [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-(2-oxa-6-azabicyclo [5.1.0] octan-6-yl) pyrido[4,3-d] pyrimidin-2-yl] oxymethyl] cyclopropyl] methoxy]-dimethyl-silane 4 (0.4 g, 43% yield) as a brown solid. LCMS (ESI): m/z 707.75 [M+H]⁺ _. Step-3: To a stirred solution of tert-butyl-[[1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-4-(2-oxa-6-azabicyclo [5.1.0] octan-6-yl) pyrido[4,3-d] pyrimidin-2-yl] oxymethyl] cyclopropyl] methoxy]-dimethyl-silane 4 (0.35 g, 495.13 μmol) in Tetrahydrofuran (5 mL) was added tetrabutylammoniumfluride (1M in Tetrahydrofuran, 0.51 mL, 1.98 mmol) at 0 °C and allowed to stir at room temperature for 16 h. The reaction mixture was diluted with water, extracted with Ethyl acetate, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude which was purified by flash column chromatography by using silica gel (100-200 mesh) eluted at 80% of ethyl acetate in Petroleum ether to afford [1- [[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-(2-oxa-6- azabicyclo[5.1.0]octan-6-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol 5 (0.25 g, 55% yield) as an off white solid. LCMS (ES+I): m/z 593.61 [M+H]⁺. Step-4: To a stirred solution of [1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-4-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]-methanol 5 (0.1 g, 168.74 μmol) in the mixture of acetonitrile (2 mL) and dichloromethane (2 mL) was added Dess-Martin Periodinane (143 mg, 0.33 mmol) at 0 °C and allowed to stir at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulphate, filtered and concentrated to get crude which was triturated with 30% ethyl acetate in petroleum ether afford 1-[[7-[8-ethyl- 7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-(2-oxa-6-azabicyclo [5.1.0] octan-6-yl) pyrido [4, 3-d] pyrimidin-2-yl]oxymethyl]-cyclopropanecarbaldehyde 6 (0.06 g, 48% yield) as an off-white solid. LCMS (ESI): m/z 591.40 [M+H] ⁺ _. Step-5: To a stirred solution of 1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-4-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopro-panecarbaldehyde 6 (0.06 g, 101.59 μmol) and 3-[1-methyl-7-[1-(4- piperidylmethyl)-4-piperidyl]indazol-3-yl]piperidine-2,6-dione C-47 (43.03 mg, 80.04 μmol, Trifluoroacetic acid salt) in DMSO (4 mL) were added anhydrous Sodium acetate (33.33 mg, 406.36 μmol), Acetic acid (24.40 mg, 406.36 μmol) and sodium cynoborohydride (6.38 mg, 101.59 μmol) at room temperature. The resulting reaction mixture was heated to stir at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure to get crude which was purified by prep-HPLC method to afford 3-[7-[1-[[1-[[1-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-4-(2-oxa-6-azabicyclo [5.1.0] octan-6-yl) pyrido[4,3- d] pyrimidin-2-yl] oxymethyl] cyclopropyl] methyl]-4-piperidyl] methyl]-4-piperidyl]-1- methyl-indazol-3-yl] piperidine-2,6-dione 7 (0.015 g, 14% yield) as a white solid. LCMS (ESI): m/z 998.85[M+H]⁺. Prep-HPLC method: Column/dimensions: X-bridge C8 (10*250mm) 5um Mobile Phase A: 10mM ammonium bicarbonate +0.1% ammonia solution in water Mobile Phase B acetonitrile+0.1% ammonia solution Gradient (Time/%B): 0/50, 3/50, 7/63 ,12/63 Flow Rate: 7 mL/minutes. Solubility: Acetonitrile+ THF+ water. Step-6: To a stirred solution of 3-[7-[1-[[1-[[1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-4-(2-oxa-6-azabicyclo [5.1.0] octan-6-yl) pyrido[4,3-d] pyrimidin-2-yl] oxymethyl] cyclopropyl] methyl]-4-piperidyl] methyl]-4-piperidyl]-1-methyl-indazol-3-yl] piperidine-2,6-dione 7 (0.015 g, 15.03 μmol) in DCM (1 mL) was added 4M HCl in 1,4-dioxane (0.05 mL) at 0 °C and stirred for 10 minutes. The reaction mixture was concentrated, triturated with pentane to afford 3-[7-[1-[[1-[[1-[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4- (2-oxa-6-azabicyclo [5.1.0] octan-6-yl) pyrido[4,3-d] pyrimidin-2-yl] oxymethyl] cyclopropyl] methyl]-4-piperidyl] methyl]-4-piperidyl]-1-methyl-indazol-3-yl] piperidine-2,6-dione Compound 111 (10 mg, 56% yield, Hydrochloric acid) as an off white solid. LCMS (ESI): m/z 954.79 [M+H] ⁺ _. ¹H-NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 9.95 (s, 1H), 9.58 (s, 1H), 7.77 (t, J = 6.00 Hz, 1H), 7.60 (d, J = 8.00 Hz, 1H), 7.36-7.36 (m, 2H), 7.27 (d, J = 7.20 Hz, 1H), 7.16 (t, J = 7.60 Hz, 1H), 7.05-7.05 (m, 1H), 4.55-4.45 (m, 1H), 4.4-4.2 (m, 7H), 4.1-4.0 (m, 2H), 3.7-3.6 (m, 9H), 3.3-3.15 (m, 5H), 3.1-2.9 (m, 5H), 2.7-2.6 (m, 2H), 2.4-2.25 (m, 2H), 2.25-2.0 (m, 8H), 1.85-1.5 (m, 3H), 1.3-1.15 (m, 2H), 0.95-0.7 (m, 6H).

