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WO2025006783A2 - Composés hétérobifonctionnels pour la dégradation de kras - Google Patents

Composés hétérobifonctionnels pour la dégradation de kras Download PDF

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WO2025006783A2
WO2025006783A2 PCT/US2024/035874 US2024035874W WO2025006783A2 WO 2025006783 A2 WO2025006783 A2 WO 2025006783A2 US 2024035874 W US2024035874 W US 2024035874W WO 2025006783 A2 WO2025006783 A2 WO 2025006783A2
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compound
independently selected
alkyl
certain embodiments
kras
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WO2025006783A3 (fr
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Corey Don Anderson
Xinpeng CHENG
Christopher G. Nasveschuk
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • KRAS Kirsten rat sarcoma viral oncogene homolog
  • 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).
  • the RAS GTPases 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).
  • NSCLC non-small cell lung cancer
  • 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”.
  • KRAS 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).
  • 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.).
  • RTKs receptor tyrosine kinases
  • Id. converging resistance mechanisms
  • 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.
  • KRAS degraders are described in Fell, J.B. et al. Identification of the Clinical Development Candidate MRTX849, a Covalent KRAS G12C Inhibitor for the Treatment of Cancer, J. Med. Chem.202063 (13), 6679-6693; Fell, J.B. et al., Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS G12C with In Vivo Activity, ACS Med. Chem. Lett. 2018, 9, 12, 1230–1234; Wang, X. et al. “Identification of MRTX1133, a Noncovalent, Potent and Selective KRAS G12D Inhibitor, J. Med.
  • 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.
  • 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).
  • a Targeting Ligand that binds to KRAS
  • an E3 Ligase binding portion Heterocyclic Moiety A or Heterocyclic Moiety B
  • a Linker that covalently links the Targeting Ligand to the E3 Ligase binding portion.
  • 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.
  • a compound of the present invention is a selective degrader of G12D or G12V containing KRAS mutants.
  • the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic Moiety A is selected from: and y is 0, 1, 2, 3, or 4; in certain embodiments y is 0; in certain embodiments y is 1; R 1 and R 6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R 1 and R 6 are combined to form a one or two carbon bridge to form a fused cycle, for example when R 1 and R 6 are combined to form a one carbon bridge is and a two carbon bridge is ; in certain embodiments R 1 and R 6 are both hydrogen; each R 2 is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R 9 , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; in certain embodiments R 2 is hydrogen or CH3; each R 5
  • R 51C is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD 3 ;
  • R 51D and R 51E are hydrogen or together with X B and the carbon atoms to which they are attached, form a 5-, 6-, or 7-membered ring;
  • z is independently selected at each instance from 0, 1, 2, 3, and 4, as allowed by valence; in certain embodiments z is 0; in certain embodiments z is 1; q is 1, 2, or 3; w is 1, 2, or 3;
  • X B is selected from -CH 2 -, -O-, -NH-, -N(R 4 )-, and -S-;
  • X C is -CH 2 -, -O-, or -S-;
  • R 33 is selected from: , and each 33 of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl,
  • Linker is selected from ; wherein: X 1 and X 2 are independently at each occurrence selected from bond, heterocycle, NR 2 , C(R 2 ) 2 , O, C(O), and S; R 20 , R 21 , R 22 , R 23 , and R 24 are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO 2 -, -S(O)-, -C(S)-, -C(O)NR 2 -, -NR 2 C(O)-, -O-, -S-, -NR 2 -, -C(R 40 R 40 )-, -P(O)(OR 26 )O-, -P(O)(OR 26 )-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle
  • the present invention provides a compound of Formula II, Formula III, or Formula IV: ; ; ; or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic Moiety B is selected from: and ; Q is CH 2 , NR 2 , , O, or S; R 17 is selected from: and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ; R 18 is selected from: and , each of which is attached to the azaglutarimide moiety through a C-N bond and each of which R 18 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ; 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 R 5 and substituted with one R 12 substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from
  • KRAS Targeting Ligand D is selected from: , and ; wherein R 31B is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR 7 R 8 , -OR 7 , and -SR 7 ; and all other variables are as defined herein.
  • KRAS Targeting Ligand A , KRAS Targeting Ligand B , KRAS Targeting Ligand C , and KRAS Targeting Ligand D are selected from: , , , and
  • the present invention provides a compound of Formula V: or a pharmaceutically acceptable salt thereof; wherein: KRAS Targeting Ligand E is selected from: , and ; R 33C is , a 33C nd each of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR 7 R 8 , -OR 7 , and - SR 7 ; 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
  • KRAS Targeting Ligand F is selected from: , and ;
  • R 29B is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 145 , R 146 , and R 147 ;
  • each R 145 , R 146 , and R 147 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 , -OR 11 , -SR 11 , -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O) 2 R 14 , and -P(O)(R 14 ) 2 ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 15 ; and all other variables are as defined here
  • 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.
  • a method to treat a patient with a disorder mediated by KRAS 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.
  • a method of treatment 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.
  • a compound of the present invention is administered to a human to treat a cancer.
  • a compound of the present invention is used to treat lung cancer.
  • the lung cancer is non-small cell lung cancer.
  • a compound of the present invention is used to treat colorectal or rectal cancer.
  • a compound of the present invention is used to treat pancreatic cancer.
  • a compound of the present invention is used to treat pancreatic ductal adenocarcinoma (PDAC).
  • PDAC pancreatic ductal adenocarcinoma
  • the compound of the present invention provides one or more, and even may provide multiple advantages over traditional treatment with a KRAS ligand.
  • 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.
  • 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.
  • the mutation encodes a missense substitution at a codon selected from glycine-12 (G12), glycine-13 (G13), glutamine 61 (Q61), or any combination thereof.
  • 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,
  • the mutation is G12D.
  • 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®).
  • 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.
  • 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.
  • a KRAS inhibitor such as Sotorasib (AMG- 510; Lumakras®), adagrasib (MRTX849; Krazati®), 12VC1, ARS-1620, ARS-3248, ARS- 853, AZD4785, Bi-2852, BI 182391
  • 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. 1 Specific 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)).
  • the mutant KRAS mediated disorder has two substitutions selected from the table above.
  • 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.
  • the non-KRAS mutation is selected from a mutation in TP53, STK1, EGFR, or a combination thereof.
  • the KRAS mediated disorder is mutant KRAS mediated cancer.
  • a compound of the present invention is used to treat G12D mutant KRAS cancer.
  • a compound of the present invention is used to treat G12V mutant KRAS cancer.
  • the compound of the present invention provides an improved efficacy and/or safety profile relative to at least one known KRAS inhibitor.
  • 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.
  • 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.
  • KRAS Targeting Ligand is KRAS Targeting Ligand A , KRAS Targeting Ligand B , KRAS Targeting Ligand C , KRAS Targeting Ligand D .
  • 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.
  • 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.
  • 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.
  • 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.
  • a compound of the present invention, or its pharmaceutically acceptable salt thereof includes a deuterium atom or multiple deuterium atoms.
  • 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
  • a Targeting Ligand that binds to KRAS
  • an E3 Ligase binding portion Heterocyclic Moiety A or Heterocyclic Moiety B
  • a Linker that covalently links the Targeting Ligand to the E3 Ligase binding portion.
  • 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.
  • a compound of the present invention is a selective degrader of G12D or G12V containing KRAS mutants.
  • the present invention includes a compound of the present invention with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F 31 P, 32 P, 35 S, 36 Cl, and 125 I respectively.
  • isotopically labelled compounds can be used in metabolic studies (with, for example 14 C), reaction kinetic studies (with, for example 2 H or 3 H), 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.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F 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.
  • 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.
  • the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of the present invention.
  • 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.
  • the alkyl residue may be deuterated (in non-limiting embodiments, CDH 2 , CD 2 H, CD 3, CH 2 CD 3 , CD 2 CD 3 , CHDCH 2 D, CH 2 CD 3 , CHDCHD 2 , OCDH 2 , OCD 2 H, or OCD 3 etc.).
  • the unsubstituted carbons may be deuterated.
  • a compound of the present invention is isotopically labeled.
  • At least one R group is isotopically labeled with 1, 2, or more isotopes as allowed by valence.
  • the isotopic label is deuterium.
  • 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 ⁇ , ⁇ or ⁇ , or primary, secondary or tertiary isotope effect).
  • the isotopic label is 13 C.
  • the isotopic label is 18 F.
  • the compound of the present invention may form a solvate with a solvent (including water).
  • the invention includes a solvated form of the compound.
  • solvate refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules.
  • solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents.
  • 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-d 6 , DMSO-d 6 (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.
  • Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group. Unless denoted otherwise, “alkyl” is typically a C 1 -C 8 alkyl. In certain non-limiting embodiments, the alkyl group contains from 1 to 12 carbon atoms, more generally from 1 to 6 carbon atoms or from 1 to 4 carbon atoms. In certain non-limiting embodiments, the alkyl contains from 1 to 8 carbon atoms.
  • the alkyl is C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , or C 1 -C 6 .
  • the specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species.
  • the term C 1 -C 6 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and therefore each subset is considered separately disclosed.
  • C 1 -C 4 alkyl 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.
  • 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.
  • alkyl also encompasses cycloalkyl or carbocyclic groups.
  • cycloalkyl or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context.
  • 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.
  • alkoxy denotes a group of the formula -O-alkyl.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.
  • 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 C 2 -C 8 alkenyl. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. In certain non-limiting embodiments, the alkenyl contains from 2 to 12 carbon atoms, from 2 to 6 carbon atoms or from 2 to 4 carbon atoms.
  • the alkenyl is C 2 , C 2 -C 3 , C 2 -C 4 , C 2 -C 5 , or C 2 -C 6 alkenyl.
  • alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl also embodies “cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z” alkenyl geometry.
  • 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 C 2 -C 8 alkynyl.
  • the specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. In certain non-limiting embodiments, the alkynyl contains from 2 to 12 carbon atoms, more generally from 2 to 6 carbon atoms or from 2 to 4 carbon atoms.
  • the alkynyl is C 2 , C 2 -C 3 , C 2 -C 4 , C 2 -C 5 , or C 2 - C 6 alkynyl.
  • 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.
  • 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 C 1 -C 2 alkylene, C 1 -C 3 alkylene, C 1 -C 4 alkylene, C 1 -C 5 alkylene, or C 1 -C 6 alkylene.
  • 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 C 2 -C 4 alkenylene.
  • 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 C 2 -C 4 alkynylene.
  • cyano denotes a -C ⁇ N group.
  • 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 C 1 -C 4 haloalkyl.
  • 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 .
  • 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.
  • 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 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6–14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocycle groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • the one or more fused carbocyclyl or heterocycle groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocycle groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4-methylenedioxyphenyl group.
  • “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.
  • aryl is an “aryl” group.
