Heterobifunctional compounds for the degradation of kras

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

[0001] 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 KRASG12C. Cell Chem Biol. 27(1):19- 31.e6(2020 Jan 16); Bond, M.J. et al. Targeted Degradation of Oncogenic KRASG12Cby 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 KRASG12CInhibitor 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 KRASG12DInhibitor, 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 MoietyAor Heterocyclic MoietyB), 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 MoietyAis selected from: and y is 0, 1, 2, 3, or 4; in certain embodiments y is 0; in certain embodiments y is 1; R1and R6are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R1and R6are combined to form a one or two carbon bridge to form a fused cycle, for example when R1and R6are combined to form a one carbon bridge is and a two carbon bridge is ; in certain embodiments R1and R6are both hydrogen; each R2is 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 R2is hydrogen or CH3; each R5is 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 R5is alkyl, haloalkyl, or F; R16is selected from: , and R12, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5; R18Bis 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; R12is the attachment point to Linker; R7and R8at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R14each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; in certain embodiments R7and R8are independently selected at each instance form hydrogen and alkyl; each R9is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR7R8, -OR7, and -SR7each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; each R10is 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; R11and R13at 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 R14is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R15; each R15is 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 LigandAis selected from: , and ; or KRAS Targeting LigandAis selected from: , ; R29is 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; R30and R31are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR7R8, -OR7, and -SR7; R32is heterocycle optionally substituted with 1, 2, 3, or 4 R51groups as allowed by valence; In certain embodiments, R32is selected from: , , , , and ; In certain embodiments, R32is selected from , and ; R4is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or bicycle; R51is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR7R8, -OR7, and -SR7; R51Bis selected from halogen, cyano, haloalkyl, -OR7, and -SR7. R51Cis selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD3; R51Dand R51Eare hydrogen or together with XBand 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; XBis selected from -CH2-, -O-, -NH-, -N(R4)-, and -S-; XCis -CH2-, -O-, or -S-; R33is selected from: , and each33 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-; R38and R39are 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 R44are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; each R45, R46, and R47is 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; R133and R134are independently selected from hydrogen and C1-C3alkyl; or R133and R134, together with the carbon atom to which they are attached form a C3-C6cycloalkyl optionally substituted with 1, 2, 3, or 4 halogen atoms as allowed by valence; R135and R136are independently selected from hydrogen and C1-C6alkyl; or R135and R136, together with the nitrogen atom to which they are attached form a heterocycle, optionally substituted with 1, 2, 3, or 4 R137groups wherein R137is independently selected at each instance from C1-C6alkyl, C1-C6haloalkyl, -OR7, -NR7R8, and halogen. In certain embodiments Linker is selected from ; wherein: X1and X2are independently at each occurrence selected from bond, heterocycle, NR2, C(R2)2, O, C(O), and S; R20, R21, R22, R23, and R24are 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; R26is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and R40is 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 MoietyBis selected from: and ; Q is CH2, NR2, , O, or S; R17is selected from: and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5; R18is selected from: and , each of which is attached to the azaglutarimide moiety through a C-N bond and each of which R18is 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 R5and substituted with one R12substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5and substituted with one R12substituent; KRAS Targeting LigandBis selected from: KRAS Targeting LigandCis selected from: and ; wherein R32Bis selected from: and ; In certain embodiments, R32Bis 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; XDis selected from -CH2-, -O-, and -S-; R32Cis selected from: and ; R151is independently selected at each instance from hydrogen, C2-C8alkyl (including for example, C3-C8alkyl and C4-C8alkyl), haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR77R88, -OR7, and -SR7; R77and R88at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R114each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; each R114is independently selected from hydrogen, C2-C8alkyl (including for example, C3-C8alkyl and C4-C8alkyl), haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, -O-C2-C8alkyl (including for example, C3-C8alkyl and C4-C8alkyl), -N(H)(alkyl), and -N(alkyl)2each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R15; XEis selected from -O-, and -S-; qq is 2, or 3; R33Dis , or ; each of which R33Dis 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 R33Dis the formula includes a compound of Formula ; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; R3is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R3Cis independently selected from C2-C8alkyl (including for example, C3-C8alkyl and C4-C8alkyl), haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R7Cis independently selected from hydrogen, C2-C8alkyl (including for example, C3- C8alkyl and C4-C8alkyl), haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R14each 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; R29Cis selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R45C, R46C, and R47C; each R45C, R46C, and R47Cis independently selected from hydrogen, C3-C8alkyl (including for example, C4-C8alkyl and C5-C8alkyl), 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; R29Dis selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R45D, R46D, and R47D; each R45D, R46D, and R47Dis 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; R29Eis 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 LigandDis selected from: , and ; wherein R31Bis 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 LigandA, KRAS Targeting LigandB, KRAS Targeting LigandC, and KRAS Targeting LigandD, 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 LigandEis selected from: , and ; R33Cis , a33C 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 R33Cis the formula includes a compound of Formula ; R33Eis , and ea33E 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, R33Cis selected from , , and . In another aspect, the present invention provides a compound of Formula VI: or a pharmaceutically acceptable salt thereof;

[0002] wherein: KRAS Targeting LigandFis selected from: , and ; R29Bis 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 R147is 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 LigandA, KRAS Targeting LigandB, KRAS Targeting LigandC, KRAS Targeting LigandD. 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 MoietyAor Heterocyclic MoietyB), 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 as2H,3H,11C,13C,14C,15N,17O,18O,18F31P,32P,35S,36Cl, and125I respectively. In certain embodiments, isotopically labelled compounds can be used in metabolic studies (with, for example14C), reaction kinetic studies (with, for example2H or3H), 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, an18F 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, CD3,CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3etc.). 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 is13C. In other embodiments, the isotopic label is18F. 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)NH2is 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-C8alkyl. 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-C6alkyl 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-C4alkyl 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-C8alkenyl. 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-C8alkynyl. 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-C4haloalkyl. 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 (“C6–14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; 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 MoietyA” and “Heterocyclic MoietyB” 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-C5or 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-C6aliphatic 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-C4aliphatic 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

[0003] and or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

[0004] 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

[0005] and or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

[0006] and or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

[0007] and or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

[0008] and or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

[0009] 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

[0010] 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

[0011] ; 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 LinkerBis selected from: X22is 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 LigandA, KRAS Targeting LigandB, KRAS Targeting LigandC, and KRAS Targeting LigandD; and all other variables are defined herein. In certain embodiments KRAS Targeting Ligand is KRAS Targeting LigandA. In certain embodiments KRAS Targeting Ligand is KRAS Targeting LigandB. In certain embodiments KRAS Targeting Ligand is KRAS Targeting LigandC. In certain embodiments KRAS Targeting Ligand is KRAS Targeting LigandD. In certain embodiments KRAS Targeting Ligand is KRAS Targeting LigandE. In certain embodiments KRAS Targeting Ligand is KRAS Targeting LigandF. In certain embodiments X22is 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 X22is selected from haloalkyl, alkenyl, alkynyl, halogen, heterocycle, -NR7R8, -OR7, -SR7, -C(O)R9, -OC(O)R9, and -NR7C(O)R9. In certain embodiments X22is 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. R33Bis , or ; and all other variables are as defined herein. In certain embodiments R33Bis In certain embodiments R33Bis In certain embodiments R33Bis . In certain embodiments R33Bis In certain embodiments R33Bis or . In alternative aspects the compound of Formula XX is selected from:

[0012] 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 MoietyAis selected from: and ; Heterocyclic MoietyBis selected from:

[0013] and ; y is 1, 2, 3, or 4; R1and R6are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R1and R6are combined to form a one or two carbon bridge to form a fused cycle, each R2is 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 R5is 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; R16is selected from: and R12, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5; R17is selected from: , and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5; R18is selected from: , , , , and , each of which is attached to the azaglutarimide moiety through a C-N bond and each of which R18is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5; R18Bis 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 R5and substituted with one R12substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5and substituted with one R12substituent; 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; R12is the attachment point to Linker; R7and R8at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R14each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; each R9is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR7R8, -OR7, and -SR7each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; each R10is 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; R11and R13at 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 R14is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R15; each R15is 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: X1and X2are independently at each occurrence selected from bond, heterocycle, NR2, C(R2)2, O, C(O), and S; R20, R21, R22, R23, and R24are 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; R26is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; R40is 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 LigandAis selected from: , , , , and KRAS Targeting LigandBis selected from: and KRAS Targeting LigandCis selected from:

[0014] , , , , and ; KRAS Targeting LigandDis selected from: , and ; or KRAS Targeting LigandA, KRAS Targeting LigandB, KRAS Targeting LigandC, or KRAS Targeting LigandD, is selected from: , , and ; R29is 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; R30and R31are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR7R8, -OR7, and -SR7; R32is heterocycle optionally substituted with 1, 2, 3, or 4 R51groups as allowed by valence; R4is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or bicycle; R51is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR7R8, -OR7, and -SR7; R51Bis selected from halogen, cyano, haloalkyl, -OR7, and -SR7. R51Cis selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD3; R51Dand R51Eare hydrogen or together with XBand 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; XBis selected from -CH2-, -O-, -NH-, -N(R4)-, and -S-; XCis -CH2-, -O-, or -S-; R33is selected from: and e33 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-; R38and R39are 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 R44are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; each R45, R46, and R47is 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; R133and R134are independently selected from hydrogen and C1-C3alkyl; or R133and R134, together with the carbon atom to which they are attached form a C3-C6cycloalkyl optionally substituted with 1, 2, 3, or 4 halogen atoms as allowed by valence; R135and R136are independently selected from hydrogen and C1-C6alkyl; or R135and R136, together with the nitrogen atom to which they are attached form a heterocycle, optionally substituted with 1, 2, 3, or 4 R137groups wherein R137is independently selected at each instance from C1-C6alkyl, C1-C6haloalkyl, -OR7, -NR7R8, and halogen; R32Bis 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; XDis selected from -CH2-, -O-, and -S-; R31Bis independently selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR7R8, -OR7, and -SR7. A2.The compound of embodiment A1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBare 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 MoietyBis . A9.The compound of embodiment A8, wherein R2is H. A10. The compound of embodiment A8, wherein R2is CH3. A11. The compound of embodiment A1, wherein Heterocyclic MoietyBis . A12. The compound of any one of embodiments A1-A11, wherein R1is hydrogen. A13. The compound of any one of embodiments A1-A11, wherein R1is CH3. A14. The compound of any one of embodiments A1-A11, wherein R1and R6combined form a one-carbon bridge. A15. The compound of embodiment A1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBis A16. The compound of any one of embodiments A1-A15, wherein R16and R17are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. A17. The compound of any one of embodiments A1-A15, wherein R16and R17are selected from , , , , , , and A18. The compound of any one of embodiments A1-A15, wherein R16and R17are selected from

[0015] , and . A19. The compound of any one of embodiments A1-A15, wherein R16and R17are selected from and . A20. The compound of any one of embodiments A1-A15, wherein R16and R17are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. A21. The compound of any one of embodiments A1-A15, wherein R16and R17are selected from , , , , and A22. The compound of any one of embodiments A1-A15, wherein R16and R17are selected from , and . A23. The compound of any one of embodiments A1-A15, wherein R16and R17are selected from , , , , , , and . A24. The compound of any one of embodiments A1-A15, wherein R16and R17are selected from