Table 16A – Non-limiting Examples of Compounds of the Present Invention

Table 16B – Additional Non-limiting Examples of Compounds of the Present Invention Example 5. HiBiT KRAS Degradation Assay Selected compounds of the invention were tested in a KRAS degradation assay using the HiBiT Method. Phenol red-free Dulbecco’s modified Eagle medium (DMEM), phenol-red free Leibovitz’s L-15 medium, fetal bovine serum (FBS), and 1 M HEPES were purchased from Thermo Fisher Scientific (Waltham, MA, USA). The Nano-Glo® HiBiT Lytic Assay System was purchased from Promega (Madison, WI, USA). Cell culture flasks and 384-well microplates were acquired from VWR (Radnor, PA, USA). The following ready-to-use HiBiT reporter cell lines were acquired from Promega (Madison, WI, USA): HEK293-KRAS-WT (Cat#CS3023186) exclusively expressing HiBiT-KRAS-WT wild-type protein (also referred to here as HEK293.8); HEK293-KRAS-G12D (Cat#CS3023372) exclusively expressing HiBiT- KRAS-G12D mutant protein (also referred to here as HEK293.7); and SW620-KRAS-G12V (Cat#3023152) exclusively expressing HiBiT-KRAS-G12V mutant protein (also referred to here as SW620.2). For each of these cell lines, the HiBiT fusion tag was genetically engineered into the N-terminus of endogenously expressed KRAS via CRISPR. HiBiT-KRAS degradation was evaluated by the quantification of luminescent signals using the Nano-Glo® HiBiT Lytic Assay kit. Test compounds were added to 384-well plates in duplicate using an 11-point half-log dilution series, with the highest dose set to 10 μΜ. The HEK293.8, HEK293.7, or SW620.2 cells in their respective growth medium were then added into the compound-containing 384-well plates. The HEK293-KRAS-WT and HEK293-KRAS- G12D cells were cultured in DMEM-based growth medium supplemented with 10% FBS and 10 mM HEPES; while SW620-KRAS-G12V cells were maintained in L-15 medium supplemented with 10% FBS and 10 mM HEPES. The cellular plating density per well in the 30 μL total assay volume for each cell line is as follows: 10,000 cells for HEK293-KRAS-WT and HEK293-KRAS-G12D cells; and 7,000 cells for SW620-KRAS-G12V cells. Upon cell addition, plates with HEK293.8 or HEK293.7 cells were incubated with compounds at 37 °C with 5% CO2 for 24 hours. As a CO2 and air mixture are detrimental to SW620-KRAS-G12V cells using L-15 medium, this cell line was incubated in a humidified 37 °C incubator without CO_2. Following the 24-hour incubation, Nano-Glo^® HiBiT Lytic Assay reagents were added to the cells per the manufacturer’s instructions. Luminescence was acquired using an EnVision™ Multilabel Reader (PerkinElmer, Santa Clara, CA, USA). Quantification of luminescence responses measured in the presence of compound were normalized to a high signal/no degradation control (untreated cells+lytic detection reagent) and a low signal/full degradation control (untreated cells, no lytic detection reagent). Data were analyzed with a 4-parameter logistic fit to generate sigmoidal dose-response curves. The DC₅₀ is the concentration of compound at which exactly 50% of the total cellular KRAS has been degraded. The Emax, or maximum effect of each compound, represents the amount of residual protein remaining in the cell following compound treatment. The IP, or inflection point of the dose-response curve, is the concentration of compound at which 50% of the observed degradation response is achieved. Tables 17-19 show the activity of selected compounds of this disclosure in the in vitro KRAS HiBiT degradation assays with SW620-KRAS-G12V, HEK293-KRAS-G12D, and HEK293-KRAS-WT cells, respectively, wherein each compound number corresponds to the compound numbering set forth in Synthesis 1-35 described herein. The experiment was conducted at least once for each compound identified in Tables 17-19, where if the experiment was conducted multiple times, then the data shown in the table is the average of the two or more experiments. “++++” represents a DC₅₀ or IP value of less than 100 nM or an Emax of less than 10%. “+++” represents a DC₅₀ or IP value of 100 nM–500 nM or an Emax value of 10%–50%. “++” represents a DC50 or IP value of 500 nM–1000 nM or an Emax value of 50% –90%. “+” represents a DC₅₀ or IP value of greater than 1000 nM or an Emax value of more than 90%. N.A. means the Emax is greater than or equal to 50%. Table 17. in vitro