  • heterocycle is a 6-carbon aromatic group fused to a cycloalkyl wherein the point of attachment is the aryl ring.
  • aryl include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the aromatic ring.
  • 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.
  • Heterocyclic Moiety A and “Heterocyclic Moiety B ” that are in the present invention and separately defined.
  • Heterocyclic rings comprise monocyclic 3, 4, 5, 6, 7, 8, 9, or 10 membered rings, as well as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). It does not include rings containing -O-O-, -O-S- or -S-S- portions.
  • 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].
  • 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.,
  • partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.
  • 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,
  • heterocyclyl 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.
  • heterocycle 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
  • heterocycle examples include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring.
  • indoline tetrahydroquinoline
  • tetrahydroisoquinoline tetrahydroisoquinoline
  • dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring.
  • aryl is an “aryl” group.
  • heteroaryl denotes a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ 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
  • 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.
  • 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 .
  • 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.
  • 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.
  • “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.
  • 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.
  • the aliphatic group contains from 1 to 8 carbon atoms.
  • the aliphatic group is C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 or C 1 -C 6 .
  • the specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species.
  • C 1 -C 6 aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species.
  • C 1 -C 4 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.
  • 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.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • Heteroaliphatic is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties.
  • heteroaliphatic is used to indicate a heteroaliphatic group (cyclic, acyclic, branched or unbranched) having 1-20 carbon atoms.
  • 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.
  • dosage forms examples 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.
  • parenter” administration of a pharmaceutical composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), intrasternal injection, or infusion techniques.
  • compositions are compositions comprising at least one active agent, and at least one excipient.
  • 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.
  • 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.
  • 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.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • 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.
  • 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-(CH 2 )n-COOH where n is 0-4, and the like, or using a different acid that produces the same counterion.
  • inorganic acids such as hydrochloric, hydrobromic,
  • 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.
  • 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.
  • the patient is a human.
  • the patient or subject is a non-human animal in need of such therapy and responsive thereto.
  • 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 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
  • the compound of the present invention is selected from
  • 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
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from and or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is selected from
  • 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
  • the present invention provides a compound of Formula X: or a pharmaceutically acceptable salt thereof; wherein Linker B is selected from: X 22 is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 7 R 8 , -OR 7 , -SR 7 , -C(O)R 9 , -C(S)R 9 , -S(O)R 9 , -S(O) 2 R 9 , -OC(O)R 9 , -OC(S)R 9 , -OS(O)R 9 , -OS(O) 2 R 9 , -SC(O)R 9 , -OS(O) 2 R 9 , -NR 7 C(O)R 9 , -NR 7 C(S)R 9 , -NR 7 S(O)R 9 , -NR 7 S(O)R 9 ,
  • KRAS Targeting Ligand is KRAS Targeting Ligand A . In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand B . In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand C . In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand D . In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand E . In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand F .
  • X 22 is selected from haloalkyl, alkenyl, alkynyl, halogen, heterocycle, - NR 7 R 8 , -OR 7 , -SR 7 , -C(O)R 9 , -C(S)R 9 , -S(O)R 9 , -S(O) 2 R 9 , -OC(O)R 9 , -OC(S)R 9 , -OS(O)R 9 , - OS(O) 2 R 9 , -SC(O)R 9 , -OS(O) 2 R 9 , -NR 7 C(O)R 9 , -NR 7 C(S)R 9 , -NR 7 S(O)R 9 , -NR 7 S(O) 2 R 9 , -P(O)(R 9 ) 2 , -SP(O)(R 9 ) 2 , -NR 7 P(O)(R 9 ) 2 , and -
  • X 22 is selected from haloalkyl, alkenyl, alkynyl, halogen, heterocycle, -NR 7 R 8 , -OR 7 , -SR 7 , -C(O)R 9 , -OC(O)R 9 , and -NR 7 C(O)R 9 .
  • X 22 is selected from haloalkyl, alkenyl, alkynyl, halogen, heterocycle, -NH 2 , -N(alkyl)H, -OH, -C(O)OH, -C(O)Oalkyl, -NHC(O)Oalkyl, and -NalkylC(O)Oalkyl.
  • the present invention provides a compound of Formula XX and .
  • the compound of Formula XX is selected from: or a pharmaceutically acceptable salt thereof.
  • the compound of Formula XX is selected from: and ; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula XX is selected from: or a pharmaceutically acceptable salt thereof.
  • the compound of Formula XX is ; or a pharmaceutically acceptable salt thereof.
  • R 33B is , or ; and all other variables are as defined herein.
  • R 33B is In certain embodiments R 33B is In certain embodiments R 33B is In certain embodiments R 33B is . In certain embodiments R 33B is In certain embodiments R 33B is or .
  • the compound of Formula XX is selected from:
  • the invention is a compound of Formula: ; ; ; or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic Moiety A is selected from: and ; Heterocyclic Moiety B is selected from:
  • each R 2 is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R 9 , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;
  • each R 5 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 7 R 8 , -OR 7 , -SR 7 , -C(O)R 9 , -C(S)R 9 , -S(O)R 9 , -S(O) 2 R
  • KRAS Targeting Ligand D is selected from: , and ; or KRAS Targeting Ligand A , KRAS Targeting Ligand B , KRAS Targeting Ligand C , or KRAS Targeting Ligand D , is selected from: , , and ;
  • R 29 is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 45 , R 46 , and R 47 ;
  • R 30 and R 31 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR 7 R 8 , -OR 7 , and -SR 7 ;
  • R 32 is heterocycle optionally substituted with 1, 2, 3, or 4 R 51 groups as allowed by valence;
  • R 4 is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl
  • R 51C is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD 3 ;
  • R 51D and R 51E are hydrogen or together with X B and the carbon atoms to which they are attached, form a 5-, 6-, or 7-membered ring;
  • z is independently selected at each instance from 1, 2, 3, and 4, as allowed by valence;
  • q is 1, 2, or 3;
  • w is 1, 2, or 3;
  • X B is selected from -CH 2 -, -O-, -NH-, -N(R 4 )-, and -S-;
  • X C is -CH 2 -, -O-, or -S-;
  • R 33 is selected from: and e 33 ach of which R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl,
  • the compound of embodiment A1, wherein Heterocyclic Moiety A and Heterocyclic Moiety B is A30.
  • the compound of embodiment A29, wherein R 18 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 .
  • A31. The compound of embodiment A29, wherein R 18 is which is attached to the azaglutarimide moiety through a C-N bond and optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 .
  • A32. The compound of embodiment A29, wherein R 18 is , , or A33.
  • the compound of embodiment A29, wherein R 18 is , or A34.
  • the compound of embodiment A1, wherein Heterocyclic Moiety A and Heterocyclic Moiety B is A35.
  • the compound of embodiment A1, wherein Heterocyclic Moiety A and Heterocyclic Moiety B is .
  • A36. The compound of any one of embodiments A29-A35, wherein R 1 is hydrogen.
  • A37. The compound of any one of embodiments A29-A35, wherein R 1 is CH3.
  • A38. The compound of any one of embodiments A29-A35, wherein R 1 and R 6 combined form a one-carbon bridge.
  • the compound of embodiment A1, wherein Heterocyclic Moiety A and Heterocyclic Moiety B is A40.
  • the compound of embodiment A1, wherein Heterocyclic Moiety A and Heterocyclic Moiety B is .
  • R 6 is hydrogen.
  • A42 The compound of any one of embodiments A1-A40, wherein R 6 is methyl.
  • A43 The compound of any one of embodiments A1-A42, wherein each R 5 is independently selected from hydrogen, alkyl, haloalkyl, and halogen.
  • A44 The compound of any one of embodiments A1-A42, wherein each R 5 is hydrogen.
  • A45 The compound of any one of embodiments A1-A42, wherein one R 5 is F.
  • A46 The compound of any one of embodiments A1-A42, wherein R 5 is -NR 7 R 8 or - OR 7 .
  • A47 The compound of embodiment A46, wherein R 7 is hydrogen.
  • the compound of embodiment A46, wherein R 7 is methyl.
  • A49. The compound of any one of embodiments A46-A48, wherein R 8 is hydrogen.
  • A50. The compound of any one of embodiments A46-A48, wherein R 8 is methyl.
  • A51. The compound of any one of embodiments A1-A42, wherein R 5 is aryl or heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R 10 .
  • A52. The compound of any one of embodiments A1-A42, wherein R 5 is cyano.
  • A53. The compound of any one of embodiments A1-A42, wherein R 5 is nitro.
  • A55 The compound of any one of embodiments A1-A42, wherein R 5 -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 X 1 is bond.
  • A57. The compound of embodiment A55, wherein X 1 is heterocycle.
  • A58. The compound of embodiment A55, wherein X 1 is NR 2 .
  • A59. The compound of embodiment A55, wherein X 1 is C(O).
  • A60. The compound of any one of embodiments A55-A59, wherein X 2 is bond.
  • A61. The compound of any one of embodiments A55-A59, wherein X 2 is heterocycle.
  • Linker is of formula: A91.
  • A92. The compound of any one of embodiments A55-A90, wherein R 24 is CH 2 .
  • A93. The compound of any one of embodiments A55-A90, wherein R 24 is heterocycle.
  • A94. The compound of any one of embodiments A55-A90, wherein R 24 is aryl.
  • A95 The compound of any one of embodiments A55-A90, wherein R 24 is phenyl.
  • A96 The compound of any one of embodiments A55-A90, wherein R 24 is bicycle.
  • A98 The compound of any one of embodiments A55-A90, wherein R 24 is C(O).
  • A98 The compound of any one of embodiments A1-A97, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof.
  • A99 The compound of embodiment A98, wherein the KRAS Targeting Ligand A is A100.
  • the compound of embodiment A98, wherein the KRAS Targeting Ligand A is .
  • A101 The compound of embodiment A98, wherein the KRAS Targeting Ligand A is A102.
  • the compound of embodiment A98, wherein the KRAS Targeting Ligand A is A103.
  • the compound of embodiment A98, wherein the KRAS Targeting Ligand A is A104.
  • the compound of embodiment A98, wherein the KRAS Targeting Ligand A is A105.
  • the compound of embodiment A98, wherein the KRAS Targeting Ligand A is A106.
  • the compound of embodiment A98, wherein the KRAS Targeting Ligand A is A107.
  • the compound of embodiment A98, wherein the KRAS Targeting Ligand A is A108.
  • the compound of any one of embodiments A1-A97, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof.
  • KRAS Targeting Ligand B is A110.
  • the compound of embodiment A108, wherein KRAS Targeting Ligand B is A111.
  • the compound of embodiment A108, wherein KRAS Targeting Ligand B is A112.
  • KRAS Targeting Ligand C is A136.
  • KRAS Targeting Ligand C is A137.
  • KRAS Targeting Ligand C is A138.
  • KRAS Targeting Ligand C is A139.
  • KRAS Targeting Ligand C is A140.