[0016] , and A25. The compound of any one of embodiments A1-A15, wherein R16and R17are selected from and . A26. The compound of any one of embodiments A1-A15, wherein R16and R17are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. A27. The compound of any one of embodiments A1-A15, wherein R16and R17are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. A28. The compound of any one of embodiments A1-A15, wherein R16and R17are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. A29. The compound of embodiment A1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBis A30. The compound of embodiment A29, wherein R18is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. A31. The compound of embodiment A29, wherein R18is 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 R18is , , or A33. The compound of embodiment A29, wherein R18is , or A34. The compound of embodiment A1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBis A35. The compound of embodiment A1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBis . A36. The compound of any one of embodiments A29-A35, wherein R1is hydrogen. A37. The compound of any one of embodiments A29-A35, wherein R1is CH3. A38. The compound of any one of embodiments A29-A35, wherein R1and R6combined form a one-carbon bridge. A39. The compound of embodiment A1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBis A40. The compound of embodiment A1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBis . A41. The compound of any one of embodiments A1-A40, wherein R6is hydrogen. A42. The compound of any one of embodiments A1-A40, wherein R6is methyl. A43. The compound of any one of embodiments A1-A42, wherein each R5is independently selected from hydrogen, alkyl, haloalkyl, and halogen. A44. The compound of any one of embodiments A1-A42, wherein each R5is hydrogen. A45. The compound of any one of embodiments A1-A42, wherein one R5is F. A46. The compound of any one of embodiments A1-A42, wherein R5is -NR7R8or - OR7. A47. The compound of embodiment A46, wherein R7is hydrogen. A48. The compound of embodiment A46, wherein R7is methyl. A49. The compound of any one of embodiments A46-A48, wherein R8is hydrogen. A50. The compound of any one of embodiments A46-A48, wherein R8is methyl. A51. The compound of any one of embodiments A1-A42, wherein R5is 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 R5is cyano. A53. The compound of any one of embodiments A1-A42, wherein R5is 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 X1is bond. A57. The compound of embodiment A55, wherein X1is heterocycle. A58. The compound of embodiment A55, wherein X1is NR2. A59. The compound of embodiment A55, wherein X1is C(O). A60. The compound of any one of embodiments A55-A59, wherein X2is bond. A61. The compound of any one of embodiments A55-A59, wherein X2is heterocycle. A62. The compound of any one of embodiments A55-A59, wherein X2is NR2. A63. The compound of any one of embodiments A55-A59, wherein X2is C(O). A64. The compound of any one of embodiments A55-A63, wherein R20is bond. A65. The compound of any one of embodiments A55-A63, wherein R20is CH2. A66. The compound of any one of embodiments A55-A63, wherein R20is heterocycle. A67. The compound of any one of embodiments A55-A63, wherein R20is aryl. A68. The compound of any one of embodiments A55-A63, wherein R20is phenyl. A69. The compound of any one of embodiments A55-A63, wherein R20is bicycle. A70. The compound of any one of embodiments A55-A69, wherein R21is bond. A71. The compound of any one of embodiments A55-A69, wherein R21is CH2. A72. The compound of any one of embodiments A55-A69, wherein R21is heterocycle. A73. The compound of any one of embodiments A55-A69, wherein R21is aryl. A74. The compound of any one of embodiments A55-A69, wherein R21is phenyl. A75. The compound of any one of embodiments A55-A69, wherein R21is 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 R22is bond. A78. The compound of any one of embodiments A55-A76, wherein R22is CH2. A79. The compound of any one of embodiments A55-A76, wherein R22is heterocycle. A80. The compound of any one of embodiments A55-A76, wherein R22is aryl. A81. The compound of any one of embodiments A55-A76, wherein R22is phenyl. A82. The compound of any one of embodiments 55-76, wherein R22is 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 R23is bond. A85. The compound of any one of embodiments A55-A83, wherein R23is CH2. A86. The compound of any one of embodiments A55-A83, wherein R23is heterocycle. A87. The compound of any one of embodiments A55-A83, wherein R23is aryl. A88. The compound of any one of embodiments A55-A83, wherein R23is phenyl. A89. The compound of any one of embodiments A55-A83, wherein R23is 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 R24is bond. A92. The compound of any one of embodiments A55-A90, wherein R24is CH2. A93. The compound of any one of embodiments A55-A90, wherein R24is heterocycle. A94. The compound of any one of embodiments A55-A90, wherein R24is aryl. A95. The compound of any one of embodiments A55-A90, wherein R24is phenyl. A96. The compound of any one of embodiments A55-A90, wherein R24is bicycle. A97. The compound of any one of embodiments A55-A90, wherein R24is 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 LigandAis A100. The compound of embodiment A98, wherein the KRAS Targeting LigandAis . A101. The compound of embodiment A98, wherein the KRAS Targeting LigandAis A102. The compound of embodiment A98, wherein the KRAS Targeting LigandAis A103. The compound of embodiment A98, wherein the KRAS Targeting LigandAis A104. The compound of embodiment A98, wherein the KRAS Targeting LigandAis A105. The compound of embodiment A98, wherein the KRAS Targeting LigandAis A106. The compound of embodiment A98, wherein the KRAS Targeting LigandAis A107. The compound of embodiment A98, wherein the KRAS Targeting LigandAis 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 LigandBis A110. The compound of embodiment A108, wherein KRAS Targeting LigandBis A111. The compound of embodiment A108, wherein KRAS Targeting LigandBis A112. The compound of embodiment A108, wherein KRAS Targeting LigandBis A113. The compound of embodiment A108, wherein KRAS Targeting LigandBis A114. The compound of embodiment A108, wherein KRAS Targeting LigandBis A115. The compound of embodiment A108, wherein KRAS Targeting LigandBis 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 LigandDis . A118. The compound of embodiment A116, wherein KRAS Targeting LigandDis A119. The compound of embodiment A116, wherein KRAS Targeting LigandDis A120. The compound of embodiment A116, wherein KRAS Targeting LigandDis A121. The compound of embodiment A116, wherein KRAS Targeting LigandDis A122. The compound of embodiment A116, wherein KRAS Targeting LigandDis A123. The compound of embodiment A116, wherein KRAS Targeting LigandDis A124. The compound of any one of embodiments A1-A123, wherein R32is a heterocycle optionally substituted with 1, 2, 3, or 4 R51groups as allowed by valence. A125. The compound of any one of embodiments A1-A123, wherein R32is selected from and A126. The compound of any one of embodiments A1-A123, wherein R32is selected from and . A127. The compound of any one of embodiments A1-A123, wherein R32is 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 LigandCis A130. The compound of embodiment A128, wherein KRAS Targeting LigandCis A131. The compound of embodiment A128, wherein KRAS Targeting LigandCis A132. The compound of embodiment A128, wherein KRAS Targeting LigandCis A133. The compound of embodiment A128, wherein KRAS Targeting LigandCis A134. The compound of embodiment A128, wherein KRAS Targeting LigandCis A135. The compound of embodiment A128, wherein KRAS Targeting LigandCis A136. The compound of embodiment A128, wherein KRAS Targeting LigandCis A137. The compound of embodiment A128, wherein KRAS Targeting LigandCis A138. The compound of embodiment A128, wherein KRAS Targeting LigandCis A139. The compound of embodiment A128, wherein KRAS Targeting LigandCis A140. The compound of embodiment A128, wherein KRAS Targeting LigandCis A141. The compound of embodiment A128, wherein KRAS Targeting LigandCis A142. The compound of embodiment A128, wherein KRAS Targeting LigandCis A143. The compound of any one of embodiments A128-A142, wherein R32Bis selected from and A144. The compound of any one of embodiments A1-A143, wherein R32or R32Bis A145. The compound of any one of embodiments A1-A143, wherein R32or R32Bis A146. The compound of any one of embodiments A1-A145, wherein R51Bis selected from halogen, cyano, and -OR7. A147. The compound of any one of embodiments A1-A146, wherein R51Cis selected from hydrogen, alkyl, alkynyl, cyano, and CD3. A148. The compound of any one of embodiments A1-A142, wherein R32or R32Bis A149. The compound of any one of embodiments A1-A142, wherein R32or R32Bis A150. The compound of any one of embodiments A1-A142, wherein R32or R32Bis A151. The compound of any one of embodiments A1-A142, wherein R32or R32Bis A152. The compound of any one of embodiments A1-A142, wherein R32or R32Bis A153. The compound of any one of embodiments A1-A142, wherein R32or R32Bis A154. The compound of any one of embodiments A1-A153, wherein R29is 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 R29is aryl. A156. The compound of any one of embodiments A1-A154, wherein R29is heteroaryl. A157. The compound of any one of embodiments A1-A154, wherein R29is bicycle. A158. The compound of any one of embodiments A1-A153, wherein R29is A159. The compound of any one of embodiments A1-A158, wherein R45is -OR11. A160. The compound of embodiment A159, wherein R11is H. A161. The compound of any one of embodiments A1-A158, wherein R46is selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, -OR11, and C(O)R14. A162. The compound of any one of embodiments A1-A158, wherein R46is selected from alkyl, alkynyl, and halogen. A163. The compound of any one of embodiments A1-A158, wherein R46is ethyl. A164. The compound of any one of embodiments A1-A158, wherein R46is -CCH. A165. The compound of any one of embodiments A1-A158, wherein R46is chloro. A166. The compound of any one of embodiments A1-A158, wherein R46is bromo. A167. The compound of any one of embodiments A1-A166, wherein R47is selected from hydrogen, alkyl, haloalkyl, halogen, and -OR11. A168. The compound of any one of embodiments A1-A166, wherein R47is hydrogen. A169. The compound of any one of embodiments A1-A166, wherein R47is halogen. A170. The compound of any one of embodiments A1-A166, wherein R47is fluoro. A171. The compound of any one of embodiments A1-A166, wherein R47is chloro. A172. The compound of any one of embodiments A1-A171, wherein R33is A173. The compound of any one of embodiments A1-A171, wherein R33is A174. The compound of any one of embodiments A1-A171, wherein R33is 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 R33is A179. The compound of any one of embodiments A1-A171, wherein R33is A180. The compound of any one of embodiments A1-A171, wherein R33is A181. The compound of any one of embodiments A1-A171, wherein R33is A182. The compound of any one of embodiments A1-A171, wherein R33is A183. The compound of any one of embodiments A1-A171, wherein R33is A184. The compound of any one of embodiments A1-A171, wherein R33is A185. The compound of any one of embodiments A1-A171, wherein R33is A186. The compound of any one of embodiments A1-A171, wherein R33is 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: ;

[0017] ; or ; or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic MoietyAis selected from: and