KRAS HiBiT degradation assays with SW620-KRAS-G12V cells Table 18. in vitro KRAS HiBiT degradation assays with HEK293-KRAS-G12D cells Table 19. in vitro KRAS HiBiT degradation assays with HEK293-KRAS-WT cells Example 6. HiBiT KRAS Degradation Assay Selected compounds of the invention were tested in a KRAS degradation assay using the HiBiT Method. Phenol red-free Dulbecco’s modified Eagle medium (DMEM), phenol-red free Leibovitz’s L-15 medium, fetal bovine serum (FBS), and 1 M HEPES were purchased from Thermo Fisher Scientific (Waltham, MA, USA). The Nano-Glo® HiBiT Lytic Assay System was purchased from Promega (Madison, WI, USA). Cell culture flasks and 384-well microplates were acquired from VWR (Radnor, PA, USA). The following ready-to-use HiBiT reporter cell lines were acquired from Promega (Madison, WI, USA): HEK293-KRAS-WT (Cat#CS3023186) exclusively expressing HiBiT-KRAS-WT wild-type protein (also referred to here as HEK293.8); HEK293-KRAS-G12D (Cat#CS3023372) exclusively expressing HiBiT- KRAS-G12D mutant protein (also referred to here as HEK293.7); and SW620-KRAS-G12V (Cat#3023152) exclusively expressing HiBiT-KRAS-G12V mutant protein (also referred to here as SW620.2). For each of these cell lines, the HiBiT fusion tag was genetically engineered into the N-terminus of endogenously expressed KRAS via CRISPR. HiBiT-KRAS degradation was evaluated by the quantification of luminescent signals using the Nano-Glo® HiBiT Lytic Assay kit. Test compounds were added to 384-well plates in duplicate using an 11-point half-log dilution series, with the highest dose set to 10 μΜ. The HEK293.8, HEK293.7, or SW620.2 cells in their respective growth medium were then added into the compound-containing 384-well plates. The HEK293-KRAS-WT and HEK293-KRAS- G12D cells were cultured in DMEM-based growth medium supplemented with 10% FBS and 10 mM HEPES; while SW620-KRAS-G12V cells were maintained in L-15 medium supplemented with 10% FBS and 10 mM HEPES. The cellular plating density per well in the 30 μL total assay volume for each cell line is as follows: 10,000 cells for HEK293-KRAS-WT and HEK293-KRAS-G12D cells; and 7,000 cells for SW620-KRAS-G12V cells. Upon cell addition, plates with HEK293.8 or HEK293.7 cells were incubated with compounds at 37 °C with 5% CO₂ for 24 hours. As a CO₂ and air mixture are detrimental to SW620-KRAS-G12V cells using L-15 medium, this cell line was incubated in a humidified 37 °C incubator without CO_2. Following the 24-hour incubation, Nano-Glo^® HiBiT Lytic Assay reagents were added to the cells per the manufacturer’s instructions. Luminescence was acquired using an EnVision™ Multilabel Reader (PerkinElmer, Santa Clara, CA, USA). Quantification of luminescence responses measured in the presence of compound were normalized to a high signal/no degradation control (untreated cells+lytic detection reagent) and a low signal/full degradation control (untreated cells, no lytic detection reagent). Data were analyzed with a 4-parameter logistic fit to generate sigmoidal dose-response curves. The DC₅₀ is the concentration of compound at which exactly 50% of the total cellular KRAS has been degraded. The Emax, or maximum effect of each compound, represents the amount of residual protein remaining in the cell following compound treatment. The IP, or inflection point of the dose-response curve, is the concentration of compound at which 50% of the observed degradation response is achieved. Tables 20-22 show the activity of selected compounds of this disclosure in the in vitro KRAS HiBiT degradation assays with SW620-KRAS-G12V, HEK293-KRAS-G12D, and HEK293-KRAS-WT cells, respectively, wherein each compound number corresponds to the compound numbering set forth in Synthesis 1-35 described herein. The experiment was conducted at least once for each compound identified in Tables 20, 21, and 22, where if the experiment was conducted multiple times, then the data shown in the table is the average of the two or more experiments.. “++++” represents a DC₅₀ or IP value of less than 100 nM or an Emax of less than 10%. “+++” represents a DC₅₀ or IP value of 100 nM–500 nM or an Emax value of 10%–50%. “++” represents a DC₅₀ or IP value of 500 nM–1000 nM or an Emax value of 50% –90%. “+” represents a DC₅₀ or IP value of greater than 1000 nM or an Emax value of more than 90%. N.A. means