  • KRAS Targeting Ligand C is A141.
  • KRAS Targeting Ligand C is A142.
  • KRAS Targeting Ligand C is A143.
  • the compound of any one of embodiments A1-A142, wherein R 32 or R 32B is A150.
  • the compound of any one of embodiments A1-A142, wherein R 32 or R 32B is A151.
  • the compound of any one of embodiments A1-A142, wherein R 32 or R 32B is A152.
  • the compound of any one of embodiments A1-A142, wherein R 32 or R 32B is A153.
  • the compound of any one of embodiments A1-A142, wherein R 32 or R 32B is A154.
  • R 29 is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 45 , R 46 , and R 47 .
  • A155 The compound of any one of embodiments A1-A154, wherein R 29 is aryl.
  • A156 The compound of any one of embodiments A1-A154, wherein R 29 is heteroaryl.
  • A157 The compound of any one of embodiments A1-A154, wherein R 29 is bicycle.
  • A158 The compound of any one of embodiments A1-A153, wherein R 29 is A159.
  • the compound of any one of embodiments A1-A158, wherein R 45 is -OR 11 .
  • A160 The compound of embodiment A159, wherein R 11 is H. A161.
  • A163 The compound of any one of embodiments A1-A158, wherein R 46 is ethyl.
  • A164 The compound of any one of embodiments A1-A158, wherein R 46 is -CCH. A165.
  • 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.
  • A192. The pharmaceutical composition of embodiment A191, wherein the liquid dosage form is suitable for parenteral administration.
  • 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.
  • Heterocyclic Moiety A is selected from:
  • Heterocyclic Moiety B is selected from: and ; y is 1, 2, 3, or 4; R 1 and R 6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R 1 and R 6 are combined to form a one or two carbon bridge to form a fused cycle, each R 2 is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R 9 , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; each R 5 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 7 R 8 , -OR 7 , -SR 7 , -C(O)R 9 , -C(S)R 9 , -S(O
  • KRAS Targeting Ligand D is selected from: , , and ;
  • KRAS Targeting Ligand A , KRAS Targeting Ligand B , KRAS Targeting Ligand C , or KRAS Targeting Ligand D is selected from: , and ;
  • KRAS Targeting Ligand E is selected from: and
  • KRAS Targeting Ligand F is selected from: and R 29 is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 45 , R 46 , and R 47 ;
  • R 29B is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 145 , R 146 , and R 147 ;
  • each R 145 , R 146 , and R 147 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 , -OR 11
  • each R 5 is independently selected from hydrogen, alkyl, haloalkyl, and halogen.
  • B44 The compound of any one of embodiments B1-B42, wherein each R 5 is hydrogen.
  • B45 The compound of any one of embodiments B1-B42, wherein one R 5 is F.
  • B46 The compound of any one of embodiments B1-B42, wherein R 5 is -NR 7 R 8 or - OR 7 .
  • B47 The compound of embodiment B46, wherein R 7 is hydrogen.
  • B48 The compound of embodiment B46, wherein R 7 is methyl.
  • B49 The compound of any one of embodiments B46-B48, wherein R 8 is hydrogen.
  • B50 The compound of any one of embodiments B46-B48, wherein R 8 is hydrogen.
  • the compound of embodiment B98, wherein the KRAS Targeting Ligand A is B106.
  • the compound of embodiment B98, wherein the KRAS Targeting Ligand A is B107.
  • the compound of any one of embodiments B1-B97, wherein the compound is of Formula or a pharmaceutically acceptable salt thereof.
  • B108. The compound of embodiment B107, wherein KRAS Targeting Ligand B is B109.
  • KRAS Targeting Ligand B is B110.
  • KRAS Targeting Ligand B is B111.
  • KRAS Targeting Ligand B is B112.
  • the compound of embodiment B107, wherein KRAS Targeting Ligand B is B113.
  • the compound of embodiment B107, wherein KRAS Targeting Ligand B is B114.
  • the compound of embodiment B107, wherein KRAS Targeting Ligand B is B115.
  • B116. The compound of embodiment B115, wherein KRAS Targeting Ligand D is B117.
  • the compound of embodiment B115, wherein KRAS Targeting Ligand D is B118.
  • the compound of embodiment B115, wherein KRAS Targeting Ligand D is B119.
  • the compound of embodiment B115, wherein KRAS Targeting Ligand D is B120.
  • the compound of embodiment B115, wherein KRAS Targeting Ligand D is B121.
  • KRAS Targeting Ligand C is B134.
  • KRAS Targeting Ligand C is B135.
  • KRAS Targeting Ligand C is B136.
  • KRAS Targeting Ligand C is B137.
  • KRAS Targeting Ligand C is B138.
  • KRAS Targeting Ligand C is B139.
  • KRAS Targeting Ligand C is B140.
  • KRAS Targeting Ligand C is B141.
  • KRAS Targeting Ligand C is B142.
  • 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.
  • 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 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.
  • 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.
  • embodiment B209 wherein the cancer is mediated by KRAS G12D. B212.
  • KRAS Targeting Ligand D is selected from: , , and ;
  • KRAS Targeting Ligand A , KRAS Targeting Ligand B , KRAS Targeting Ligand C , or KRAS Targeting Ligand D is selected from: , and ;
  • KRAS Targeting Ligand E is selected from: , , , and ;
  • KRAS Targeting Ligand F is selected from:
  • R 29 is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 45 , R 46 , and R 47 ;
  • R 29B is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 145 , R 146 , and R 147 ;
  • each R 145 , R 146 , and R 147 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11
  • each R 5 is independently selected from hydrogen, alkyl, haloalkyl, and halogen.
  • CIS The compound of any one of embodiments Cl -Cl 7, wherein R 2i is bond, -O-, -NR 2 -, -S-, alkyl, heterocycle, aryl, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R 40 .
  • Linker Heterocyclic Targeting Moiety 8 Ligand 8 or a pharmaceutically acceptable salt thereof; wherein KRAS Targeting
  • a pharmaceutical composition comprising a compound of any one of embodiments C1-C29, oorr aa pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • 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.
  • KRAS Targeting Ligand is selected from KRAS Targeting Ligand A , KRAS Targeting Ligand®, KRAS Targeting Ligand C , and KRAS Targeting Ligand D .
  • KRAS Targeting Ligand G is selected from KRAS Targeting Ligand B , KRAS Targeting Ligand C , KRAS Targeting Ligand D , KRAS Targeting Ligand E Fnd KRAS Targeting Ligand F .
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • the compound of the present in vention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • 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.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present in vention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof,
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • 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.
  • the compound of the present invention is of Formula:
  • 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.
  • the compound of the present invention is of Formula:
  • 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.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • 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.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • 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.
  • KRAS Targeting Ligand is KRAS Targeting Ligand A . In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand B . In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand C . In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand D . In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand E . In certain embodiments KRAS Targeting Ligand is KRAS Targeting Ligand F .
  • R 1 is hydrogen
  • R. 1 is alkyl
  • R 1 is halogen. In certain embodiments, R. 1 is halogen, wherein the halogen is F. In certain embodiments, R 1 is halogen, wherein the halogen is C1. In certain embodiments, R 1 is halogen, wherein the halogen is Br. In certain embodiments, R 1 is halogen, wherein the halogen is I.
  • R 6 is alkyl
  • R° is haloalkyl
  • R 1 and R 6 are combined to form a single carbon bridge.
  • R‘ and R 6 are both hydrogen.
  • R 2 is hydrogen
  • R 2 is alkyl
  • R 2 is haloalkyl
  • R 2 is alkenyl
  • R 2 is alkynyl. In certain embodiments R 2 is aryl. In certain embodiments. R 2 is aryl, wherein the aryl is substituted with 1, 2, 3, or 4 substituents independently selected from R 10 . In certain embodiments, R 2 is phenyl. In certain embodiments, R 2 is phenyl substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .
  • R 2 is heteroaryl. In certain embodiments, R 2 is heteroaryl, wherein the heteroaryl is substituted with 1, 2, 3, or 4 substituents independently selected from R !0 ,
  • R 2 is heterocycle. In certain embodiments, R 2 is heterocycle, wherein the heterocycle is substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .
  • R 2 is C(O)R 9 . In certain embodiments, R 2 is C(O)R 9 , wherein C(O)R 9 is substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .
  • R 1 , R 2 , and R 6 are each hydrogen.
  • R 5 is hydrogen
  • each R 5 is selected from alkyl, haloalkyl, and halogen.
  • R 5 is alkyl
  • R is haloalkyl
  • R 3 is alkenyl
  • R 5 is alkynyl.
  • R 5 is halogen. In certain embodiments, R 5 is halogen, wherein the halogen is F. In certain embodiments, R 5 is halogen, wherein the halogen is C1. In certain embodiments, R 5 is halogen, wherein the halogen is Br. In certain embodiments, R s is halogen, wherein the halogen is I.
  • R 5 is heteroaryl. In certain embodiments, R 5 is aryl. In certain embodiments, R 3 is heterocycle.
  • R 3 is cyano
  • R 5 is -NR 7 R 8 .
  • R 3 is -NR 7 C(O)R 9 .
  • R 5 is -NR 7 C(S)R 9 .
  • R 3 is -NR 7 C(O)R 9 .
  • R 5 is -NR 7 S(O) 2 R 9 .
  • R 5 is -OR 7 "
  • R 3 is -SR 7 .
  • R 5 is -S(O) 2 R 9 .
  • R 3 is -C(O)R 9 .
  • R 7 and R 8 are -C(O)R 9 .
  • R 7 is hydrogen
  • R 7 is alkyl
  • R 7 is methyl
  • R 7 is haloalkyi.
  • R 7 is CFJ.
  • R ? is aryl.
  • R 7 is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R 10 .
  • R 7 is heteroaryl. In certain embodiments R 7 is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R 10 .
  • R 7 is heterocycle. In certain embodiments R 7 is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R 10 .
  • R 7 is C(O)R 14 .
  • R 7 is C(O) alkyl.
  • R 8 is hydrogen
  • R 8 is alkyl
  • R 8 is methyl
  • R 8 is haloalkyi.
  • R 8 is CF 3 .
  • R 7 and R 8 are both hydrogen.
  • R 9 is hydrogen
  • R 9 is alkyl
  • R 9 is methyl
  • R 9 is ethyl
  • R 9 is haloalkyi.
  • R 3 is CF 3 .
  • R 9 is aryl. In certain embodiments R 9 is and optionally substituted with 1, 2, or 3 substituents independently selected from R 10 .
  • R 9 is heteroaryl. In certain embodiments R s is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R 10 . In certain embodiments R 9 is heterocycle. In certain embodiments R 9 is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R 10 .
  • R 9 is -NR 7 R 8 .
  • R 9 is -NH 2 .
  • R 9 is -N(CH 3 )H.
  • R 9 is -N(CH 3 ) 2 .
  • R 9 is -OR 7 .