[0018] Heterocyclic MoietyBis selected from: and ; y is 1, 2, 3, or 4; R1and R6are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R1and R6are combined to form a one or two carbon bridge to form a fused cycle, each R2is 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 R5is 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; R16is selected from: , and R12, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5; R17is selected from: and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5; R18is selected from: and each of which is attached to the azaglutarimide moiety through a C- N bond and each of which R18is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5; R18Bis 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 R5and substituted with one R12substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5and substituted with one R12substituent; 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; R12is the attachment point to Linker; R7and R8at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R14each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; each R9is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR7R8, -OR7, and -SR7each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; each R10is 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; R11and R13at 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 R14is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R15; each R15is 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: X1and X2are independently at each occurrence selected from bond, heterocycle, NR2, C(R2)2, O, C(O), and S; R20, R21, R22, R23, and R24are 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; R26is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle; R40is 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 LigandAis selected from: and KRAS Targeting LigandBis selected from: and ; KRAS Targeting LigandCis selected from:

[0019] and ; KRAS Targeting LigandDis selected from: , , and ;

[0020] or KRAS Targeting LigandA, KRAS Targeting LigandB, KRAS Targeting LigandC, or KRAS Targeting LigandD, is selected from: , and ; KRAS Targeting LigandEis selected from: and KRAS Targeting LigandFis selected from: and R29is 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; R29Bis 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 R147is 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; R30and R31are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR7R8, -OR7, and -SR7; R32is heterocycle optionally substituted with 1, 2, 3, or 4 R51groups as allowed by valence; R4is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or bicycle; R51is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR7R8, -OR7, and -SR7; R51Bis selected from halogen, cyano, haloalkyl, -OR7, and -SR7; R51Cis selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD3; R51Dand R51Eare hydrogen or together with XBand 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; XBis selected from -CH2-, -O-, -NH-, -N(R4)-, and -S-; XCis -CH2-, -O-, or -S-; R33is selected from: an33 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; R33Cis33C , 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; R3is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R33Eis33E , , 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; R3Cis independently selected from C2-C8alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R7Cis independently selected from hydrogen, C2-C8alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R14each 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-; R38and R39are 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 R44are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; each R45, R46, and R47is 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; R133and R134are independently selected from hydrogen and C1-C3alkyl; or R133and 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; R135and R136are independently selected from hydrogen and C1-C6alkyl; or R135and R136, together with the nitrogen atom to which they are attached form a heterocycle, optionally substituted with 1, 2, 3, or 4 R137groups; R137is independently selected at each instance from C1-C6alkyl, C1-C6haloalkyl, -OR7, -NR7R8, and halogen; R32Bis selected from: and q is 1, 2, or 3; w is 1, 2, or 3; XDis selected from -CH2-, -O-, and -S-; R32Cis selected from: and R151is independently selected at each instance from hydrogen, C2-C8alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR77R88, -OR7, and -SR7; R77and R88at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R114each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; each R114is independently selected from hydrogen, C2-C8alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, -O-C2-C8alkyl, -N(H)(alkyl), and - N(alkyl)2each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R15; XEis selected from -O-, and -S-; qq is 2, or 3; R33Dis , or each of which R33Dis 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; R29Cis selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R45C, R46C, and R47C; each R45C, R46C, and R47Cis independently selected from hydrogen, C3-C8alkyl, 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; R29Dis selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R45D, R46D, and R47D; each R45D, R46D, and R47Dis 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; R29Eis 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 R31Bis independently selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR7R8, -OR7, and -SR7. B2.The compound of embodiment B1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBare 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 MoietyBis . B9.The compound of embodiment B8, wherein R2is H. B10. The compound of embodiment B8, wherein R2is CH3. B11. The compound of embodiment B1, wherein Heterocyclic MoietyBis B12. The compound of any one of embodiments B1-B11, wherein R1is hydrogen. B13. The compound of any one of embodiments B1-B11, wherein R1is CH3. B14. The compound of any one of embodiments B1-B11, wherein R1and R6combined form a one-carbon bridge. B15. The compound of embodiment B1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBare B16. The compound of any one of embodiments B1-B15, wherein R16and R17are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. B17. The compound of any one of embodiments B1-B15, wherein R16and R17are selected from , , , , , , and B18. The compound of any one of embodiments B1-B15, wherein R16and R17are selected from , and B19. The compound of any one of embodiments B1-B15, wherein R16and R17are selected from , and B20. The compound of any one of embodiments B1-B15, wherein R16and R17are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. B21. The compound of any one of embodiments B1-B15, wherein R16and R17are selected from , , , , , , , and B22. The compound of any one of embodiments B1-B15, wherein R16and R17are selected from , and B23. The compound of any one of embodiments B1-B15, wherein R16and R17are selected from and . B24. The compound of any one of embodiments B1-B15, wherein R16and R17are selected from , , , , , , , , , , , and B25. The compound of any one of embodiments B1-B15, wherein R16and R17are selected from and . B26. The compound of any one of embodiments B1-B15, wherein R16and R17are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. B27. The compound of any one of embodiments B1-B15, wherein R16and R17are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. B28. The compound of any one of embodiments B1-B15, wherein R16and R17are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. B29. The compound of embodiment B1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBare or B30. The compound of embodiment B29, wherein R18is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. B31. The compound of embodiment B29, wherein R18is 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 R18and R18Bare , or B33. The compound of embodiment B29, wherein R18and R18Bare or B34. The compound of embodiment B1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBare B35. The compound of embodiment B1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBare B36. The compound of any one of embodiments B34-B35, wherein R1is hydrogen. B37. The compound of any one of embodiments B34-B35, wherein R1is CH3. B38. The compound of any one of embodiments B34-B35, wherein R1and R6combined form a one-carbon bridge. B39. The compound of embodiment B1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBare B40. The compound of embodiment B1, wherein Heterocyclic MoietyBis B41. The compound of any one of embodiments B1-B40, wherein R6is hydrogen. B42. The compound of any one of embodiments B1-B40, wherein R6is methyl. B43. The compound of any one of embodiments B1-B42, wherein each R5is independently selected from hydrogen, alkyl, haloalkyl, and halogen. B44. The compound of any one of embodiments B1-B42, wherein each R5is hydrogen. B45. The compound of any one of embodiments B1-B42, wherein one R5is F. B46. The compound of any one of embodiments B1-B42, wherein R5is -NR7R8or - OR7. B47. The compound of embodiment B46, wherein R7is hydrogen. B48. The compound of embodiment B46, wherein R7is methyl. B49. The compound of any one of embodiments B46-B48, wherein R8is hydrogen. B50. The compound of any one of embodiments B46-B48, wherein R8is methyl. B51. The compound of any one of embodiments B1-B42, wherein R5is 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 R5is cyano. B53. The compound of any one of embodiments B1-B42, wherein R5is 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 X1is bond. B57. The compound of embodiment B55, wherein X1is heterocycle. B58. The compound of embodiment B55, wherein X1is NR2. B59. The compound of embodiment B55, wherein X1is C(O). B60. The compound of any one of embodiments B55-B59, wherein X2is bond. B61. The compound of any one of embodiments B55-B59, wherein X2is heterocycle. B62. The compound of any one of embodiments B55-B59, wherein X2is NR2. B63. The compound of any one of embodiments B55-B59, wherein X2is C(O). B64. The compound of any one of embodiments B55-B63, wherein R20is bond. B65. The compound of any one of embodiments B55-B63, wherein R20is CH2. B66. The compound of any one of embodiments B55-B63, wherein R20is heterocycle. B67. The compound of any one of embodiments B55-B63, wherein R20is aryl. B68. The compound of any one of embodiments B55-B63, wherein R20is phenyl. B69. The compound of any one of embodiments B55-B63, wherein R20is bicycle. B70. The compound of any one of embodiments B55-B69, wherein R21is bond. B71. The compound of any one of embodiments B55-B69, wherein R21is CH2. B72. The compound of any one of embodiments B55-B69, wherein R21is heterocycle. B73. The compound of any one of embodiments B55-B69, wherein R21is aryl. B74. The compound of any one of embodiments B55-B69, wherein R21is phenyl. B75. The compound of any one of embodiments B55-B69, wherein R21is 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 R22is bond. B78. The compound of any one of embodiments B55-B76, wherein R22is CH2. B79. The compound of any one of embodiments B55-B76, wherein R22is heterocycle. B80. The compound of any one of embodiments B55-B76, wherein R22is aryl. B81. The compound of any one of embodiments B55-B76, wherein R22is phenyl. B82. The compound of any one of embodiments B55-B76, wherein R22is 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 R23is bond. B85. The compound of any one of embodiments B55-B83, wherein R23is CH2. B86. The compound of any one of embodiments B55-B83, wherein R23is heterocycle. B87. The compound of any one of embodiments B55-B83, wherein R23is aryl. B88. The compound of any one of embodiments B55-B83, wherein R23is phenyl. B89. The compound of any one of embodiments B55-B83, wherein R23is 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 R24is bond. B92. The compound of any one of embodiments B55-B90, wherein R24is CH2. B93. The compound of any one of embodiments B55-B90, wherein R24is heterocycle. B94. The compound of any one of embodiments B55-B90, wherein R24is aryl. B95. The compound of any one of embodiments B55-B90, wherein R24is phenyl. B96. The compound of any one of embodiments B55-B90, wherein R24is bicycle. B97. The compound of any one of embodiments B55-B90, wherein R24is 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 LigandAis B100. The compound of embodiment B98, wherein the KRAS Targeting LigandAis B101. The compound of embodiment B98, wherein the KRAS Targeting LigandAis B102. The compound of embodiment B98, wherein the KRAS Targeting LigandAis B103. The compound of embodiment B98, wherein the KRAS Targeting LigandAis B104. The compound of embodiment B98, wherein the KRAS Targeting LigandAis B105. The compound of embodiment B98, wherein the KRAS Targeting LigandAis B106. The compound of embodiment B98, wherein the KRAS Targeting LigandAis 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 LigandBis B109. The compound of embodiment B107, wherein KRAS Targeting LigandBis B110. The compound of embodiment B107, wherein KRAS Targeting LigandBis B111. The compound of embodiment B107, wherein KRAS Targeting LigandBis B112. The compound of embodiment B107, wherein KRAS Targeting LigandBis B113. The compound of embodiment B107, wherein KRAS Targeting LigandBis B114. The compound of embodiment B107, wherein KRAS Targeting LigandBis 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 LigandDis B117. The compound of embodiment B115, wherein KRAS Targeting LigandDis B118. The compound of embodiment B115, wherein KRAS Targeting LigandDis B119. The compound of embodiment B115, wherein KRAS Targeting LigandDis B120. The compound of embodiment B115, wherein KRAS Targeting LigandDis B121. The compound of embodiment B115, wherein KRAS Targeting LigandDis B122. The compound of embodiment B115, wherein KRAS Targeting LigandDis 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 LigandEis B125. The compound of embodiment B123, wherein KRAS Targeting LigandEis 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 R32is a heterocycle optionally substituted with 1, 2, 3, or 4 R51groups as allowed by valence. B128. The compound of any one of embodiments B1-B126, wherein R32is selected from B129. The compound of any one of embodiments B1-B126, wherein R32is selected from and B130. The compound of any one of embodiments B1-B126, wherein R32is 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 LigandCis B133. The compound of embodiment B131, wherein KRAS Targeting LigandCis B134. The compound of embodiment B131, wherein KRAS Targeting LigandCis B135. The compound of embodiment B131, wherein KRAS Targeting LigandCis B136. The compound of embodiment B131, wherein KRAS Targeting LigandCis B137. The compound of embodiment B131, wherein KRAS Targeting LigandCis B138. The compound of embodiment B131, wherein KRAS Targeting LigandCis B139. The compound of embodiment B131, wherein KRAS Targeting LigandCis B140. The compound of embodiment B131, wherein KRAS Targeting LigandCis B141. The compound of embodiment B131, wherein KRAS Targeting LigandCis B142. The compound of embodiment B131, wherein KRAS Targeting LigandCis B143. The compound of embodiment B131, wherein KRAS Targeting LigandCis B144. The compound of embodiment B131, wherein KRAS Targeting LigandCis B145. The compound of embodiment B131, wherein KRAS Targeting LigandCis , , or B146. The compound of any one of embodiments B131-B145, wherein R32Bis selected from and B147. The compound of any one of embodiments B1-B146, wherein R32and R32Bare B148. The compound of any one of embodiments B1-B146, wherein R32and R32Bare B149. The compound of any one of embodiments B1-B148, wherein R51Bis selected from halogen, cyano, and -OR7. B150. The compound of any one of embodiments B1-B149, wherein R51Cis selected from hydrogen, alkyl, alkynyl, cyano, and CD3. B151. The compound of any one of embodiments B1-B146, wherein R32and R32Bare B152. The compound of any one of embodiments B1-B146, wherein R32and R32Bare B153. The compound of any one of embodiments B1-B146, wherein R32and R32Bare B154. The compound of any one of embodiments B1-B146, wherein R32and R32Bare B155. The compound of any one of embodiments B1-B146, wherein R32and R32Bare B156. The compound of any one of embodiments B1-B146, wherein R32and R32Bare B157. The compound of embodiment B131, wherein KRAS Targeting LigandCis B158. The compound of any one of embodiments B1-B125, B127-B144 and B146- B157, wherein R29is 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 R29is 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 R29is 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 R29is 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 R29is B163. The compound of any one of embodiments B158-B162, wherein R45is -OR11. B164. The compound of embodiment B163, wherein R11is H. B165. The compound of any one of embodiments B158-B164, wherein R46is selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, -OR11, and C(O)R14. B166. The compound of any one of embodiments B158-B164, wherein R46is selected from alkyl, alkynyl, and halogen. B167. The compound of any one of embodiments B158-B164, wherein R46is ethyl. B168. The compound of any one of embodiments B158-B164, wherein R46is -CCH. B169. The compound of any one of embodiments B158-B164, wherein R46is chloro. B170. The compound of any one of embodiments B158-B164, wherein R46is bromo. B171. The compound of any one of embodiments B158-B170, wherein R47is selected from hydrogen, alkyl, haloalkyl, halogen, and -OR11. B172. The compound of any one of embodiments B158-B170, wherein R47is hydrogen. B173. The compound of any one of embodiments B158-B170, wherein R47is halogen. B174. The compound of any one of embodiments B158-B170, wherein R47is fluoro. B175. The compound of any one of embodiments B158-B170, wherein R47is chloro. B176. The compound of any one of embodiments B1-B122, B126-B143, and B145- B175, wherein R33is . B177. The compound of any one of embodiments B1-B175, wherein R33, R33Cand R33Dare B178. The compound of any one of embodiments B1-B122 and B126-B175, wherein R33and R33Dare B179. The compound of any one of embodiments B1-B175, wherein R33, R33Cand R33Dare B180. The compound of any one of embodiments B1-B175, wherein R33, R33Cand R33Dare 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 R33is B185. The compound of embodiment B176, wherein R33is B186. The compound of embodiment B176, wherein R33is B187. The compound of embodiment B176, wherein R33is B188. The compound of embodiment B178, wherein R33and R33Dare . B189. The compound of embodiment B180, wherein R33, R33Cand R33Dare B190. The compound of embodiment B176, wherein R33is B191. The compound of embodiment B176, wherein R33is B192. A compound selected from:

[0021] 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 MoietyAis selected from: and Heterocyclic MoietyBis selected from: and y is 1, 2, 3, or 4; R1and R6are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R1and R6are combined to form a one or two carbon bridge to form a fused cycle, each R2is 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 R5is 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; R16is selected from: and R12, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5; R17is selected from: and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5; R18is selected from: and , each of which is attached to the azaglutarimide moiety through a C- N bond and each of which R18is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5; R18Bis 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 R5and substituted with one R12substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5and substituted with one R12substituent; 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; R12is the attachment point to Linker; R7and R8at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R14each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; each R9is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR7R8, -OR7, and -SR7each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; each R10is 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; R11and R13at 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 R14is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R15; each R15is 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: X1and X2are independently at each occurrence selected from bond, heterocycle, NR2, C(R2)2, O, C(O), and S; R20, R21, R22, R23, and R24are 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; R26is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle; R40is 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 LigandAis selected from: and B KRAS Targeting Ligand is selected from: and KRAS Targeting LigandCis selected from:

[0022] and KRAS Targeting LigandDis selected from: , , and ;

[0023] or KRAS Targeting LigandA, KRAS Targeting LigandB, KRAS Targeting LigandC, or KRAS Targeting LigandD, is selected from: , and ; KRAS Targeting LigandEis selected from: , , , and ; KRAS Targeting LigandFis selected from: , and R29is 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; R29Bis 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 R147is 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; R30and R31are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR7R8, -OR7, and -SR7; R32is heterocycle optionally substituted with 1, 2, 3, or 4 R51groups as allowed by valence; R4is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or bicycle; R51is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR7R8, -OR7, and -SR7; R51Bis selected from halogen, cyano, haloalkyl, -OR7, and -SR7; R51Cis selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD3; R51Dand R51Eare hydrogen or together with XBand 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; XBis selected from -CH2-, -O-, -NH-, -N(R4)-, and -S-; XCis -CH2-, -O-, or -S-; R33is selected from: an33 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; R33Cis33C 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; R3is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R33Eis ,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; R3Cis independently selected from hydrogen, C2-C8alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R7Cis independently selected from hydrogen, C2-C8alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R14each 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-; R38and R39are 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 R44are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; each R45, R46, and R47is 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; R133and R134are independently selected from hydrogen and C1-C3alkyl; or R133and 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; R135and R136are independently selected from hydrogen and C1-C6alkyl; or R135and R136, together with the nitrogen atom to which they are attached form a heterocycle, optionally substituted with 1, 2, 3, or 4 R137groups; R137is independently selected at each instance from C1-C6alkyl, C1-C6haloalkyl, -OR7, -NR7R8, and halogen; R32Bis selected from: , , , and q is 1, 2, or 3; w is 1, 2, or 3; XDis selected from -CH2-, -O-, and -S-; R32Cis selected from: , , , , , and R151is independently selected at each instance from hydrogen, C2-C8alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR77R88, -OR7, and -SR7; R77and R88at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R114each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; each R114is independently selected from hydrogen, C2-C8alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, -O-C2-C8alkyl, -N(H)(alkyl), and -N(alkyl)2each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R15; XEis selected from -O-, and -S-; qq is 2, or 3; R33Dis , or each of which R33Dis 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; R29Cis selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R45C, R46C, and R47C; each R45C, R46C, and R47Cis independently selected from hydrogen, C3-C8alkyl, 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; R29Dis selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R45D, R46D, and R47D; each R45D, R46D, and R47Dis 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; R29Eis 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 R31Bis independently selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR7R8, -OR7, and -SR7. C2.The compound of embodiment C1, wherein Heterocyclic MoietyAand Heterocyclic MoietyBare 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 R1is hydrogen. 15 C6.The compound of any one of embodiments C1-C5, wherein R16and R17are selected from . lected from -150-

[0024]

[0025] C8.The compound of embodiment Cl, wherein Heterocyclic MoietyAand Heterocyclic

[0026] MoietyBare

[0027] C9.The compound of embodiment C8, wherein R18is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rs.

[0028] C10. The compound of embodiment C8, wherein R18and R5are

[0029]

[0030] Cl l. The compound of embodiment Cl , wherein Heterocyclic .A and

[0031] Heterocyclic Moiety8are

[0032] C12. The compound of any one of embodiments Cl -Cl 1, w'herein R6is hydrogen.

[0033] C13. The compound of any one of embodiments Cl -Cl 2, wherein each R5is independently selected from hydrogen, alkyl, haloalkyl, and halogen.

[0034] C14. The compound of any one of embodiments Cl -Cl 3, wherein Linker is of formula:

[0035] C15. The compound of any one of embodiments Cl -Cl 4, wherein X1is bond, heterocycle, or -NR2-.

[0036] C16. The compound of any one of embodiments C1-C15, wherein R23is bond, heterocycle, or -NR2-.

[0037] C17. The compound of any one of embodiments Cl -Cl 6, wherein R20is alkyl, heterocycle, aryl, heteroaryl or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R40.

[0038] CIS. The compound of any one of embodiments Cl -Cl 7, wherein R2iis 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.

[0039] C19. The compound of any one of embodiments Cl -Cl 8, wherein R22is 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 Ligand8is

[0040] 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 LigandDis

[0041] C22. The compound of any one of embodiments C1 -C19, wherein the compound is of Formula KRAS

[0042] Lin Heterocyclic Targeting ker Moiety8Ligand8or a pharmaceutically acceptable salt thereof; wherein KRAS Targeting

[0043] C23. The compound of any one of embodiments Cl -Cl 9, w'herein the compound is

[0044] 5 of Formula

[0045] KRAS Heterocycl argeting Li ic T nker Moiety8Ligand8or a pharmaceutically acceptable salt thereof.

[0046] C24. The compound of any one of embodiments C1-C23, wherein R32is

[0047] 10 C25. The compound of any one of embodiments Cl -Cl 9, wherein the compound is of Formula

[0048] KRAS

[0049] Linker Heterocyclic Targeting Moiety8Ligand8or a pharmaceutically acceptable salt thereof; wherein KRAS Targeting

[0050] R31 p^32B p32B R3' p^3z'.C

[0051] R31

[0052] N N N N Nr N

[0053] R33 R33 N R33

[0054] R28DNR298 N R28

[0055] 15 F F , or s F

[0056] C26. The compound of embodiment C25, wh 52B |g seJectej fj-om

[0057] -154-

[0058]

[0059] C27. The compound of any one of embodiments C1-C26, wherein R29i

[0060] C28. The compound of embodiment Cl, wherein the compound is selected from the compounds of Table 16B or a pharmaceutically acceptable salt thereof.

[0061] C29. A compound of Table 16A or a pharmaceutically acceptable salt thereof.

[0062] 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.

[0063] C31. The pharmaceutical composition of embodiment C30 for the treatment of a KRAS mediated cancer.

[0064] 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.

[0065] 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.

[0066] 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

[0067] KRAS Targeting Ligand is selected from KRAS Targeting LigandA, KRAS Targeting Ligand®, KRAS Targeting LigandC, and KRAS Targeting LigandD.

[0068] KRAS Targeting LigandGis selected from KRAS Targeting LigandB, KRAS Targeting LigandC, KRAS Targeting LigandD, KRAS Targeting LigandEFnd KRAS Targeting LigandF.

[0069] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0070] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0071] 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.

[0072] 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.