the Emax is greater than or equal to 50%. Table 20. in vitro KRAS HiBiT degradation assays with HEK293-KRAS-G12V cells Table 21 in vitro KRAS HiBiT degradation assays with HEK293-KRAS-G12D cells Table 22. in vitro KRAS HiBiT degradation assays with HEK293-KRAS-WT cells Example 7: HiBiT KRAS Degradation Assay Phenol red-free Dulbecco’s modified Eagle medium (DMEM), phenol-red free Leibovitz’s L-15 medium, fetal bovine serum (FBS), and 1 M HEPES were purchased from Thermo Fisher Scientific (Waltham, MA, USA). The Nano-Glo® HiBiT Lytic Assay System was purchased from Promega (Madison, WI, USA). Cell culture flasks and 384-well microplates were acquired from VWR (Radnor, PA, USA). The following ready-to-use HiBiT reporter cell lines were acquired from Promega (Madison, WI, USA): HEK293-KRAS-WT (Cat#CS3023186) exclusively expressing HiBiT-KRAS-WT wild-type protein (also referred to here as HEK293.8); and HEK293-KRAS-G12D (Cat#CS3023372) exclusively expressing HiBiT-KRAS-G12D mutant protein (also referred to here as HEK293.7). For each of these cell lines, the HiBiT fusion tag was genetically engineered into the N-terminus of endogenously expressed KRAS via CRISPR. HiBiT-KRAS degradation was evaluated by the quantification of luminescent signals using the Nano-Glo® HiBiT Lytic Assay kit. Test compounds were added to 384-well plates in duplicate using an 11-point half-log dilution series, with the highest dose set to 10 μΜ. The HEK293.8 or HEK293.7 cells in their respective growth medium were then added into the compound-containing 384-well plates. The HEK293-KRAS-WT and HEK293-KRAS-G12D cells were cultured in DMEM-based growth medium supplemented with 10% FBS and 10 mM HEPES. The cellular plating density per well in the 30 μL total assay volume 10,000 cells for both the HEK293-KRAS-WT and HEK293-KRAS-G12D cells. Upon cell addition, plates with HEK293.8 or HEK293.7 cells were incubated with compounds at 37 °C with 5% CO₂ for 24 hours. Following the 24-hour incubation, Nano-Glo^® HiBiT Lytic Assay reagents were added to the cells per the manufacturer’s instructions. Luminescence was acquired using an EnVision™ Multilabel Reader (PerkinElmer, Santa Clara, CA, USA). Quantification of luminescence responses measured in the presence of compound were normalized to a high signal/no degradation control (untreated cells + lytic detection reagent) and a low signal/full degradation control (untreated cells, no lytic detection reagent). Data were analyzed with a 4-parameter logistic fit to generate sigmoidal dose-response curves. The DC50 is the concentration of compound at which exactly 50% of the total cellular KRAS has been degraded. The Emax, or maximum effect of each compound, represents the amount of residual protein remaining in the cell following compound treatment. The IP, or inflection point of the dose-response curve, is the concentration of compound at which 50% of the observed degradation response is achieved. Tables 23 and 24 show the activity of selected compounds of this invention in the in vitro KRAS HiBiT degradation assays with HEK293-KRAS-G12D and HEK293-KRAS-WT cells, respectively, wherein each compound number corresponds to the compound numbering set forth in Synthesis 1-35 described herein. The experiment was conducted at least once for each compound identified in Tables 23-24, where if the experiment was conducted multiple times, then the data shown in the table is the average of the two or more experiments. “++++” represents a DC₅₀ or IP value of less than 100 nM or an Emax of less than 10%. “+++” represents a DC₅₀ or IP value of 100 nM–500 nM or an Emax value of 10%–50%. “++” represents a DC₅₀ or IP value of 500 nM–1000 nM or an Emax value of 50% –90%. “+” represents a DC₅₀ or IP value of greater than 1000 nM or an Emax value of more than 90%. N.A. means the Emax is greater than or equal to 50%. Table 23. in vitro KRAS HiBiT degradation assays with HEK293-KRAS-G12D cells Table 24. in vitro KRAS HiBiT degradation assays with HEK293-KRAS-WT cells 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 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 modifications may be made thereto without departing from the spirit or scope of the invention as defined in the appended claims. Additionally, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the present application.