  • R 9 is -OH.
  • R 9 is -SR 7 .
  • R 9 is -SH.
  • R i0 is hydrogen
  • R 10 is alkyl
  • R 10 is methyl
  • R 10 is ethyl
  • R 10 is haloalkyl
  • R 10 is CF 3 .
  • R 10 is aryl. In certain embodiments R 10 is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R 13 .
  • R 10 is heteroaryl. In certain embodiments R 10 is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R 15 .
  • R 10 is heterocycle. In certain embodiments R 10 is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R 15 .
  • R 10 is -NR 11 R 13 .
  • R 10 is -NH 2 .
  • R 10 is -N(CH 3 )H.
  • R 10 is -N(CH 3 ) 2 .
  • R 1C is -OR 11 .
  • R 10 is -OH.
  • R 10 is -SR 11 .
  • R 10 is -SH.
  • R 10 is alkenyl
  • R 10 is alkynyl. In certain embodiments R 10 is cyano.
  • R 10 is nitro
  • R 10 is -C(O)R 14 .
  • R 10 is -C(O)alkyl.
  • R 10 is -C(O)N(alkyl) 2 .
  • R 10 is -C(O)N(II)(a1kyl).
  • R 10 is -C(S) R 14 .
  • R 10 is -C(S)alkyl
  • R 10 is -C(S)N(alkyl) 2 .
  • R 10 is -C(S)N(H)(alkyl).
  • R 10 is -S(O)R 34 .
  • R 10 is -S(O) 2 R 14 .
  • R 10 is -P(O)(R 14 ) 2 .
  • R 11 is hydrogen
  • R 11 is alkyl
  • R 11 is methyl
  • R 11 is haloalkyl
  • R 11 is CF 3 .
  • R 11 is aryl.
  • R 13 is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R 15 .
  • R 11 is heteroaryl. In certain embodiments R 11 is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R 15 .
  • R 11 is heterocycle.
  • R n is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R 15 .
  • R 11 is C(O)R 14 .
  • R 11 is C(O)alkyl.
  • R 13 is hydrogen
  • R 13 is alkyl. in certain embodiments R 13 is methyl.
  • R 13 is haloalkyl
  • R 13 is C F 3.
  • Embodiments of R 14 are C F 3.
  • R 14 is hydrogen
  • R 14 is alkyl
  • R 14 is methyl
  • R 14 is ethyl
  • R 14 is haioaikyl.
  • R 14 is CF 3 .
  • R 14 is aryl. In certain embodiments R 14 is and optionally substituted with 1, 2, or 3 substituents independently selected from R 15 .
  • R 14 is heteroaryl. In certain embodiments R 14 is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R 15 .
  • R 14 is heterocycle. In certain embodiments R 14 is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R 15 .
  • R 14 is -NH 2 .
  • R 14 is -N(H)(alkyl).
  • R 14 is -N(alkyl) 2 .
  • R 14 is -OH.
  • R 14 is alkoxy
  • R 13 is hydrogen
  • each R 15 is selected from alkyl, haioaikyl, and halogen.
  • R 15 is alkyl
  • R 15 is haioaikyl.
  • R 15 is alkenyl
  • R 15 is alkynyl.
  • R 15 is halogen
  • R 15 is aryl
  • R 15 is heteroaryl. hr certain embodiments R 15 is heterocycle.
  • R 15 is cyano
  • R 15 is nitro
  • R 15 is amino. In certain embodiments R 15 is hydroxyl.
  • R 15 is alkoxy
  • R 15 is -N(H)(alkyl).
  • R 15 is -N(alkyl) 2 .
  • Cycle-A is phenyl optionally substituted with 1 or 2 substituents independently selected from R 5 .
  • Cycle-A is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from R s .
  • Cycle-A is a 5- to 8-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from R s .
  • Cycle-A is a 5- to 8-membered cycloalkyl optionally substituted with 1 or 2 substituents independently selected from R 5 .
  • Cycle-A is a 5- to 8-membered cycloalkenyl optionally substituted with 1 or 2 substituents independently selected from R 5 .
  • Cycle-A is phenyl
  • Cycle-A is a 5- or 6-membered heteroaryl.
  • Cycle-A is a 5- to 8-membered heterocycle.
  • Cycle-A is a 5- to 8-membered cycloalkyl.
  • Cycle-A is a 5- to 8-membered cycloalkenyl.
  • Cycle ⁇ B is phenyl optionally substituted with 1 or 2 substituents independently selected from R 5 .
  • Cycle-B is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from R s .
  • Cycle-B is a 5- to 8-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from R 5 .
  • Cycle-B Is a 5- to 8-membered cycloalkyl optionally substituted with 1 or 2 substituents independently selected from R 5 .
  • Cycle-B is a 5- to 8-membered cycloalkenyl optionally substituted with 1 or 2 substituents independently selected from R 5 .
  • Cycle-B is phenyl
  • Cycle-B is a 5- or 6 ⁇ membered heteroaryi.
  • Cycle-B is a 5- to 8-membered heterocycle. In certain embodiments Cycle-B is a 5- to 8-membered cycloalkyl.
  • Cycle-B is a 5- to 8-membered cycloalkenyl.
  • Cycle-A is phenyl optionally substituted with 1 or 2 substituents independently selected from R s and Cycle-B is phenyl.
  • Cycle-B is phenyl optionally substituted with 1 or 2 substituents independently selected from R 5 and Cycle-A is phenyl.
  • Cycle-A and Cycle-B are both phenyl.
  • spirocycle is a cycloalkyl optionally substituted with 1, 2, 3, or
  • cycloalkene is a cycloalkyl optionally substituted with 1, 2 5 3, or 4 substituents independently selected from R 5 and substituted with one R 12 substituent.
  • heterocycle is a cycloalkyl optionally substituted with 1, 2, 3. or 4 substituents independently selected from R 3 and substituted with one R 12 substituent.
  • spirocycle is piperidine optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 and substituted with one R 12 substituent.
  • spirocycle is a pyrrolidine optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 3 and substituted with one R 12 substituent.
  • R 16 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 .
  • R 16 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 . In certain embodiments R 16 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 .
  • R 16 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 .
  • R 16 is R 12 .
  • R 16 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ,
  • R 17 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ,
  • R 17 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 .
  • R 17 is which is optionally substituted w'ith 1, 2, 3, or 4 substituents independently selected from R 5 .
  • R 17 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 . In certain embodiments R 17 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 .
  • R 18 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 .
  • R 18 is which is optionally substituted with 1, 2, 3. or 4 substituents independently selected from R 5 .
  • R 18 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 .
  • R 18 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 .
  • R 18 is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 .
  • R 16 and R 17 are selected from
  • R 16 and R 17 are selected from
  • R 16 and R 17 are selected from
  • R 18 is selected from In certain embodiments R 18 is selected from
  • each Y is independently selected from N, CH, or CR 5 , 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.
  • each Y is independently selected from N, CH, or CR 5 , wherein 0, 1, or 2, (as context allows) instances of Y are selected to be N and are selected to produce a stable ring as well known to those skilled in the art and that forms a pharmaceutically acceptable compound.
  • Non-limiting examples of include the following: Additional examples of include the following: to certain embodiments is selected from :
  • Non-limiting examples of R 16 , R 17 , and R 18 include:
  • X 22 is hydrogen
  • X 22 is alkyl
  • X 22 is haloalkyl
  • X 22 is alkenyl
  • X 22 is alkynyl
  • X 22 is halogen
  • X 22 is aryl
  • X 22 is heteroaryl
  • X 22 is heterocycle
  • X 22 is cyano. In certain embodiments X 22 is nitro.
  • X 22 is -NR 7 R 8 .
  • X 22 is -OR 7 .
  • X 22 is -SR 7 .
  • X 22 is -C(O)R 9 .
  • X 22 is -C(S)R 9 .
  • X 22 is -S(O)R 9 .
  • X 22 is -S(O) 2 R 9 .
  • X 22 is -OC(O)R 9 .
  • X 22 is -OC(S)R 9 .
  • X 22 is -OS(O)R 9 .
  • X 22 is -OS(O) 2 R 9 .
  • X 22 is -SC(O)R 9 .
  • X 22 is -OS(O) 2 R 9 .
  • X 22 is -NR 7 C(O)R 9 .
  • X 22 is -NR 7 C(S)R 9 .
  • X 22 is -NR 7 S(O)R 9 .
  • X 22 is -NR 7 S(O)zR 9 .
  • X 22 is -P(O)(R 9 ) 2 .
  • X 22 is -SP(O)(R 9 ) 2 .
  • X 22 is -NR 7 P(O)(R 9 ) 2 .
  • X 22 is -OP(O)(R 9 ) 2 .
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is of
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula :
  • the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula: In certain embodiments, the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula
  • the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula :
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula In certain embodiments the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula In certain embodiments, the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula: .
  • the Heterocyclic Moieiy A and Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety 8 is of Formula: In certain embodiments, the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety B is of Formula :
  • the Heterocyclic Moiety B is of Formula: In certain embodiments, the Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Mc-iety A and Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is of Formula:
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is selected from: In certain embodiments the Heterocyclic Moiety A and Heterocyclic Moiety B is selected from:
  • Heterocyclic Moiety 8 is selected from:
  • Heterocyclic Moiety 8 is selected from:
  • Heterocyclic Moiety A and Heterocyclic Moiety B is selected from: In certain embodiments the Heterocyclic Moiety B is selected from:
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is selected from: In certain embodiments the Heterocyclic Moiety A and Heterocyclic Moiety B is selected from:
  • Heterocyclic Moiety A and Heterocyclic Moiety B is selected from: and
  • the Heterocyclic Moiety A and Heterocyclic Moiety B is selected from: In certain embodiments the Heterocyclic Moiety A and Heterocyclic Moiety B is selected from: Embodiments of KRAS Targeting Ligand
  • KRAS Targeting Ligand is selected from:
  • KRAS Targeting Ligand is selected from: , ,
  • KRAS Targeting Ligand is selected from: In certain embodiments, KRAS Targeting Ligand is selected from:
  • KRAS Targeting Ligand is selected from:
  • KRAS Targeting Ligand is selected from: In certain embodiments, KRAS Targeting Ligand is selected from:
  • KRAS Targeting Ligand is selected from: In certain embodiments. KRAS Targeting Ligand is selected from: In certain embodiments, KRAS Targeting Ligand is selected from:
  • KRAS Targeting Ligand is selected from:
  • R 31 is R 31B .