[0073] In certain embodiments, the compound of the present in vention is of Formula: or a pharmaceutically acceptable salt thereof.

[0074] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0075] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0076] 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.

[0077] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0078] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0079] In certain embodiments, the compound of the present invention is of Formula:

[0080] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula:

[0081] or a pharmaceutically acceptable salt thereof.

[0082] In certain embodiments, the compound of the present invention is of Formula:

[0083] 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.

[0084] In certain embodiments, the compound of the present in vention is of Formula: or a pharmaceutically acceptable salt thereof.

[0085] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0086] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0087] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof,

[0088] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0089] In certain embodiments, the compound of the present invention is of Formula:

[0090] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0091] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0092] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0093] 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.

[0094] In certain embodiments, the compound of the present invention is of Formula:

[0095] or a pharmaceutically acceptable salt thereof.

[0096] 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.

[0097] In certain embodiments, the compound of the present invention is of Formula:

[0098] or a pharmaceutically acceptable salt thereof.

[0099] 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.

[0100] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0101] 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.

[0102] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0103] In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

[0104] 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.

[0105] In certain embodiments KRAS Targeting Ligand is KRAS Targeting LigandA. In certain embodiments KRAS Targeting Ligand is KRAS Targeting LigandB. In certain embodiments KRAS Targeting Ligand is KRAS Targeting LigandC. In certain embodiments KRAS Targeting Ligand is KRAS Targeting LigandD. In certain embodiments KRAS Targeting Ligand is KRAS Targeting LigandE. In certain embodiments KRAS Targeting Ligand is KRAS Targeting LigandF.

[0106] Embodiments of R1and R6

[0107] In certain embodiments R1is hydrogen.

[0108] In certain embodiments R.1is alkyl.

[0109] In certain embodiments R1is halogen. In certain embodiments, R.1is halogen, wherein the halogen is F. In certain embodiments, R1is halogen, wherein the halogen is C1. In certain embodiments, R1is halogen, wherein the halogen is Br. In certain embodiments, R1is halogen, wherein the halogen is I.

[0110] In certain embodiments R6is alkyl.

[0111] In certain embodiments R° is haloalkyl.

[0112] In certain embodiments R1and R6are combined to form a single carbon bridge.

[0113] In certain embodiments R‘ and R6are both hydrogen.

[0114] Embodiments of R2

[0115] In certain embodiments R2is hydrogen.

[0116] In certain embodiments R2is alkyl.

[0117] In certain embodiments R2is haloalkyl.

[0118] In certain embodiments R2is alkenyl.

[0119] In certain embodiments R2is alkynyl. In certain embodiments R2is aryl. In certain embodiments. R2is aryl, wherein the aryl is substituted with 1, 2, 3, or 4 substituents independently selected from R10. In certain embodiments, R2is phenyl. In certain embodiments, R2is phenyl substituted with 1, 2, 3, or 4 substituents independently selected from R10.

[0120] In certain embodiments R2is heteroaryl. In certain embodiments, R2is heteroaryl, wherein the heteroaryl is substituted with 1, 2, 3, or 4 substituents independently selected from R!0,

[0121] In certain embodiments R2is heterocycle. In certain embodiments, R2is heterocycle, wherein the heterocycle is substituted with 1, 2, 3, or 4 substituents independently selected from R10.

[0122] In certain embodiments R2is C(O)R9. In certain embodiments, R2is C(O)R9, wherein C(O)R9is substituted with 1, 2, 3, or 4 substituents independently selected from R10.

[0123] In certain embodiments R1, R2, and R6are each hydrogen.

[0124] Embodiments of R5

[0125] In certain embodiments R5is hydrogen.

[0126] In certain embodiments each R5is selected from alkyl, haloalkyl, and halogen.

[0127] In certain embodiments R5is alkyl.

[0128] In certain embodiments R;is haloalkyl.

[0129] In certain embodiments R3is alkenyl.

[0130] In certain embodiments R5is alkynyl.

[0131] In certain embodiments R5is halogen. In certain embodiments, R5is halogen, wherein the halogen is F. In certain embodiments, R5is halogen, wherein the halogen is C1. In certain embodiments, R5is halogen, wherein the halogen is Br. In certain embodiments, Rsis halogen, wherein the halogen is I.

[0132] In certain embodiments R5is heteroaryl. In certain embodiments, R5is aryl. In certain embodiments, R3is heterocycle.

[0133] In certain embodiments R3is cyano.

[0134] In certain embodiments R5is -NR7R8. In certain embodiments, R3is -NR7C(O)R9, In certain embodiments, R5is -NR7C(S)R9. In certain embodiments, R3is -NR7C(O)R9. In certain embodiments, R5is -NR7S(O)2R9.

[0135] In certain embodiments R5is -OR7"

[0136] In certain embodiments R3is -SR7. In certain embodiments, R5is -S(O)2R9.

[0137] In certain embodiments R3is -C(O)R9. Embodiments of R7and R8

[0138] Tn certain embodiments R7is hydrogen.

[0139] In certain embodiments R7is alkyl.

[0140] In certain embodiments R7is methyl.

[0141] In certain embodiments R7is haloalkyi.

[0142] In certain embodiments R7is CFJ.

[0143] In certain embodiments R?is aryl. In certain embodiments R7is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R10.

[0144] In certain embodiments R7is heteroaryl. In certain embodiments R7is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R10.

[0145] In certain embodiments R7is heterocycle. In certain embodiments R7is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R10.

[0146] In certain embodiments R7is C(O)R14.

[0147] In certain embodiments R7is C(O) alkyl.

[0148] In certain embodiments R8is hydrogen.

[0149] In certain embodiments R8is alkyl.

[0150] In certain embodiments R8is methyl.

[0151] In certain embodiments R8is haloalkyi.

[0152] In certain embodiments R8is CF3.

[0153] In certain embodiments R7and R8are both hydrogen.

[0154] Embodiments of R3

[0155] In certain embodiments R9is hydrogen.

[0156] In certain embodiments R9is alkyl.

[0157] In certain embodiments R9is methyl.

[0158] In certain embodiments R9is ethyl.

[0159] In certain embodiments R9is haloalkyi.

[0160] In certain embodiments R3is CF3.

[0161] In certain embodiments R9is aryl. In certain embodiments R9is and optionally substituted with 1, 2, or 3 substituents independently selected from R10.

[0162] In certain embodiments R9is heteroaryl. In certain embodiments Rsis heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R10. In certain embodiments R9is heterocycle. In certain embodiments R9is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R10.

[0163] Tn certain embodiments R9is -NR7R8.

[0164] In certain embodiments R9is -NH2.

[0165] In certain embodiments R9is -N(CH3)H.

[0166] In certain embodiments R9is -N(CH3)2.

[0167] In certain embodiments R9is -OR7.

[0168] In certain embodiments R9is -OH.

[0169] In certain embodiments R9is -SR7.

[0170] In certain embodiments R9is -SH.

[0171] Embodiments of R10

[0172] In certain embodiments Ri0is hydrogen.

[0173] In certain embodiments R10is alkyl.

[0174] In certain embodiments R10is methyl.

[0175] In certain embodiments R10is ethyl.

[0176] In certain embodiments R10is haloalkyl.

[0177] In certain embodiments R10is CF3.

[0178] In certain embodiments R10is aryl. In certain embodiments R10is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R13.

[0179] In certain embodiments R10is heteroaryl. In certain embodiments R10is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R15.

[0180] In certain embodiments R10is heterocycle. In certain embodiments R10is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R15.

[0181] In certain embodiments R10is -NR11R13.

[0182] In certain embodiments R10is -NH2.

[0183] In certain embodiments R10is -N(CH3)H.

[0184] In certain embodiments R10is -N(CH3)2.

[0185] In certain embodiments R1Cis -OR11.

[0186] In certain embodiments R10is -OH.

[0187] In certain embodiments R10is -SR11.

[0188] In certain embodiments R10is -SH.

[0189] In certain embodiments R10is alkenyl.

[0190] In certain embodiments R10is alkynyl. In certain embodiments R10is cyano.

[0191] In certain embodiments R10is nitro.

[0192] Tn certain embodiments R10is -C(O)R14.

[0193] In certain embodiments R10is -C(O)alkyl.

[0194] In certain embodiments R10is -C(O)N(alkyl)2.

[0195] In certain embodiments R10is -C(O)N(II)(a1kyl).

[0196] In certain embodiments R10is -C(S) R14.

[0197] In certain embodiments R10is -C(S)alkyl

[0198] In certain embodiments R10is -C(S)N(alkyl)2.

[0199] In certain embodiments R10is -C(S)N(H)(alkyl).

[0200] In certain embodiments R10is -S(O)R34.

[0201] In certain embodiments R10is -S(O)2R14.

[0202] In certain embodiments R10is -P(O)(R14)2.

[0203] Embodiments of R11and R13

[0204] In certain embodiments R11is hydrogen.

[0205] In certain embodiments R11is alkyl.

[0206] In certain embodiments R11is methyl.

[0207] In certain embodiments R11is haloalkyl.

[0208] In certain embodiments R11is CF3.

[0209] In certain embodiments R11is aryl. In certain embodiments R13is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R15.

[0210] In certain embodiments R11is heteroaryl. In certain embodiments R11is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R15.

[0211] In certain embodiments R11is heterocycle. In certain embodiments Rnis heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R15.

[0212] In certain embodiments R11is C(O)R14.

[0213] In certain embodiments R11is C(O)alkyl.

[0214] In certain embodiments R13is hydrogen.

[0215] In certain embodiments R13is alkyl. in certain embodiments R13is methyl.

[0216] In certain embodiments R13is haloalkyl.

[0217] In certain embodiments R13is CF3. Embodiments of R14

[0218] In certain embodiments R14is hydrogen.

[0219] Tn certain embodiments R14is alkyl.

[0220] In certain embodiments R14is methyl.

[0221] In certain embodiments R14is ethyl.

[0222] In certain embodiments R14is haioaikyl.

[0223] In certain embodiments R14is CF3.

[0224] In certain embodiments R14is aryl. In certain embodiments R14is and optionally substituted with 1, 2, or 3 substituents independently selected from R15.

[0225] In certain embodiments R14is heteroaryl. In certain embodiments R14is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R15.

[0226] In certain embodiments R14is heterocycle. In certain embodiments R14is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R15.

[0227] In certain embodiments R14is -NH2.

[0228] In certain embodiments R14is -N(H)(alkyl).

[0229] In certain embodiments R14is -N(alkyl)2.

[0230] In certain embodiments R14is -OH.

[0231] In certain embodiments R14is alkoxy.

[0232] Embodiments of R15

[0233] In certain embodiments R13is hydrogen.

[0234] In certain embodiments each R15is selected from alkyl, haioaikyl, and halogen.

[0235] In certain embodiments R15is alkyl.

[0236] In certain embodiments R15is haioaikyl.

[0237] In certain embodiments R15is alkenyl.

[0238] In certain embodiments R15is alkynyl.

[0239] In certain embodiments R15is halogen.

[0240] In certain embodiments R15is aryl.

[0241] In certain embodiments R15is heteroaryl. hr certain embodiments R15is heterocycle.

[0242] In certain embodiments R15is cyano.