Claims

CLAIMS We claim

1 . A compound of Formula: or a pharmaceutically acceptable salt thereof; wherein:

Heterocy clic Moiety ^A is selected from: and

Heterocyclic Moiety^B is selected from: and y is L 2, 3, or 4; R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R⁶ are combined to form a. one or two carbon bridge to form a fused cycle, each R² is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aiyl, heteroaiyl, 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 , 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 R ¹⁸ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RL

.

R^18B is a. wherein the bicycle is a. 9-membered bicycle which is attached to the azaglutarimide moiety through a C-N bond and is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R³;

Q is CH₂, NR², , O, or S;

Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2. 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent;

Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R³ and substituted with one R¹² substituent;

Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryd, 5- to 8- membered heterocycle, 5- to 8-membered cycloaikyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R³;

Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloaikyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵;

R¹² is the attachment point to Linker;

R⁷ and R^s 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 R⁹is independently selected from hy drogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R*, -OR⁷, find -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, alkyd, haloalkyl. alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NRⁿR¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R^M, -S(O)₂R¹⁴, and -P(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 R^|D:

R¹¹ and R¹-’ 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)₂.R¹⁴, 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 of Formula:

X’ 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, heteroaryl, lactic acid, glycolic acid, find 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, and heterocycle;

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, -NHSO₂Calkyl), -N(alkyl)SO₂alkyl, -NHSO₂Catyl, heteroaryl or heterocycle), -N(alkyI)SO₂(aryl, heteroaryl oorr heterocycle), -NHSO₂alkenyl, -N(aIkyl)SO₂alkenyl, ~NHSO₂.alkynyl, -N(alkyl)SO₂alkynyl. haloalky], aryl, heteroaiyd, heterocycle, and cycloalkyl;

KRAS Targeting Ligand^A is selected from:

KRAS Targeting Ligand^B is selected from: KRAS Targeting Ligand'³ is selected from:

KRAS Targeting Ligand^D is selected from: or KRAS Targeting Ligand ^A, KRAS Targeting Ligand^B , KRAS Targeting Ligand^C , or

KRAS Targeting Ligand^D, is selected from:

KRAS Targeting Ligand^E is selected from:

KRAS Targeting Ligand^F is selected from:

R²⁹ is selected from ary l, heteroaiyl, and bicycle each of which is optionally substituted with 1, 2. 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷;

R^29B is selected from aryl, heteroaiyl, and bicycle each of which is optionally substituted with L 2, 3, or 4 substituents independently selected from R¹⁴⁵, R¹⁴⁶, and R¹⁴⁷: each R¹⁴⁵, R¹⁴⁶, and R¹⁴⁷ is independently selected from hydrogen, alkyi. haloalkyl, alkenyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O).’R¹⁴, and -P(O)(R¹⁴)z; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3. or 4 substituents independently selected from R¹⁵;