  • KRAS Targeting Ligand E is In certain embodiments KRAS Targeting Ligand E is
  • KRAS Targeting Ligand E is In an alternative embodiment, KRAS Targeting Ligand E is
  • KRAS Targeting Llgand F is In certain embodiments KRAS Targeting Ligand F is
  • R 29 is selected from the group consisting of:
  • R 29B is selected from the group consisting of:
  • R 29B is selected from the group consisting of:
  • R 29D is selected from the group consisting of:
  • R 32 is selected from:
  • Non-limiting examples of R 33 include
  • R 33B is selected from:
  • R 33B is selected from:
  • R 33B include:
  • R 33C is
  • R 33C is
  • R 33C is
  • R 33D is
  • R 33D is
  • R 33D is
  • R 33D is
  • R 33E is
  • R 33E is
  • R 33E is Exemplary Compounds of the Present Invention to certain embodiments, compounds of Formula I or their pharmaceutically acceptable sails thereof are provided as described below:
  • the compound of the present invention is selected from:
  • the compound of the present invention is selected from:
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from
  • the compound of the present invention is selected from
  • 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
  • the KRAS-degrading compound of the present invention is provided without regard to stereochemistry.
  • 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.
  • the KRAS-degrading compound has two enantiomerically enriched and/or substantially pure stereocenters.
  • one stereocenter is in the R configuration and any others present are either enantiomerically enriched or substantially pure.
  • one stereoeenter is in the S configuration and any others present are either enantiomerically enriched or substantially pure.
  • one stereoeenter is in the R configuration and any others present are without regard to stereochemistry, enantiomerically enriched or substantially pure.
  • one stereocenter is in the S configuration and any others present are without regard to stereochemistry, enantiomerically enriched or substantially pure.
  • E3 ligase binding moiety 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.
  • the linker contains one or more moieties with a chiral center.
  • Non-limiting examples include heterocycle with an enantiomericaHy enriched or substantially pure stereocenter for example piperidine with a substituent meta- or ortho to the nitrogen or linking in the meta- or ortho- configuration; piperazine with a substituent or linking In the meta- or ortho- configuration; pyrrolidinone with or without a substituent; and pyrrolidine with or without a substituent.
  • 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
  • the linker includes In certain embodiments the linker includes or
  • the linker includes or
  • the linker includes In certain embodiments the linker includes
  • alkyl is a C 1 -C 10 alkyl, C 1 -C 9 alkyl, C 1 -C 8 alkyl, C 1 -C 7 alkyL C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, or C 1 -C 2 alkyl.
  • alkyl has one carbon
  • alkyl has two carbons.
  • alkyl has three carbons.
  • alkyl has four carbons.
  • alkyl has five carbons.
  • alkyl has six carbons.
  • alkyl include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.
  • alkyl examples include: isopropyl, isobutyl, isopentyl, and isohexyl.
  • alkyl examples include: .s'ec-butyi, sec-pentyl, and sec-hexyl.
  • alkyl examples include: tert-butyl, tert-pentyl, and tert-hexyl.
  • alkyl include: neopentyl, 3-pentyl, and active pentyl.
  • cycloalkyl is a C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkyl, C 3 - C 6 cycloalkyl, C 3 -C 5 cycloalkyl, C 3 -C 4 cycloalkyl, C 4 -C 8 cycloalkyl, C 5 -C 8 cycloalkyl, or C 6 - C 8 cycloalkyl.
  • cycloalkyl has three carbons.
  • cycloalkyl has four carbons.
  • cycloalkyl has five carbons. In certain embodiments “cycloalkyl” has six carbons.
  • cycloalkyl has seven carbons.
  • cycloalky!” has eight carbons.
  • cycloalkyl has nine carbons.
  • cycloalkyl has ten carbons.
  • cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyk cyclooctyl, and cyclodecyl.
  • haloalkyl is a C 1 -C 10 haloalkyl, C 1 -C 9 haloalkyl, C 1 - C 8 haloalkyl, C 1 -C 7 haloalkyl, C 1 -C 6 haloalkyl, C 1 -C 5 haloalkyl, C 1 -C 4 haloalkyl, C 1 -C 3 haloalkyl, and C 1 -C 2 haloalkyl.
  • haloalkyl has one carbon
  • haloalkyl has one carbon and one halogen.
  • haloalkyl has one carbon and two halogens.
  • haloalkyl has one carbon and three halogens.
  • haloalkyl has two carbons.
  • haloalkyl has three carbons.
  • haloalkyl has four carbons.
  • haloalkyl has five carbons.
  • haloalkyl has six carbons.
  • haloalkyl include:
  • haloalkyl include:
  • haloalkyl include:
  • haloalkyl examples 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.
  • heterocycle refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocycle refers to a cyclic ring with two nitrogens and 3,
  • heterocycle refers to a cyclic ring with one oxygen and 3, 4,
  • heterocycle refers to a cyclic ring with one sulfur and 3, 4, 5,
  • heterocycle examples include aziridine, oxirane, thiirane, azetidine, 1,3 -diazetidine, oxetane, and thietane.
  • heterocycle examples include pyrrolidine, 3-pyrroline, 2- pyrroline, pyrazolidine, and hnidazolidine.
  • heterocycle examples include tetrahydrofuran, 1,3- dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxafeiolane.
  • heterocycle examples include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.
  • heterocycle iinncclluuddee indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzoforan wherein the point of attachment for each group is on the heterocycle ring.
  • heterocycle also include:
  • heterocycle includes: Additional non-limiting examples of “heterocycle” include: Additional non-limiting examples of “heterocycle” include:
  • heterocycle also include:
  • heterocycle also include:
  • heterocycle includes:
  • heterocycle includes:
  • heteroaryl is a 5 membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.
  • Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.
  • heteroaryl is a 6 membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).
  • Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include: and
  • heteroaryl is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups that are bicyclic include indole, benzofiiran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole.
  • heteroaryl groups that are bicyclic include:
  • heteroaryl groups that are bicyclic include:
  • heteroaryl groups that are bicyclic include: , and
  • heteroaryl is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.
  • heteroaryl groups that are bicyclic include:
  • aryl is phenyl
  • aryl is napthyl
  • 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:
  • bivalent bicycle groups 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.
  • bivalent bicycle groups include:
  • bivalent bicycle examples include: Embodiments of optional substituents to certain embodiments wherein a variable can be optionally substituted it is not substituted,
  • variable can be optionally substituted it is substituted with 1 substituent.
  • variable can be optionally substituted it is substituted with 2 substituents.
  • variable can be optionally substituted it is substituted with 3 substituents.
  • variable can be optionally substituted it is substituted with 4 substituents.
  • 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.
  • 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.
  • the aliphatic group contains from 1 to about 8 carbon atoms.
  • 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.
  • C1-C5 aliphatic 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.
  • C1-C4 aliphatic as used herein indicates a straight, or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety.
  • 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.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • heteroaliphatic is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties.
  • heteroaiiphatic is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, un substituted, branched or unbranched) having 1-20 carbon atoms.
  • the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety.
  • heteroaiiphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.
  • 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.
  • any desired linker, as described herein, can be used as long as the resulting compound has a stable shelf life, for example at least 1 month, 2 months, 3 months, 6 months or 1 year as part of a pharmaceutically acceptable dosage form, and itself is pharmaceutically acceptable.
  • Linker as described herein can be used in either direction, i.e., either the left end is linked to the E3 Ligase binding portion and the right end to the KRAS Targeting Ligand, or the left end is linked to the KRAS Targeting Ligand and the right end is linked to the E3 Ligase binding portion.
  • Linker is a bond
  • 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.
  • 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.
  • 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).
  • 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.
  • 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 are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain the desired half-life and hydrophilicity.
  • 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.
  • Linker is selected from:
  • 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:
  • 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.
  • Linker is selected from: In certain embodiments Linker is selected from:
  • Non-limiting examples of moieties of R 20 , R 21 , R 22 , R 23 , and R 24 include:
  • moieties of R 20 , R 21 , R 22 , R 23 , and R 24 include:
  • moieties of R 20 , R 21 , R 22 , R 23 , and R 24 include:
  • 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.
  • the Linker is flanked, substituted, or interspersed with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group.
  • the Linker may be asymmetric or symmetrical.
  • Linker can be a nonlinear chain, and can be, or include, aliphatic or aromatic or heteroaromatic cyclic moieties.
  • the Linker group may be any suitable moiety as described herein.
  • the Linker is selected from the group consisting of:
  • the Linker is selected from the group consisting of:
  • the Linker is selected from the group consisting of:
  • the Linker is selected from the group consisting of:
  • the Linker is selected from the group consisting of:
  • the Linker is selected from the group consisting of:
  • the Linker is selected from the group consisting of:
  • a compound of the present invention or a pharmaceutically acceptable salt thereof can be used in an effective amount to treat a KRAS mediated disorder in a patient, in need thereof.
  • Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for treating cancer in a patient in need thereof; wherein there is a need of KRAS inhibition for foe treatment of cancer.
  • a compound of the present invention is used to treat a KRAS mediated cancer, wherein the KRAS has mutated from the wild-type.
  • KRAS mutations There are a number of possibilities for KRAS mutations.
  • the KRAS mutation is a missense mutation encoding a substituted codons.
  • 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.
  • the mutation is a G12D mutation.
  • 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).
  • a covalent inhibitor such as sotorasib or adagrasib.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a compound of the present invention is more active against a disorder driven by a mutated KRAS than wild-type KRAS.
  • the KRAS mediated disorder is mutant KRZ ⁇ S mediated cancer.
  • 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
  • a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12D substitution.
  • a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12V substitution.
  • a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12C substitution.
  • a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12R substitution.
  • 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.
  • 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.
  • 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.
  • a pharmaceutically acceptable excipient, carrier, or adjuvant i.e., a pharmaceutically acceptable composition
  • the patient is administered an additional therapeutic agent.
  • the compound as described herein, and the additional therapeutic agent are administered simultaneously or sequentially.
  • the patient is a human.
  • 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.
  • the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where mutant KRAS is implicated in the disease state.
  • Another aspect of the present invention provides a method of treating a proliferative disease.
  • the method comprises administering an effective amount of a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof and optionally a pharmaceutically acceptable carrier to a patient in need thereof.
  • the disease is mediated by KRAS.
  • KRAS plays a role in tire initiation or development of the disease.
  • the disease or disorder is cancer or a proliferation disease.
  • the KRAS mediated disorder is an abnormal cell proliferation, including, but not limited to, a solid or hematological cancer.
  • Solid tumors that can be treated with, the compounds described herein include, but are not limited to lung cancers, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), breast cancers including inflammatory breast cancer, ER-positive breast cancer including tamoxifen resistant ER-positive breast cancer, and triple negative breast cancer, colon cancers, midline carcinomas, liver cancers, renal cancers, prostate cancers including castrate resistant prostate cancer (CRPC), brain cancers including gliomas, glioblastomas, neuroblastoma, and medulloblastoma including MYC-amplified medulloblastoma, colorectal cancers, Wilm's tumor, Ewing’s sarcoma, rhabdomyosarcomas, ependymomas, head and neck cancers, melanomas, squamous cell carcinomas, ovarian cancers, pancreatic cancers including pancreatic ductal adenocarcinomas (PDAC) and
  • the hematological cancer is acute myelogenous leukemia.