[0243] In certain embodiments R15is nitro.

[0244] In certain embodiments R15is amino. In certain embodiments R15is hydroxyl.

[0245] In certain embodiments R15is alkoxy.

[0246] Tn certain embodiments R15is -N(H)(alkyl).

[0247] In certain embodiments R15is -N(alkyl)2.

[0248] Embodiments of Cyde-A and Cycle-B

[0249] In certain embodiments Cycle-A is phenyl optionally substituted with 1 or 2 substituents independently selected from R5.

[0250] In certain embodiments Cycle-A is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from Rs.

[0251] In certain embodiments Cycle-A is a 5- to 8-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from Rs.

[0252] In certain embodiments Cycle-A is a 5- to 8-membered cycloalkyl optionally substituted with 1 or 2 substituents independently selected from R5.

[0253] In certain embodiments Cycle-A is a 5- to 8-membered cycloalkenyl optionally substituted with 1 or 2 substituents independently selected from R5.

[0254] In certain embodiments Cycle-A is phenyl.

[0255] In certain embodiments Cycle-A is a 5- or 6-membered heteroaryl.

[0256] In certain embodiments Cycle-A is a 5- to 8-membered heterocycle.

[0257] In certain embodiments Cycle-A is a 5- to 8-membered cycloalkyl.

[0258] In certain embodiments Cycle-A is a 5- to 8-membered cycloalkenyl.

[0259] In certain embodiments Cycle~B is phenyl optionally substituted with 1 or 2 substituents independently selected from R5.

[0260] In certain embodiments Cycle-B is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from Rs.

[0261] In certain embodiments Cycle-B is a 5- to 8-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from R5.

[0262] In certain embodiments Cycle-B Is a 5- to 8-membered cycloalkyl optionally substituted with 1 or 2 substituents independently selected from R5.

[0263] In certain embodiments Cycle-B is a 5- to 8-membered cycloalkenyl optionally substituted with 1 or 2 substituents independently selected from R5.

[0264] In certain embodiments Cycle-B is phenyl.

[0265] In certain embodiments Cycle-B is a 5- or 6~membered heteroaryi.

[0266] In certain embodiments Cycle-B is a 5- to 8-membered heterocycle. In certain embodiments Cycle-B is a 5- to 8-membered cycloalkyl.

[0267] In certain embodiments Cycle-B is a 5- to 8-membered cycloalkenyl.

[0268] In certain embodiments Cycle-A is phenyl optionally substituted with 1 or 2 substituents independently selected from Rsand Cycle-B is phenyl.

[0269] In certain embodiments Cycle-B is phenyl optionally substituted with 1 or 2 substituents independently selected from R5and Cycle-A is phenyl.

[0270] In certain embodiments Cycle-A and Cycle-B are both phenyl.

[0271] Embodiments of Spirocycle

[0272] In certain embodiments spirocycle is a cycloalkyl optionally substituted with 1, 2, 3, or

[0273] 4 substituents independently selected from R5and substituted with one R12substituent.

[0274] In certain embodiments cycloalkene is a cycloalkyl optionally substituted with 1, 253, or 4 substituents independently selected from R5and substituted with one R12substituent.

[0275] In certain embodiments heterocycle is a cycloalkyl optionally substituted with 1, 2, 3. or 4 substituents independently selected from R3and substituted with one R12substituent.

[0276] In certain embodiments spirocycle is piperidine optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5and substituted with one R12substituent.

[0277] In certain embodiments spirocycle is a pyrrolidine optionally substituted with 1, 2, 3, or 4 substituents independently selected from R3and substituted with one R12substituent.

[0278] Embodiments of R16, R17, and R18

[0279] In certain embodiments R16is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5.

[0280] In certain embodiments R16is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. In certain embodiments R16is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5.

[0281] In certain embodiments R16is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5.

[0282] In certain embodiments R16is R12.

[0283] In certain embodiments R16is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5,

[0284] In certain embodiments R17is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5,

[0285] In certain embodiments R17is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5.

[0286] In certain embodiments R17is which is optionally substituted w'ith 1, 2, 3, or 4 substituents independently selected from R5.

[0287] In certain embodiments R17is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5. In certain embodiments R17is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5.

[0288] In certain embodiments R18is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5.

[0289] In certain embodiments R18is which is optionally substituted with 1, 2, 3. or 4 substituents independently selected from R5.

[0290] In certain embodiments R18is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5.

[0291] In certain embodiments R18is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5.

[0292] In certain embodiments R18is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5.

[0293] In certain embodiments R16and R17are selected from

[0294] In certain embodiments R16and R17are selected from

[0295] In certain embodiments R16and R17are selected from

[0296] In certain embodiments R18is selected from In certain embodiments R18is selected from

[0297] In certain embodiments is selected from

[0298] , and

[0299] In certain embodiments is selected from

[0300]

[0301] In certain embodiments is selected from

[0302] In certain embodiments is selected from

[0303] 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.

[0304] 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.

[0305] Non-limiting examples of include the following: Additional examples of include the following: to certain embodiments is selected from :

[0306] and

[0307] Non-limiting examples of R16, R17, and R18include: and

[0308] Embodiments of X22

[0309] In certain embodiments X22is hydrogen.

[0310] In certain embodiments X22is alkyl.

[0311] In certain embodiments X22is haloalkyl.

[0312] In certain embodiments X22is alkenyl.

[0313] In certain embodiments X22is alkynyl.

[0314] In certain embodiments X22is halogen.

[0315] In certain embodiments X22is aryl.

[0316] In certain embodiments X22is heteroaryl.

[0317] In certain embodiments X22is heterocycle.

[0318] In certain embodiments X22is cyano. In certain embodiments X22is nitro.

[0319] In certain embodiments X22is -NR7R8.

[0320] In certain embodiments X22is -OR7.

[0321] In certain embodiments X22is -SR7.

[0322] In certain embodiments X22is -C(O)R9.

[0323] In certain embodiments X22is -C(S)R9.

[0324] In certain embodiments X22is -S(O)R9.

[0325] In certain embodiments X22is -S(O)2R9.

[0326] In certain embodiments X22is -OC(O)R9.

[0327] In certain embodiments X22is -OC(S)R9.

[0328] In certain embodiments X22is -OS(O)R9.

[0329] In certain embodiments X22is -OS(O)2R9.

[0330] In certain embodiments X22is -SC(O)R9.

[0331] In certain embodiments X22is -OS(O)2R9.

[0332] In certain embodiments X22is -NR7C(O)R9.

[0333] In certain embodiments X22is -NR7C(S)R9.

[0334] In certain embodiments X22is -NR7S(O)R9.

[0335] In certain embodiments X22is -NR7S(O)zR9.

[0336] In certain embodiments X22is -P(O)(R9)2.

[0337] In certain embodiments X22is -SP(O)(R9)2.

[0338] In certain embodiments X22is -NR7P(O)(R9)2.

[0339] In certain embodiments X22is -OP(O)(R9)2.

[0340] Embodiments of Heterocyclic MoietyAand Heterocyclic MoietyB

[0341] In certain embodiments, the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula:

[0342]

[0343] In certain embodiments, the Heterocyclic MoietyAand Heterocyclic MoietyBis of

[0344] Formula: In certain embodiments, the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula:

[0345] In certain embodiments, the Heterocyclic MoietyBis of Formula :

[0346] In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0347] In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0348] In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0349] In certain embodiments, the Heterocyclic MoietyBis of Formula: In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0350] In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0351] In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0352]

[0353] In certain embodiments, the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula

[0354]

[0355] In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0356]

[0357] In certain embodiments, the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula:

[0358] In certain embodiments, the Heterocyclic MoietyBis of Formula :

[0359]

[0360] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula

[0361] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula

[0362] In certain embodiments, the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula In certain embodiments, the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula: .

[0363] In certain embodiments, the Heterocyclic MoieiyAand Heterocyclic MoietyBis of Formula:

[0364] In certain embodiments, the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula:

[0365] in certain embodiments, the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula:

[0366] In certain embodiments, the Heterocyclic Moiety8is of Formula: In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0367] In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0368] In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0369] In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0370]

[0371] In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0372] In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0373] In certain embodiments, the Heterocyclic MoietyBis of Formula :

[0374] In certain embodiments, the Heterocyclic MoietyBis of Formula: In certain embodiments, the Heterocyclic MoietyBis of Formula:

[0375] In certain embodiments, the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula:

[0376] In certain embodiments, the Heterocyclic Mc-ietyAand Heterocyclic MoietyBis of Formula:

[0377] In certain embodiments, the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula:

[0378] In certain embodiments, the Heterocyclic MoietyAand Heterocyclic MoietyBis of Formula:

[0379] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from: In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from:

[0380] In certain embodiments the Heterocyclic Moiety8is selected from:

[0381] In certain embodiments the Heterocyclic Moiety8is selected from:

[0382] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from:

[0383] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from:

[0384] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from:

[0385] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from: In certain embodiments the Heterocyclic MoietyBis selected from:

[0386] In certain embodiments the Heterocyclic MoietyBis selected from:

[0387] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from:

[0388] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from:

[0389] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from:

[0390] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from: In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from:

[0391] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from:

[0392] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from:

[0393] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from: and

[0394] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from:

[0395] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from:

[0396] In certain embodiments the Heterocyclic MoietyAis selected from:

[0397] In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from: In certain embodiments the Heterocyclic MoietyAand Heterocyclic MoietyBis selected from: Embodiments of KRAS Targeting Ligand

[0398] In certain embodiments, KRAS Targeting Ligand is selected from:

[0399]

[0400] In certain embodiments, KRAS Targeting Ligand is selected from: , ,

[0401] In certain embodiments, KRAS Targeting Ligand is selected from: In certain embodiments, KRAS Targeting Ligand is selected from:

[0402] In certain embodiments, KRAS Targeting Ligand is selected from:

[0403]

[0404] In certain embodiments, KRAS Targeting Ligand is selected from: In certain embodiments, KRAS Targeting Ligand is selected from:

[0405] 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:

[0406] In certain embodiments. KRAS Targeting Ligand is selected from:

[0407] In certain embodiments, R31is R31B.