R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR,⁷R^S, -OR⁷, and -SR⁷;

R³² is heterocycle optionally substituted with 1, 2. 3, or 4 R⁵¹ groups as allowed by valence;

R⁴ is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or bicycle;

R⁵¹ is independently selected at each instance from hydrogen, alkyd, haloalkyl, alkenyl, alkynyl. halogen, cyano, nitro. -NR⁷R*, -OR⁷, and -SR⁷;

R^51B is selected from halogen, cyano, haloalkyl, -OR', and -SR⁷;

R^51C is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD₃;

R ^51D and R^31E are hydrogen or together with X^B and the carbon atoms to which they are attached, form a. 5-. 6-. or 7 -membered ring; z is independently selected at each instance from 0, I , 2, 3, and 4, as allowed by valence;

X^B is selected from -CH₂-, -O -. -NH-, -N(R⁴)-, and -S-;

X^c is -CH₂ -, -O-, or -S-, R³³ is selected from: each of which R³³ IS optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion ol the molecule and the remaining attachment point is attached to the Linker;

R^33C is each of which R ^33C is optionally substituted with 1. 2, 3. or 4 substituents independently selected from alkyl, halogen haloalkyl. alkenyl, alkynyl, aiyd, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR'; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker;

R³ is independently selected from hydrogen, alkyd, haloalkyl. alkenyl, alkynyl, and. heteroaryl, heterocycle, and bicycle;

R^33E is each of which R ^33E is optionally substituted with 1, 2, 3. or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle. -NR'R^S. -OR', and -SR⁷; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker;

R^3C is independently selected from hydrogen, C2-C8 alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle;

R^7C is independently selected from hydrogen, C2-C8 alkyl, haloalkyl, alkenyl, alkynyl, and, 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;

Xis selected from -O-, -NH-, -N(alkyl)-, and -S-; R³⁸ and R³⁹ are independently selected from hydrogen, alkyl, haioalkyi, alkenyl, alkynyl, halogen, aryl, heteroaryl, and heterocycle each of which except hydrogen and halogen is optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R⁾⁰;

R⁴ⁱ. R⁴², R⁴'¹, and R⁴⁴ are independently selected from hydrogen, alkyd, haioalkyi, alkenyl, alkynyl, and halogen; each R⁴³,R⁴⁶, find R⁴' is independently selected from hydrogen, alkyl, haioalkyi. alkenyl, alkynyl, halogen, and. heteroaryl, heterocycle, cyano, nitro. -NR¹¹R¹³. -OR¹¹, -SR¹¹, -C(O)R¹⁴. -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(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; p is 3, 4, 5, 6. 7, or 8;

R¹³³ and R¹’⁴ are independently' selected from hydrogen and C1 -C3alky I; or R¹³³ and R¹³⁴, together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted with 1, 2, 3, or 4 halogen atoms as allowed by valence;

R¹³⁵ and R¹³⁶ are independently selected from hydrogen and C1-C6 alkyd; or R¹³⁵ and R¹³⁶, together with the nitrogen atom to which they' are attached form a heterocycle, optionally-' substituted with 1, 2, 3. or 4 R¹³⁷ groups;

R¹³⁵ independently selected at each instance from C 1-C6alkyl, C1-C6haloalkyl, -OR⁷, - NR⁷R⁸. and halogen;

R³²¹³ is selected from: q is L 2, or 3: w is 1, 2, or 3;

X^D is selected from -CH₂-, -O-, and -S-;

R^32C is selected from: R ' ^; is independently selected at each instance from hydrogen, C2-C8 alkyl, haloaikyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷⁷R⁸⁸, -OR⁷, and -SR⁷;

R" and R⁸⁸ at each instance are independently selected from hydrogen, alkyl, haloaikyl, alkenyl, alkynyl, aryl, heteroaiyl, heterocycle: and C(O)R¹¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹¹⁴ is independently selected from hydrogen. C2-C8 alkyl, haloaikyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, -O-C₂-C8 alkyl, -N(H)falkyl), and -N(alkyl)₂ each of which except hydrogen is optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R¹⁵;

X^E is selected from -O-, and -S-; qq is 2, or 3; each of which R^53D is optionally substituted with 1. 2, 3, or 4 substituents independently selected from alkyl, halogen haloaikyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, - OR⁷, and -SR⁷: w herein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; zz is independently 1, 2, 3, or 4,