  • AML acute lymphoblastic leukemia
  • ALL lymphoblastic leukemia
  • CML chronic myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • CLL chronic neutrophilic leukemia
  • 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 ML
  • erythroleukemia malignant lymphoma
  • Hodgkins lymphoma Hodgkins lymphoma
  • non-Hodgkins lymphoma lymphoblastic T-cell lymphoma
  • Burkitt's lymphoma Burkitt's lymphoma
  • follicular lymphoma B
  • 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.
  • 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.
  • 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.
  • NGS next-generation sequencing
  • said method is used to treat a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immunologically-mediated diseases.
  • 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 ne
  • This application further embraces the treatment of cell proliferative disorders such as hyperplasias, dysplasias and pre-cancerous lesions.
  • Dysplasia is the earliest form of pre- cancerous lesion recognizable in a biopsy by a pathologist.
  • the compounds may be administered for the purpose of treating said hyperplasias, dysplasias or pre-cancerous lesions. Examples of pre-cancerous lesions may occur in skin, esophageal tissue, breast and cervical intra-epithelial tissue.
  • KRAS 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.
  • the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene 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.
  • KRAS refers to the KRAS4B isoform which is the gene product most frequently expressed in human cells (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol. 15:152(2022)). Dysregulated isoform expression and missense mutations at the sequences encoding the hotspot codons G12, G13, and Q61 are thought to be core drivers of cancer.
  • KRAS 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).
  • 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)).
  • KRAS mutations 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.
  • NSCLC non-small cell lung cancer
  • 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).
  • the KRAS G12V mutation is the second most common KRAS mutation found in pancreatic adenocarcinoma (Table 2).
  • KRAS mutation is an early and initiating event of pancreatic cancer. KRAS mutation occurs in 90% of all pancreatic adenocarcinoma patients (Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 23(6):703-713(2017 Jun)). Pancreatic cancer is the deadliest cancer in the United States, as the 5-year survival rate of pancreatic cancer is 8% (Siegel, R.L. et al. Cancer statistics. CA Cancer J Clin. 66:7-30(2016)).
  • Pancreatic ductal adenocarcinoma 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.
  • RNAi RNA. interference
  • 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)).
  • 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)).
  • an effective amount of a compound of the present invention is used to treat pancreatic cancer.
  • Colorectal cancer is one of the most common cancers worldwide (Porru, M. et al. Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. J Exp Clin Cancer Res. 37(l):57(2018 Mar 13). Most colorectal cancers are adenocarcinomas. KRAS is mutated in between 27.9-43.7% of all colorectal adenocarcinoma (Table 2).
  • the current standard of care in colorectal cancer is a combination of different chemotherapeutic drags, comprising either protracted infusion of 5-fluorouraciI (5-FU) modulated by leucovorin in combination with irinotecan (FOLFIRI) or with oxaliplatin (FOLFOX), capecitabine and oxaliplatin combination (XELOX), or 5-FU, leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI) (Id).
  • 5-FU 5-fluorouraciI
  • an effective amount of a compound of the present invention is used to treat colorectal cancer.
  • 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)).
  • KRAS G12D is the most frequent KRAS mutation (56%) in non- smokers (Id.).
  • the lung cancer comprises non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • 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.).
  • the NSCLC comprises lung adenocarcinoma or squamous cell carcinoma.
  • an effective amount of a compound of the present invention is used to treat lung cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • the bioactive agent is an inhibitor of a protein involved in signaling through the mitogen-associated protein kinase (MAPK) pathway.
  • MAPK mitogen-associated protein kinase
  • 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.
  • 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 marezerib.
  • EGFR epidermal growth factor receptor
  • EGFR inhibitors include rociletinib (CO- 1686), olmutinib (Olita), naquotinib (ASP8273), soloartinib (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).
  • rociletinib CO- 1686
  • 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.
  • 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.
  • an anti-EGFR antibody for example, cetuximab, panitumab, or necitumab.
  • a compound of the present invention is administered to a patient in need thereof in combination with cetuximab.
  • a compound of the present invention is administered to a patient in need thereof in combination with panitumab.
  • a compound of the present invention is administered to a patient in need thereof in combination with necitumab.
  • the bioactive agent is a son of sevenless (SOS) inhibitor
  • 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,
  • the bioactive agent is a rat sarcoma virus (RAS) protein inhibitor.
  • RAS inhibitors include but are not limited to rigosertib, RMC-6236, Reolysin and siG12D LODER.
  • the bioactive agent is an additional KRAS inhibitor.
  • 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.
  • the bioactive agent is an NRAS inhibitor.
  • the bioactive agent is an HRAS inhibitor.
  • the bioactive agent is a Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) inhibitor.
  • 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
  • the bioactive agent is a Raf inhibitor.
  • Raf inhibitors 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
  • the bioactive agent is a dual RAF/MEK inhibitor such as Avutometinib (ROS 126766, CHS 126766, VS-6766, CKI-27, R-7304, RG-7304).
  • Avutometinib ROS 126766, CHS 126766, VS-6766, CKI-27, R-7304, RG-7304.
  • 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
  • MEK162/ARRY438162 (5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N ⁇ (2- hydroxyethoxy)- 1 -methyl- 1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-FIuoro-2-
  • the bioactive agent is an extracellular signal-regulated kinase (ERK) inhibitor, including ERKl and ERK2 inhibitors.
  • 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.
  • Ulixertinib (BVD-523, VRT752271)
  • VX-lle (4-(2-((2-chloro
  • 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.
  • the immune modulator is an antibody, such as a monoclonal antibody.
  • 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).
  • BMS- 986016 Bristol-Myers Squibb
  • GSK2831781 GaxoSmithKline
  • 1MP321 Primary BioMed
  • LAG525 Novartis
  • MGD013 Novartis
  • An example of a TIM-3 inhibitor is TSR-022 (T'esaro).
  • 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.
  • 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.
  • B7-H3 e.g., MGA271
  • B7-H4 BTLA
  • HVEM TIM3
  • GAL9 GAL9
  • LAG 3 VISTA
  • KIR KIR
  • CD 160 CD 160, CGEN- 15049, CH
  • 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.
  • fulvestrant a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors.
  • Non-limiting examples of anti-estrogen compounds are provided in WO201419176 assigned to Astra Zeneca, WO2013090921, WO 2014203129, WO2014203132, and US2013/0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703, 810, as well as US20150005286, WO2014205136, and WO2014205138.
  • anti-estrogen compounds include: SERMS such as anordrin, adoxifene, 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, norethister
  • SERMS
  • 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.
  • an androgen such as testosterone
  • the prostate or testicular cancer is androgen-resistant.
  • Non-limiting examples of anti-androgen compounds are provided in WO 2011/156518 and US Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of antiandrogen compounds include: enzalutamide, apalutamide, eyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazoie, topilutamide, abiraterone acetate, and cimetidine.
  • the bioactive agent is an ALK inhibitor.
  • ALK inhibitors include but are not limited to Crizotinib, Alectinib, ceritinib, TAE684 (NVP- TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.
  • the bioactive agent is an HER-2 inhibitor.
  • HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.
  • the bioactive agent is a CD20 inhibitor.
  • CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab, tositumomab, and ocrelizumab.
  • the bioactive agent is a JAK3 inhibitor.
  • JAK3 inhibitors include tasocitinib.
  • the bioactive agent is a BCL-2 inhibitor.
  • 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
  • the bioactive agent is a kinase inhibitor.
  • 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.
  • 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-pheny
  • BTK inhibitors examples include ibrutinib (also known as PCI-32765)(ImbruvicaTM)(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-hydroxyeth
  • 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
  • the bioactive agent is a c-MET inhibitor, for example, crizotinib (Xalkori, Crizonix), tepotinib (XL880, EXEL-2880, GSK1363089, GSK089), or tivantinib (ARQ197).
  • crizotinib Xalkori, Crizonix
  • tepotinib XL880, EXEL-2880, GSK1363089, GSK089
  • tivantinib ARQ197
  • 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 (AC 2 20), Amuvatinib (MP-470), Tandutinib (MLNS 18), ENMD-2076, and KW-2449, or a combination thereof.
  • 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
  • the bioactive agent is an mTOR inhibitor.
  • mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus.
  • the bioactive agent is an HSP inhibitor.
  • HSP inhibitors include but are not limited to Geldanamycin or ]7“N ⁇ AliyIamino-17"demethoxygeldanamycin (17AAG), and Radicicol.
  • Additional bioactive compounds include, lor example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON O91O.Na, AZD 6244 (ARRY- 142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VKRAS inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a focal adhesion kinase inhibitor, a Map kinase kinase (MEK) inhibitor,
  • 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 (V
  • 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 (Bo
  • 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), c
  • 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).
  • 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.
  • 5 -fluorouracil 5 -fluorouracil
  • 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;
  • 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-doxorubi
  • 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, carfilz
  • the additional therapy is a monoclonal antibody (MAb).
  • 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.
  • 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.
  • 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 courts etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody
  • 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®).
  • 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® (panit
  • the combination therapy may include a therapeutic agent which is a non-dnig treatment.
  • the compound could be administered in addition to radiation therapy, cryotherapy, hyperthermia, and/or surgical excision of tumor tissue.
  • 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.
  • the second therapeutic agent is administered on a different dosage schedule than the compound of the present invention.
  • 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.
  • the first therapeutic agent has a treatment holiday.
  • 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.
  • both the first and second therapeutic have a. treatment holiday.
  • 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.
  • the compound is administered paternally, for example by intravaneous administration.
  • the pharmaceutical composition is administered rectally, e.g. in the form of suppositories.
  • a compound of the present invention or a pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
  • Lactose, com starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules.
  • Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • the pharmaceutical preparations can, moreover, contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • Medicaments containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also provided by the present invention, as is a process for their production, which comprises bringing one or more compounds of the present invention and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
  • the dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
  • 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.
  • 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.
  • 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.
  • compounds disclosed herein or used as described are administered once a day (QD), twice a day (BID), or three times a day (TID).
  • 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
  • the compound of the present invention is administered once a day, twice a day, three times a day, or four times a day.
  • 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.
  • 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.
  • the compound of the present invention is administered with a treatment holiday in between treatment cycles.
  • 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.
  • a loading dose is administered to begin treatment.
  • the compound may be administered about 1.5x, about 2x, about 2.5x, about 3x, about 3.5x, about 4x, about 4.5x, about 5x, about 5,5x, about 6x, about. 6.5x, about 7x, about 7.5x, about 8x, about 8.5x, about 9x, about 9.5x, or about 10x higher dose on the first day of treatment than the remaining days of treatment in the treatment cycle.