[0408] In certain embodiments KRAS Targeting LigandEis

[0409] In certain embodiments KRAS Targeting LigandEis

[0410] In certain embodiments KRAS Targeting LigandEis

[0411] In certainn embodiments KRAS Targeting LigandEis In certain embodiments KRAS Targeting LigandEis

[0412] In certain embodiments KRAS Targeting LigandEis

[0413] In certain embodiments KRAS Targeting LigandEis

[0414] In certain embodiments KRAS Targeting LigandEis

[0415] In an alternative embodiment KRAS Targeting LigandEis

[0416] In an alternative embodiment KRAS Targeting LigandEis

[0417] In an alternative embodiment KRAS Targeting LigandEis

[0418] In an alternative embodiment KRAS Targeting LigandEis In an alternative embodiment KRAS Targeting LigandEis

[0419] In certain embodiments KRAS Targeting LigandFis

[0420] In an alternative embodiment KRAS Targeting LigandFIs

[0421] In certain embodiments KRAS Targeting LigandFis

[0422] In certain embodiments KRAS Targeting LigandFis

[0423] In certain embodiments KRAS Targeting LigandFis

[0424] In certain embodiments KRAS Targeting LigandFis

[0425] In certain embodiments KRAS Targeting LlgandFis In certain embodiments KRAS Targeting LigandFis

[0426] In an alternative embodiment KRAS Targeting LigandFis

[0427] In an alternative embodiment KRAS Targeting LigandFis

[0428] In an alternative embodiment KRAS Targeting LigandFis

[0429] In an alternative embodiment KRAS Targeting LigandFis

[0430] In an alternative embodiment KRAS Targeting LigandFis

[0431] Embodiments of R29, R29B, R29C, and R29I)

[0432] In certain embodiments, R29is selected from the group consisting of:

[0433] In certain embodiments, R29Bis selected from the group consisting of:

[0434]

[0435] In certain embodiments, R29Bis selected from the group consisting of:

[0436]

[0437] In certain embodiments, R29Dis selected from the group consisting of:

[0438]

[0439] Embodiments of R32

[0440] In certain embodiments, R32is selected from:

[0441]

[0442] Embodiments of R33, R33B, R33C, R33D, and R33E

[0443] Non-limiting examples of R33include

[0444]

[0445] In certain embodiments, R33Bis selected from: and

[0446] In certain embodiments, R33Bis selected from:

[0447] Nonlimiting examples of R33Binclude:

[0448] and

[0449] In certain embodiments, R33Cis

[0450] In certain embodiments, R33Cis

[0451] In certain embodiments, R33Cis

[0452] In certain embodiments, R33Dis

[0453] In certain embodiments, R33Dis

[0454] In certain embodiments, R33Dis

[0455] In certain embodiments, R33Dis

[0456] In certain embodiments, R33Eis

[0457] In certain embodiments, R33Eis

[0458] In certain embodiments, R33Eis Exemplary Compounds of the Present Invention to certain embodiments, compounds of Formula I or their pharmaceutically acceptable sails thereof are provided as described below:

[0459]

[0460] In certain embodiments, the compound of the present invention is selected from:

[0461] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from:

[0462] and or a pharmaceutically acceptable salt thereof.

[0463] In certain embodiments, the compound of the present invention is selected from

[0464] 5

[0465] or a pharmaceutically acceptable salt thereof. hi certain embodiments, the compound of the present invention is selected from

[0466] or a pharmaceutically acceptable salt thereof. hr certain embodiments, the compound of the present invention is selected from

[0467] or a pharmaceutically acceptable salt thereof.

[0468] In certain embodiments, the compound of the present invention is selected from

[0469] or a pharmaceutically acceptable salt thereof. hi certain embodiments, the compound of the present invention is selected from

[0470] or a pharmaceutically acceptable salt thereof.

[0471] In certain embodiments, the compound of the present invention is selected from

[0472] or a pharmaceutically acceptable salt thereof. hi certain embodiments, the compound of the present invention is selected from

[0473] or a pharmaceutically acceptable salt thereof.

[0474] In certain embodiments, the compound of the present invention is selected from

[0475] or a pharmaceutically acceptable salt thereof.

[0476] In certain embodiments, the compound of the present invention is selected from

[0477] or a pharmaceutically acceptable salt thereof. hr certain embodiments, the compound of the present invention is selected from

[0478] or a pharmaceutically acceptable salt thereof.

[0479] Chirality Embodiments

[0480] 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

[0481] (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.

[0482] 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.

[0483] 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.

[0484] 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.

[0485] In certain embodiments

[0486] In certain embodiments

[0487] 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.

[0488] In certain embodiments the linker contains one or more moieties with a chiral center.

[0489] 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.

[0490] 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

[0491] In certain embodiments the linker includes In certain embodiments the linker includes or

[0492] In certain embodiments the linker includes or

[0493] In certain embodiments the linker includes

[0494] In certain embodiments the linker includes

[0495] In certain embodiments the linker includes

[0496] In certain embodiments the linker includes

[0497] In certain embodiments the linker includes

[0498] In certain embodiments the linker includes

[0499] In certain embodiments the linker includes

[0500] In certain embodiments the linker includes In certain embodiments the linker includes

[0501] In certain embodiments the linker includes

[0502] Embodiments of alkyl

[0503] 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.

[0504] In certain embodiments “alkyl” has one carbon.

[0505] Tn certain embodiments “alkyl” has two carbons.

[0506] In certain embodiments “alkyl” has three carbons.

[0507] In certain embodiments “alkyl” has four carbons.

[0508] In certain embodiments “alkyl” has five carbons.

[0509] In certain embodiments “alkyl” has six carbons.

[0510] Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0511] Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl.

[0512] Additional non-limiting examples of “alkyl” include: .s'ec-butyi, sec-pentyl, and sec-hexyl.

[0513] Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl.

[0514] Additional non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl.

[0515] Embodiments of cycloalkyl

[0516] In certain embodiments “cycloalkyl” is a C3-C8cycloalkyl, C3-C7cycloalkyl, C3- C6cycloalkyl, C3-C5cycloalkyl, C3-C4cycloalkyl, C4-C8cycloalkyl, C5-C8cycloalkyl, or C6- C8cycloalkyl.

[0517] In certain embodiments “cycloalkyl” has three carbons.

[0518] In certain embodiments “cycloalkyl” has four carbons.

[0519] In certain embodiments “cycloalkyl” has five carbons. In certain embodiments “cycloalkyl” has six carbons.

[0520] In certain embodiments “cycloalkyl” has seven carbons.

[0521] In certain embodiments “cycloalky!” has eight carbons.

[0522] In certain embodiments “cycloalkyl” has nine carbons.

[0523] In certain embodiments “cycloalkyl” has ten carbons.

[0524] Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyk cyclooctyl, and cyclodecyl.

[0525] Embodiments of haloalkyl

[0526] 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.

[0527] In certain embodiments “haloalkyl” has one carbon.

[0528] In certain embodiments “haloalkyl” has one carbon and one halogen.

[0529] In certain embodiments “haloalkyl” has one carbon and two halogens.

[0530] In certain embodiments “haloalkyl” has one carbon and three halogens.

[0531] In certain embodiments “haloalkyl" has two carbons.

[0532] In certain embodiments “haloalkyl” has three carbons.

[0533] In certain embodiments “haloalkyl” has four carbons.

[0534] In certain embodiments “haloalkyl” has five carbons.

[0535] In certain embodiments “haloalkyl” has six carbons.

[0536] Non-limiting examples of “haloalkyl” include:

[0537] Additional non-limiting examples of “haloalkyl” include:

[0538] Additional non-limiting examples of “haloalkyl” include:

[0539] 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.

[0540] 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.

[0541] In certain embodiments “heterocycle” refers to a cyclic ring with two nitrogens and 3,

[0542] 4, 5, 6, 7, or 8 carbon atoms.

[0543] In certain embodiments “heterocycle” refers to a cyclic ring with one oxygen and 3, 4,

[0544] 5, 6, 7, or 8 carbon atoms.

[0545] In certain embodiments “heterocycle” refers to a cyclic ring with one sulfur and 3, 4, 5,

[0546] 6, 7, or 8 carbon atoms.

[0547] Non-limiting examples of “heterocycle” include aziridine, oxirane, thiirane, azetidine, 1,3 -diazetidine, oxetane, and thietane.

[0548] Additional non-limiting examples of “heterocycle” include pyrrolidine, 3-pyrroline, 2- pyrroline, pyrazolidine, and hnidazolidine.

[0549] Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3- dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxafeiolane.

[0550] Additional non-limiting examples of “heterocycle” include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0551] 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.

[0552] Non-limiting examples of “heterocycle” also include:

[0553] Additional non-limiting examples of “heterocycle” include: Additional non-limiting examples of “heterocycle” include:

[0554] Non-limiting examples of “heterocycle” also include:

[0555] Non-limiting examples of “heterocycle” also include:

[0556] Additional non-limiting examples of “heterocycle” include:

[0557] Additional non-limiting examples of “heterocycle” include:

[0558] Embodiments of heteroaryl

[0559] In certain embodiments “heteroaryl” is a 5 membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0560] 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.

[0561] Additional non-limiting examples of 5 membered “heteroaryl” groups include:

[0562] 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).

[0563] Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include: and

[0564] In certain embodiments “heteroaryl” is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0565] 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.

[0566] Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:

[0567] Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:

[0568] Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: , and

[0569] In certain embodiments “heteroaryl” is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0570] Non-limiting examples of “heteroaryl” groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0571] / Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:

[0572] Embodiments of and

[0573] In certain embodiments aryl is phenyl.

[0574] In certain embodiments aryl is napthyl.

[0575] Embodiments of bicycle

[0576] 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:

[0577] 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:

[0578] 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,

[0579] In certain embodiments wherein a variable can be optionally substituted it is substituted with 1 substituent.

[0580] In certain embodiments wherein a variable can be optionally substituted it is substituted with 2 substituents.

[0581] In certain embodiments wherein a variable can be optionally substituted it is substituted with 3 substituents.

[0582] In certain embodiments wherein a variable can be optionally substituted it is substituted with 4 substituents.

[0583] Embodiments of Aliphatic and Heteroaliphatic

[0584] 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.

[0585] 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.

[0586] IV. LINKERS

[0587] 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.

[0588] 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.

[0589] In certain embodiments Linker is a bond.

[0590] 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.

[0591] 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).

[0592] 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.

[0593] In certain embodiments, Linker is selected from:

[0594] 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:

[0595] 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.

[0596] 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.

[0597] In certain embodiments Linker is selected from:

[0598]

[0599] In certain embodiments Linker is selected from: In certain embodiments Linker is selected from:

[0600] In certain embodiments Linker is selected from:

[0601]

[0602] In certain embodiments Linker is selected from:

[0603]

[0604] In certain embodiments Linker is selected from:

[0605]

[0606] In certain embodiments Linker is selected from:

[0607] Non-limiting examples of moieties of R20, R21, R22, R23, and R24include:

[0608]

[0609] Additional non-limiting examples of moieties of R20, R21, R22, R23, and R24include:

[0610] Additional non-limiting examples of moieties of R20, R21, R22, R23, and R24include:

[0611] 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.

[0612] In certain embodiments, the Linker is flanked, substituted, or interspersed with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group.

[0613] In certain embodiments, the Linker may be asymmetric or symmetrical.

[0614] In certain embodiments, Linker can be a nonlinear chain, and can be, or include, aliphatic or aromatic or heteroaromatic cyclic moieties.

[0615] In any of the embodiments of the compounds described herein, the Linker group may be any suitable moiety as described herein.

[0616] In certain embodiments, the Linker is selected from the group consisting of:

[0617] In certain embodiments, the Linker is selected from the group consisting of:

[0618] In certain embodiments, the Linker is selected from the group consisting of:

[0619] In certain embodiments, the Linker is selected from the group consisting of:

[0620] In certain embodiments, the Linker is selected from the group consisting of:

[0621]

[0622] In certain embodiments, the Linker is selected from the group consisting of:

[0623] In certain embodiments, the Linker is selected from the group consisting of:

[0624] In certain embodiments Linker or a portion thereof is selected from:

[0625] V. METHODS OF TREATMENT

[0626] 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.