R^29C is selected from aryl, heteroaiyl, and bicycle each of which is optionally substituted with 1, 2, 3. or 4 substituents independently selected from R^45C, R^46C, and R^47C; each R 4⁴5^SC^C, R^46C, and R^47C is independently selected from hydrogen, Cj-C® alkyl, haloaikyl, alkenyl, halogen, aryl, heteroaiyl, heterocycle, cyano, nitro, -NR^{i r}R^L', -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R’^!4)2: each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1. 2, 3, or 4 substituents independently selected from R¹³;

R29D is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2. 3, or 4 substituents independently selected from R^45D, R⁴⁶¹⁾. and R^47B; each R⁴⁵¹’, R^46B, and R^47D is independently selected from hydrogen, alkyl, haloaikyl, alkenyl, alkynyl, chloro, bromo, aryl, heteroaiyl, heterocycle, cyano, nitro, -NRⁿR¹³, -O-alkyl, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(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 Rⁱ⁵;

R^29E is selected from phenyl and heteroaiyi each of which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R⁴', R⁴⁶, and R⁴'; and

R^31B IS independently selected from alkyl, haloalkyi, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷.

2. ’The compound of claim I, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are

3. The compound of claim 2, wherein Q is NH. NCHs. O, or S.

4. The compound of claim 1, wherein Heterocyclic Moiety⁸ is

5. The compound of any one of claims 1-4. wherein R¹ is hydrogen.

6. The compound of any one of claims 1-5, wherein R¹⁶ and R¹⁷ are selected from

7. The compound of any one of claims 1-5, wherein R¹⁶ and R¹⁷ are selected from

8. The compound of claim 1, wherein Heterocyclic Moiety ^A and Heterocyclic Moiety® are

9. The compound of claim 8. wherein R¹⁸ is optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R⁵.

10. The compound of claim 8, wherein R ¹⁸ and R^18B are

11. The compound of claim 1, wherein Heterocyclic Moiety A B are

12. The compound of any one of claims 1-11, wherein R⁶ is hydrogen.

13. The compound of any one of claims 1 -12, wherein each R^? is independently selected from hydrogen, alkyl, haloalkyl, and halogen.

14. The compound of any one of claims 1-13, wherein Linker is of formula:

15. The compound of any one of claims 1-14, wherein X¹ is bond, heterocycle, or -NR²-.

16. The compound of any one of claims 1-15, wherein R²³ is bond, heterocycle, or -NR²-.

17. The compound of any one of claims 1-16, wherein R²⁰ is alkyl, heterocycle, aryl, -heteroaryl or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R⁴⁰.

18. The compound of any one of claims 1-17, wherein R²ⁱ is bond, -O-, -NR²-, -S-, alkyl, heterocycle, and, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R^4u.

19. The compound of any one of claims 1-18, wherein R²² is alkyl, heterocycle, aryl, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R⁴⁰.

20. The compound of any one of claims 1-19, wherein the compound is of Formula or a pharmaceutically acceptable stilt thereof, wherein KRAS Targeting Ligand³³ is

, or

21. The compound of any one of claims 1-19, wherein the compound is of Formula. or a pharmaceutically acceptable salt thereof; wherein KRAS Targeting Ligand^D is

22. The compound of any one of claims 1- 19, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof; wherein KRAS Targeting Ligand^E is

23. The compound of any one of claims 1 -19, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 1-23, wherein R^3? is

25. The compound of any one of claims 1-19, w herein the compound is of Formula or a pharmaceutically acceptable salt thereof; wherein KRAS Targeting Ligand^c is

26. The compound ofClaim 25, wherein R ³² B is selected from and

27. The compound of any one of claims 1-26, wherein R ³² is

28. The compoimd of claim 1, wherein the compound is selected from the compounds of Table 16B or a pharmaceutically acceptable salt thereof.

29. A compound of Table 16A or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising a compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

31. The pharmaceutical composition of claim 30 for the treatment of a KRAS mediated cancer.

32. A method of treating a KRAS mediated cancer comprising administering an effective amount of a compound of any one of claims 1-29 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, io a human patient in need thereof.

33. Use of a compound of any one of claims 1 -29 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the treatment of a KRAS mediated cancer.

34. Use of a compound of any one of claims 1-29 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament to treat a KRAS mediated cancer.