  • Additional exemplary loading doses include about 1.5x, about 2x, about 2.5x, about 3x, about 3.5x, about 4x, about 4.5x, about 5x, about 5.5x, about 6x, about 6.5x, about 7x, about 7.5x, about 8x, about 8.5x, about 9x, about 9.5x, or about 10x higher dose on the first 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of treatment titan the remaining days of treatment in the treatment cycle.
  • the pharmaceutical composition may also include a molar ratio of the active compound and an additional active agent.
  • 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.
  • compositions can contain any amount of active compound that achieves the desired result, for example between 0,1 and 99 weight % (wt. %) of the compound and usually at least about 5 wt. % of the compound. Some embodiments contain from about 25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % of the compound.
  • a pharmaceutically or therapeutically effective amount of the composition will be delivered to the patient.
  • the precise effective amount will vary from patient to patient, and will depend upon the species, age, the subject’s size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration.
  • the effective amount for a given situation can be determined by routine experimentation.
  • 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.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the dose ranges from about 0.01-100 mg/kg of patient bodyweight, for example about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg, -kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • 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.
  • 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.
  • the compound is administered as a pharmaceutically acceptable salt.
  • 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, n
  • 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.
  • 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.
  • 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.
  • 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
  • compositions will include an effective amount of the selected drag in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like.
  • Gamers include excipients and diluents and must be of sufficiently high purity and sufficiently low' toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Classes of carriers include, but are not limited to adjuvants, binders, buffering agents, coloring agents, diluents, disintegrants, excipients, emulsifiers, flavorants, gels, glidents, lubricants, preservatives, stabilizers, surfactants, solubilizer, tableting agents, wetting agents or solidifying material.
  • Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
  • Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers and vegetable oils.
  • Optional active agents may be included hi a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
  • 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).
  • 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.
  • buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like.
  • 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.
  • 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.
  • 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.
  • 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).
  • polycations chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin
  • polyanions vV-carboxymethyl chitosan, poly-acrylic acid
  • thiolated polymers carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan- thiobutylamidine, chitosan-
  • 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
  • compositions/combinations can be formulated 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • suitable inert carrier such as ethanol, glycerol, water, and the like
  • 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.
  • the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcomeal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device.
  • Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions.
  • 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.
  • the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is m aintained.
  • Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • aqueous and non-aqueous, isotonic sterile injection solutions which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient
  • aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • Administration via certahi parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system.
  • a formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.
  • Preparations according to the disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.
  • Sterile injectable solutions are prepared by incorporating one or more of the compounds of the disclosure in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • typical methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
  • compositions of the disclosure can be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable nonirritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of the disclosure can also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the ait of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.
  • Formulations for buccal administration include tablets, lozenges, gels and the like.
  • buccal administration can be effected using a transmucosal delivery system as known to those skilled in the art.
  • the compounds of the disclosure can also be delivered through the skin or muscosal tissue using conventional transdermal drag delivery systems, i.e., transdermal “patches” wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface.
  • the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer.
  • the laminated device can contain a single reservoir, or it can contain multiple reservoirs.
  • the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery.
  • suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like.
  • Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI).
  • DPI dry powder inhalers
  • the devices most, commonly used for respiratory delivery include nebulizers, metered- dose inhalers, and dry powder inhalers.
  • nebulizers include jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology' of the lung.
  • an oral formulation is provided.
  • the compounds of the present invention and their pharmaceutically acceptable salts possess valuable pharmacological properties.
  • the compounds were investigated in accordance with the test given hereinafter.
  • a compound as described herein, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition is used as a medicament in therapeutic and/or prophylactic treatment of a patient with KRAS activating mutations as determined with a test selected from Agilent Resolution ctDx FIRST assay, cobas KRAS Mutation Test, FoundationOne CDx, Guardant360 CDx, ONCO/Reveal Dx Lung & Colon Cancer Assay (O/RDx-LCCA), tlierascreen KRAS RGQ PCR Kit, Kir Extended RAS Panel, or a combination thereof, suffering from cancer, comprising determining the KRAS mutation status in said patient and then administering the compound, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition to said patient.
  • a test selected from Agilent Resolution ctDx FIRST assay, cobas KRAS Mutation Test, FoundationOne CDx, Guardant360 CDx, ONCO/Reveal Dx Lung & Colon Cancer Assay (O/RDx-LCCA
  • the compounds of the present invention may contain one or more asymmetric centers and can therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein.
  • Their absolute stereochemistry' may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary', with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound.
  • Chirally pure or chirally enriched compounds may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate.
  • Isolation and purification of the compounds Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used.
  • Racemic mixtures of chiral compounds of the present invention can be separated using chiral HPLC. Racemic mixtures of chiral synthetic intermediates may also be separated using chiral HPLC.
  • the compound of the present invention may be converted to a corresponding acid addition salt.
  • the conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p ⁇ toluenesulfonic acid, salicylic acid and the like.
  • an appropriate acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyr
  • a specific salt is the fumarate.
  • the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent.
  • the temperature is maintained between 0 °C and 50 °C.
  • the resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent,
  • the compounds of the present invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
  • X. GENERAL SYNTHETIC SCHEMES Non-limiting distinct methods for preparing compounds of the present invention include those provided in Schemes 1-4. As illustrated in these Schemes and the Examples below, compounds for use in the present invention can be synthesized by one skilled in the art using a range of different retrosynthetic paths. As shown in Scheme 1, compounds for use in the present invention can be prepared by chemically combining a Heterocyclic Moiety and a Linker followed by subsequent addition of a Targeting Ligand.
  • the Heterocyclic Moiety, Linker, or Targeting Ligand of Scheme 1 is a precursor intermediate that is then fully functionalized later in the synthesis.
  • Targeting Ligand is the skilled artisan may choose to use it in a protected form and then remove the protecting groups after preparing a protected compound of the present invention (see for example Scheme 1-a).
  • Scheme 1-a Similarly, one or more moieties of Linker may be installed on the KRAS Targeting Ligand before the molecule is fully assembled or even before the KRAS Targeting Ligand portion of the molecule is fully assembled (see for example Scheme 1-b).
  • Scheme 1-b In certain aspects protecting group strategies and splitting the linker into multiple moieties are both used to prepare compounds of the present invention (see for example Scheme 1-c).
  • Scheme 2 compounds for use in the present invention are prepared by chemically combining a Targeting Ligand and Linker first, followed by subsequent addition of a Heterocyclic Moiety. Like Scheme 1, this process can be accomplished with the use of protecting groups and/or adding Linker portion wise if desired. Additionally, in certain aspects Linker or a portion of Linker is installed on the Targeting Ligand before the Targeting Ligand is completed. For example, in Scheme 2-a a linker is installed on the bicyclic Targeting Ligand core in advance of installation of the R 32 and R 29 groups.
  • Step 3 in Step 1, a nucleophilic Heterocyclic Moiety displaces a leaving group on the Linker to make a Heterocyclic Moiety Linker fragment.
  • the protecting group is removed by methods known in the art to free a nucleophilic site on the linker.
  • Step 3 the nucleophilic Heterocyclic Moiety Linker fragment displaces a leaving group on the Targeting Ligand to form a compound for use in the present invention.
  • Step 1 and/or Step 2 is accomplished by a coupling reaction instead of a nucleophilic attack.
  • Scheme 4 in Scheme 4, in Step 1, a nucleophilic Targeting Ligand displaces a leaving group on the Linker to make a Targeting Ligand Linker fragment.
  • Step 2 the protecting group is removed by methods known in the art to free a nucleophilic site on the linker.
  • the nucleophilic Targeting Ligand Linker fragment displaces a leaving group on the Heterocyclic Moiety to form a compound for use in the present invention.
  • Step 1 and/or Step 2 is accomplished by a coupling reaction instead of a nucleophilic attack.
  • Step 2 Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl N-[2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl]carbamate (3; 1.3 g, 5.32 mmol) in dry DCM (30 mL) was added 4N HCl in 1,4-dioxane (13 mL) at 5 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 hours and the progress of the reaction was monitored.
  • Step 3 Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of [(2S)-1-(2-aminoethyl)pyrrolidin-2-yl]methanol hydrochloride (4; 1.1 g, 6.08 mmol) in MeOH (20 mL) was added triethylamine (3.08 g, 30.42 mmol, 4.24 mL). The reaction mixture was cooled to 5 °C and then ethyl 2,2,2-trifluoroacetate (950.83 mg, 6.69 mmol, 0.8 mL) was added. The reaction mixture was stirred at ambient temperature for 5 hours. The reaction progress was monitored by TLC and LCMS-ELSD.
  • Step 4 Into a 20 mL screw-capped glass-vial containing a well stirred solution of tert-butyl 3- (2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (6; 0.62 g, 1.43 mmol) a and 2,2,2-trifluoro-N-[2-[(2S)-2-(hydroxymethyl)pyrrolidin- 1-yl]ethyl]acetamide (5; 618.50 mg, 2.57 mmol) in dry acetonitrile (15 mL) was added cesium carbonate (1.16 g, 3.57 mmol).
  • reaction mixture was stirred at 70 °C for 2 hours and the progress of the reaction was monitored by TLC and LCMS. After complete consumption of the starting material as indicated by LCMS, reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford a crude mass.
  • Step 5 Into a 20 mL screw-capped glass-vial containing a well stirred solution of tert-butyl 3- [7-chloro-8-fluoro-2-[[(2S)-1-[2-[(2,2,2-trifluoroacetyl)amino]ethyl]pyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7; 1.45 g, 2.22 mmol) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-y
  • the resulting mixture was purged with nitrogen gas (3 x 2 minutes) and then stirred at 70 °C for 1 hour. The progress of the reaction was monitored by TLC and LCMS. After 2 hours, the reaction mixture was cooled to room temperature and purged with nitrogen for 2 minutes, then another batch of 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (8; 0.85 g, 1.66 mmol) and XPhos- Pd-G2 (72.2 mg, 0.1 eq) were added to the reaction mixture.
  • the resulting mixture was purged with nitrogen gas for 2 minutes and then stirred at 70 °C for further 1 hour and the progress of the reaction was monitored by TLC and LCMS. After complete consumption of the starting material as indicated by LCMS, the reaction mixture was concentrated to afford a crude mass.
  • reaction mixture was stirred at room temperature and the progress of the reaction was monitored by TLC and LCMS. After 16 hours, the reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 3-[7-[8-ethynyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2S)-1-[2-[(2,2,2- trifluoroacetyl)amino]ethyl]pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate and the crude was taken to the next step without purification.
  • Step 7 Into a 20 mL screw-capped glass-vial containing a well stirred solution of tert-butyl 3- [7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2S)-1-[2-[(2,2,2- trifluoroacetyl)amino]ethyl]pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (10; 0.36 g, 0.41 mmol) in THF (4 mL) and water (0.4 mL)
  • reaction mixture was stirred at 55 °C for 5 hours and the progress of the reaction was monitored by TLC and LCMS. After complete consumption of the starting material as indicated by LCMS, the reaction mixture was filtered through an anhydrous Na2SO4 bed and washed with THF (30 mL).