[0627] 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.

[0628] 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.

[0629] 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.

[0630] 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.

[0631] 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.

[0632] 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.

[0633] 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.

[0634] 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.

[0635] Tn certain embodiments a compound of the present invention is more active against a disorder driven by a mutated KRAS than wild-type KRAS.

[0636] 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

[0637] In certain embodiments a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12D substitution.

[0638] In certain embodiments, a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12V substitution.

[0639] In certain embodiments, a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12C substitution.

[0640] In certain embodiments, a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12R substitution.

[0641] 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.

[0642] 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.

[0643] 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.

[0644] 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.

[0645] 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.

[0646] 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.

[0647] In certain embodiments, the disease or disorder is cancer or a proliferation disease.

[0648] In certain embodiments, the KRAS mediated disorder is an abnormal cell proliferation, including, but not limited to, a solid or hematological cancer.

[0649] 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.

[0650] 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.

[0651] 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.

[0652] 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.

[0653] 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.

[0654] 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.

[0655] KRAS and KRAS -mutant associated disorders

[0656] 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.

[0657] KRAS

[0658] 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.

[0659] 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.

[0660] KRAS Pan

[0661] 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.

[0662] Table 2', KRAS mutation incidence in different KRAS-associated disorders.

[0663] KRAS G12D

[0664] 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).

[0665] KRAS GUV

[0666] An estimated 55,100 new patients per year in the United States each harbor a KRAS

[0667] G12V mutation. The KRAS G12V mutation is the second most common KRAS mutation found in pancreatic adenocarcinoma (Table 2).

[0668] Pancreatic Cancer

[0669] 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)).

[0670] 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)).

[0671] In certain aspects an effective amount of a compound of the present invention is used to treat pancreatic cancer.

[0672] Colorectal Cancer

[0673] 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).

[0674] In certain aspects an effective amount of a compound of the present invention is used to treat colorectal cancer.

[0675] Lung Cuneer

[0676] 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.).

[0677] 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.

[0678] In certain aspects an effective amount of a compound of the present invention is used to treat lung cancer. VI. COMBINATION THERAPY

[0679] 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.

[0680] 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.

[0681] MAPK Inhibitors

[0682] 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.

[0683] EGFR

[0684] 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.

[0685] 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.

[0686] In certain embodiments a compound of the present invention is administered to a patient in need thereof in combination with cetuximab.

[0687] In certain embodiments a compound of the present invention is administered to a patient in need thereof in combination with panitumab.

[0688] In certain embodiments a compound of the present invention is administered to a patient in need thereof in combination with necitumab.

[0689] SOS

[0690] 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,

[0691] RAS

[0692] 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.

[0693] SHP2

[0694] 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

[0695] RLY-1971. Additional SHP-2 inhibitors can be found in U.S. Patent No. 11,634,417.

[0696] RAF

[0697] 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).

[0698] 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).

[0699] MEK

[0700] 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),

[0701] MEK162 / ARRY438162 (5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N~(2- hydroxyethoxy)- 1 -methyl- 1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-FIuoro-2-

[0702] (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.

[0703] ERK

[0704] 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.

[0705] Immunotherapeuties

[0706] 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.

[0707] 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).

[0708] 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.

[0709] 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.

[0710] 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.

[0711] 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.

[0712] 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.

[0713] 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.

[0714] 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.

[0715] 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.

[0716] 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.

[0717] In certain embodiments, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

[0718] 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)-

[0719] 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).

[0720] 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.

[0721] 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).

[0722] 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-

[0723] (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.

[0724] 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).

[0725] 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).

[0726] 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.

[0727] 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.

[0728] 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.

[0729] 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.

[0730] 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).

[0731] 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™).

[0732] 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.

[0733] 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

[0734] (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

[0735] 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.

[0736] 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.

[0737] 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.

[0738] 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.

[0739] 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.

[0740] 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.

[0741] VII. PHARMACEUTICAL COMPOSITIONS

[0742] 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.

[0743] 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.

[0744] 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.

[0745] 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.

[0746] 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.

[0747] 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.

[0748] 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.

[0749] 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.

[0750] 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.

[0751] 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.

[0752] 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.

[0753] 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.

[0754] 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.

[0755] 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.

[0756] 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.

[0757] 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.

[0758] 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.

[0759] 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.

[0760] 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.

[0761] 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.

[0762] 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.

[0763] 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.

[0764] 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).

[0765] 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.

[0766] 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.

[0767] 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).

[0768] 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.

[0769] 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.

[0770] 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.

[0771] 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.

[0772] 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.

[0773] Parenteral administration includes intraarticular, intravenous, intramuscular, ...

Claims

CLAIMSWe claim1 . A compound of Formula:or a pharmaceutically acceptable salt thereof; wherein:Heterocy clic MoietyAis selected from:andHeterocyclic MoietyBis selected from:andy is L 2, 3, or 4;R1and R6are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R1and R6are combined to form a. one or two carbon bridge to form a fused cycle, each R2is 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 R5is 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;R16is selected from:. and R12, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R5;R17is selected from:and , each of which is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R5:R18is selected from:and, each of which is attached to the azaglutarimide moiety through a C-N bond and each of which R18is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RL.R18Bis 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 R5and substituted with one R12substituent;Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R3and substituted with one R12substituent;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;R12is the attachment point to Linker;R7and Rsat each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R14each 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 -SR7each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; each R10is 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)RM, -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:R11and 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 R14is 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 R15is 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 X2are independently at each occurrence selected from bond, heterocycle, NR2. C(R2)2, O, C(O), and S;R20, R21, R22, R23, and R24are 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,R26is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle;R40is 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 LigandAis selected from:KRAS Targeting LigandBis selected from:KRAS Targeting Ligand'3is selected from:KRAS Targeting LigandDis selected from:or KRAS Targeting LigandA, KRAS Targeting LigandB, KRAS Targeting LigandC, orKRAS Targeting LigandD, is selected from:KRAS Targeting LigandEis selected from:KRAS Targeting LigandFis selected from:R29is 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;R29Bis 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 R147is 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;R30and R31are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR,7RS, -OR7, and -SR7;R32is heterocycle optionally substituted with 1, 2. 3, or 4 R51groups as allowed by valence;R4is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or bicycle;R51is independently selected at each instance from hydrogen, alkyd, haloalkyl, alkenyl, alkynyl. halogen, cyano, nitro. -NR7R*, -OR7, and -SR7;R51Bis selected from halogen, cyano, haloalkyl, -OR', and -SR7;R51Cis selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD3;R51Dand R31Eare hydrogen or together with XBand 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;XBis selected from -CH2-, -O -. -NH-, -N(R4)-, and -S-;Xcis -CH2-, -O-, or -S-,R33is selected from:each of which R33IS 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 themolecule and the remaining attachment point is attached to the Linker;R33Ciseach of which R33Cis 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 themolecule and the remaining attachment point is attached to the Linker;R3is independently selected from hydrogen, alkyd, haloalkyl. alkenyl, alkynyl, and. heteroaryl, heterocycle, and bicycle;R33Eiseach of which R33Eis optionally substituted with 1, 2, 3. or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle. -NR'RS. -OR', and -SR7; wherein attachment pointis attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker;R3Cis independently selected from hydrogen, C2-C8 alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle;R7Cis independently selected from hydrogen, C2-C8 alkyl, haloalkyl, alkenyl, alkynyl, and, heteroaryl, heterocycle; and C(O)R14each 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-;R38and R39are 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 R44are 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;R133and R1’4are independently' selected from hydrogen and C1 -C3alky I; or R133and 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;R135and R136are independently selected from hydrogen and C1-C6 alkyd; or R135and R136, together with the nitrogen atom to which they' are attached form a heterocycle, optionally-' substituted with 1, 2, 3. or 4 R137groups;R135independently selected at each instance from C 1-C6alkyl, C1-C6haloalkyl, -OR7, - NR7R8. and halogen;R3213is selected from:q is L 2, or 3: w is 1, 2, or 3;XDis selected from -CH2-, -O-, and -S-;R32Cis 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 R88at each instance are independently selected from hydrogen, alkyl, haloaikyl, alkenyl, alkynyl, aryl, heteroaiyl, heterocycle: and C(O)R114each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10; each R114is 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)2each of which except hydrogen is optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R15;XEis selected from -O-, and -S-; qq is 2, or 3;each of which R53Dis 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 pointis 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,R29Cis selected from aryl, heteroaiyl, and bicycle each of which is optionally substituted with 1, 2, 3. or 4 substituents independently selected from R45C, R46C, and R47C; each R 445SCC, R46C, and R47Cis independently selected from hydrogen, Cj-C® alkyl, haloaikyl, alkenyl, halogen, aryl, heteroaiyl, heterocycle, cyano, nitro, -NRi rRL', -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 R45D, R461). and R47B; each R451’, R46B, and R47Dis 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 excepthydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ri5;R29Eis selected from phenyl and heteroaiyi each of which is optionally substituted with1, 2, 3, or 4 substituents independently selected from R4', R46, and R4'; andR31BIS independently selected from alkyl, haloalkyi, alkenyl, alkynyl, halogen, cyano, nitro, -NR7R8, -OR7, and -SR7.

2. ’The compound of claim I, wherein Heterocyclic MoietyAand Heterocyclic MoietyBare3. The compound of claim 2, wherein Q is NH. NCHs. O, or S.

4. The compound of claim 1, wherein Heterocyclic Moiety8is5. The compound of any one of claims 1-4. wherein R1is hydrogen.

6. The compound of any one of claims 1-5, wherein R16and R17are selected from7. The compound of any one of claims 1-5, wherein R16and R17are selected from8. The compound of claim 1, wherein Heterocyclic MoietyAand Heterocyclic Moiety® are9. The compound of claim 8. wherein R18isoptionally substituted with 1 , 2, 3, or 4 substituents independently selected from R5.

10. The compound of claim 8, wherein R18and R18Bare11. The compound of claim 1, wherein Heterocyclic Moiety A B are12. The compound of any one of claims 1-11, wherein R6is 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 X1is bond, heterocycle, or -NR2-.

16. The compound of any one of claims 1-15, wherein R23is bond, heterocycle, or -NR2-.

17. The compound of any one of claims 1-16, wherein R20is 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 R2iis bond, -O-, -NR2-, -S-, alkyl, heterocycle, and, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R4u.

19. The compound of any one of claims 1-18, wherein R22is 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 Formulaor a pharmaceutically acceptable stilt thereof, wherein KRAS Targeting Ligand33is, or21. The compound of any one of claims 1-19, wherein the compound is of Formula.or a pharmaceutically acceptable salt thereof; wherein KRAS Targeting LigandDis22. The compound of any one of claims 1- 19, wherein the compound is of Formulaor a pharmaceutically acceptable salt thereof; wherein KRAS Targeting LigandEis23. The compound of any one of claims 1 -19, wherein the compound is of Formulaor a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 1-23, wherein R3?is25. The compound of any one of claims 1-19, w herein the compound is of Formulaor a pharmaceutically acceptable salt thereof; wherein KRAS Targeting Ligandcis26. The compound ofClaim 25, wherein R32B is selected fromand27. The compound of any one of claims 1-26, wherein R32is28. 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.

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