  • Step 2 Into a 20 mL screw-capped glass vial containing a well-stirred solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3; 300 mg, 0.538 mmol) and 2- [2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- naphthyl]ethynyl-triisopropyl-silane (4; 413.79 mg, 0.807 mmol) in a 20 mL screw-capped glass vial containing a well-stirred solution of tert-butyl (1R,5S)-3-(
  • Xphos-Pd-G2 (42.35 mg, 0.053 mmol) was added to the reaction mixture and the reaction mixture was heated to 90 °C and stirred for 3 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford a crude residue.
  • Step 3 Into a 250 mL double-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5; 400 mg, 0.421 mmol) in dry DCM (20 mL) was added Dess–Martin Periodinane, DMP (536.6 mg, 1.27 mmol) at 0 °C under
  • reaction mixture was filtered through a pad of Celite and Celite bed was washed with DCM (100 mL). The filtrate was washed with saturated sodium bicarbonate solution (50 mL) followed by brine (50 mL) and dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude residue.
  • Step 4 Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6; 400 mg, 0.441 mmol) and piperazine (7; 190.26 mg, 2.21 mmol) in dry MeOH (10 mL) was added acetic acid (132.65 mg
  • reaction mixture was allowed to stir at ambient temperature under nitrogen atmosphere for 3 hours. Subsequently, sodium cyanoborohydride (138.81 mg, 2.21 mmol) was added to the flask and the resulting mixture was stirred for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated in vacuo to afford a crude mass. The crude mass was diluted with water (40 mL) and aqueous phase was extracted with EtOAc (2 x 100 mL).
  • Step 2 Into a 50 mL two-necked round-bottomed flask equipped with a condenser, containing a well-stirred solution of diethyl (2R,5S)-1-methylpyrrolidine-2,5-dicarboxylate (2; 250 mg, 1.09 mmol) in dry THF (15 mL) was added 2M Lithium aluminum hydride in THF (1.64 mL) at 0° C. The resulting reaction mixture was heated to 60°C for 3 hours. The progress of the reaction was monitored by TLC and LCMS-ELSD.
  • reaction mixture was quenched with 30 mL of EtOAc, solid formed was filtered off through a pad of Celite and the Celite bed was washed with THF (40 mL) followed by EtOAc (40 mL).
  • Step 3 Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of [(2R,5S)-5-(hydroxymethyl)-1-methyl-pyrrolidin-2-yl]methanol (3; 339.02 mg, 2.33 mmol) in dry toluene (10 mL) were added tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4; 500 mg, 1.17 mmol) followed and cesium carbonate (950.94 mg, 2.92 mmol) at ambient temperature under nitrogen atmosphere.
  • the resulting reaction mixture was heated to 80 °C for 18 hours .
  • the progress of the reaction was monitored by TLC and UPLC-MS.
  • the resulting mixture was diluted with water (20 mL), extracted with EtOAc (3 x 20 mL) and combined organic phases were dried (anhydrous Na 2 SO 4 ).
  • reaction mixture was filtered through a pad of Celite bed and the filtrate was concentrated under reduced pressure to afford a crude residue, which was purified by flash silica-gel (230-400 mesh) column with 5-20% MeOH/DCM while desired compound was eluting at 9-10% to afford tert-butyl 3-[7-chloro-8-fluoro-2-[[5- (hydroxymethyl)-1-methyl-pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5; 410 mg, 0.633 mmol, 82.9% purity) as a yellow solid.
  • Step 4 Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl 3-[7-chloro-8-fluoro-2-[[5-(hydroxymethyl)-1-methyl-pyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5; 1.8 g, 3.35 mmol) in anhydrous DCM (25 mL) was added TEA (1.02 g, 10.06 mmol, 1.40 mL) at ambient temperature and the resulting mixture was cooled to 0 °C.
  • Methanesulfonyl chloride (575.92 mg, 5.03 mmol, 389.93 ⁇ L) was added dropwise and the resulting reaction mixture was stirred at ambient temperature for 1 hour. Progress of reaction was monitored by TLC and UPLC-MS. After completion of the reaction, the reaction mixture was quenched with ice-water, extracted with EtOAc (3 x 25 mL).
  • Step 5 Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl 3-[7-chloro-8-fluoro-2-[[1-methyl-5-(methylsulfonyloxymethyl)pyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6; 1.8 g, 2.93 mmol) in dry DMF (1.46 mL) was added triethylamine (1.18 g, 11.71 mmol, 1.63 mL) followed by 2,2,2-trifluoro-1-piperazin-1-yl-ethanone (7; 1.73 g, 8.78 mmol) at ambient temperature and the resulting reaction mixture was stirred at 70 °C for 18 hours.
  • reaction progress was monitored by UPLC-MS and TLC. After completion of the reaction, reaction mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (anhydrous Na 2 SO 4 ), filtered and the filtrate was concentrated under reduced pressure to afford a crude mass, which was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/petroleum ether while desired compound eluting at 80% of the mobile phase to afford tert-butyl 3-[7-chloro-8-fluoro-2-[[1-methyl-5-[[4-(2,2,2- trifluoroacetyl)piperazin-1-yl]methyl]pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8; 1.26 g, 1.42 mmol, 78.9% purity)
  • Step 7 Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl 3-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1- naphthyl]-2-[[1-methyl-5-[[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]methyl]pyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10; 800 mg, 760.99 ⁇ mol) in anhydrous acetonitrile (10 mL) was added ces
  • Step 8 Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-methyl-5- [[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]methyl]pyrrolidin-2-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (11; 726 mg, 0.625 mmol) in a mixture of anhydrous THF (9 mL) and H 2 O (1
  • Step 1 Into a 250 mL sealed-tube containing a well-stirred solution of tert-butyl (1R,5S)-3-(2,7- dichloro-8-fluoropyrido[4',3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1; 5 g, 11.61 mmol) and cyclopropane-1,1-diyldimethanol (2; 1.78 g, 17.42 mmol, 1.67 mL) in 1,4- dioxane (50 mL) was added cesium carbonate (9.46 g, 29.03 mmol) and the resulting reaction mixture was stirred at 90 °C for
  • Step 2 Into a 20 mL glass-vial containing a well-stirred solution of tert-butyl (1R,5S)-3-(7- chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (3; 1 g, 1.84 mmol) and 2-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4; 992.28 mg, 2.75 mmol) in 14:1 of 1,4-dioxane/water (15 mL) was added tripotassium phosphate (1.17 g, 5.51 mmol) at ambient temperature under nitrogen atmosphere and the resulting reaction mixture was degassed by bubbling nitrogen
  • Catacxium®A-Pd-G3 (200.61 mg, 0.27 mmol) was added and the reaction mixture was stirred at 90 °C for 24 h. After completion of the reaction as indicated by LCMS, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to afford a crude mass. The crude mass was purified by flash silica-gel (230-400 mesh) column with 0-100% EtOAc/pet.
  • Step 3 Into a 100 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5; 1 g, 1.36 mmol) in dry DCM (20 mL) was added Dess-Martin periodinane (1.73 g, 4.08 mmol) at 0 °C and the reaction mixture was stirred at ambient temperature for 16 h under nitrogen atmosphere
  • reaction mass was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with DCM (100 mL). The filtrate was washed with saturated sodium bicarbonate solution (40 mL) followed by brine (60 mL), dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford a crude mass.
  • Step 4 Into a 50 mL single-necked round-bottomed flask containing a well stirred solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1- formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (6; 400 mg, 0.54 mmol) and piperazine (7; 232.28 mg, 2.70 mmol) in dry MeOH (10 mL) was added acetic acid (2.70 mmol, 0.15 mL) at ambient temperature.
  • reaction mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. Subsequently, sodium cyanoborohydride (169.46 mg, 2.70 mmol) was added to the reaction mixture and the mixture was stirred for 16 h. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure to afford a crude mass. The crude mass was diluted with water (20 mL) and the aqueous phase was extracted with EtOAc (2 x 20 mL).
  • Step 2 Into a 250 mL double-necked round-bottomed flask containing a well-stirred solution of benzyl (R)-4-(3-hydroxy-2-methylpropyl)piperazine-1-carboxylate (3; 2.00 g, 6.84 mmol) in anhydrous THF (40 mL) was added NaH (820.79 mg, 34.20 mmol) and the resulting mixture was stirred for 10 minutes.
  • Step 3 Into a 20 mL screw-capped glass vial containing a well-stirred solution of 2-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6; 600 mg, 1.67 mmol) and tert-butyl (1R,5S)-3-(2-((R)-3-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2- methylpropoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (5; 1.14 g, 1.67 mmol) in 1,4-di
  • Step 4 Into a 50 mL single-necked round-bottomed flask was added a solution tert-butyl (1R,5S)-3-(2-((R)-3-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-methylpropoxy)-7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (7; 400 mg, 0.453 mmol) in 1,4-dioxane (5 mL) and the mixture was degassed with nitrogen gas for 5 minutes.
  • Step 1 Into a 250 mL single-necked round-bottomed flask containing a well-stirred solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1; 5 g, 19.81 mmol) in anhydrous DCM (20 mL) was added DIPEA (3.07 g, 23.77 mmol, 4.14 mL) and (3R)-3-methylpiperidin-3-ol hydrochloride (2; 1.82 g, 12.03 mmol) in portions at-40 ° C under nitrogen atmosphere. The reaction was allowed to stir for 30 minutes at ambient temperature. Reaction was monitored by UPLC.
  • Step 2 Into a 20 mL glass-vial containing a well-stirred solution of (R)-1-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (3; 600 mg, 1.67 mmol) and [1- (hydroxymethyl)cyclopropyl]methanol (4; 255 mg, 2.50 mmol) in 1,4-dixoane (10 mL) was added Cesium carbonate (1.63 g, 5.00 mmol) at room temperature.
  • reaction mixture was stirred at 80 °C for 16 h. Reaction was monitored by UPLC. Thereafter, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2 x 100 mL). Combined organic layers were dried (anhydrous Na 2 SO 4 ), filtered and the filtrate was concentrated under reduced pressure.

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Abstract

L'invention concerne des composés qui dégradent la protéine KRAS (Kirsten rat sarcoma viral oncogene homolog), y compris des formes mutantes, par l'intermédiaire de l'ubiquitination de la protéine KRAS et de la dégradation protéasomale ultérieure. Les composés sont utiles pour le traitement de divers cancers.
PCT/US2024/035874 2023-06-30 2024-06-27 Composés hétérobifonctionnels pour la dégradation de kras Pending WO2025006783A2 (fr)

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US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
WO2025223215A1 (fr) * 2024-04-24 2025-10-30 重庆华森英诺生物科技有限公司 Composé hétérocyclique pour induire la dégradation de la protéine kras mutante, son procédé de préparation et son utilisation
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