Covalent KRAS-binding compounds for medical treatment

Abstract

Heteroaryl sulfonyl compounds and compositions that have a KRAS Recognition Moiety bound to an electrophile for the selective covalent modification of KRAS, for example a mutant KRAS, to treat KRAS-mediated disorders are described.

Description

[0001] COVALENT KRAS-BINDING COMPOUNDS FOR MEDICAL TREATMENT CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.63 / 404,916 which was filed on September 8, 2022 the entirety of which is hereby incorporated by reference for all purposes. FIELD OF THE INVENTION This invention provides heteroaryl sulfonyl compounds, compositions, and methods of use thereof, that include a KRAS Recognition Moiety for the selective covalent modification of KRAS, for example a mutant KRAS, to treat KRAS-mediated disorders, through, for example, tyrosine, lysine, or histidine. BACKGROUND OF THE INVENTION Most cells in the body are terminally differentiated with protective mechanisms to prevent cellular proliferation. A small subset of cells undergoes cellular proliferation mainly to replenish tissue or blood components, such as hematopoietic cells and their progeny. The body maintains a careful balance between terminal differentiation and cellular proliferation through a complex network of cellular signaling. For the cell to properly respond to external signals, it uses a carefully balanced relay of signaling proteins. One such relay protein is KRAS, which was first identified as an oncogene in Kirsten RAt Sarcoma virus. KRAS is an essential component of the mitogen-activated protein kinase (“MAPK”) pathway, which regulates cell cycling and proliferation. More specifically, it is involved in signaling pathways that initiate extracellularly and are transferred to the cell nucleus, causing the cell to grow, divide or differentiate. KRAS acts by dephosphorylating guanosine 5’- triphosphate to guanosine 5’-diphosphate and is thus referred to as a GTPase. If KRAS is mutated or upregulated, abnormal cellular proliferation can occur. For example, a single mutation of G12C or G12D can cause KRAS to continuously activate downstream proteins, regardless of input from extracellular sources. This mutation leads to unregulated cell growth and is a driver mutation in up to 20% of human cancers, including 90% of pancreatic cancers and greater than 40% of colon cancers (Cox et al. Nat. Rev. Drug Discov. 13, 828-851 (2014); Gorfe Cell, S0006-3495 (19) 32753-5 (2020)). There are several compounds in development that target KRAS for the treatment of cancer. Initial compound library screening efforts were used to find known molecules that phenotypically inhibit KRAS driven cancer such as oncrasin, tolperisone, lanperisone, and DCAI. (Wang et al. J. Med. Chem.56(13), 5219-5230). There has also been limited success in the development of classic reversible allosteric KRAS inhibitors (McCarthy et al. ACS Omega, 4, 2921-2930 (2019)). Most KRAS inhibitors that are currently being developed covalently target the G12C cysteine mutation instead of reversibly binding an allosteric binding site known as the Switch-II pocket (Goebel et al. RSC Medicinal Chemistry 11, 260 (2020), Ostrem et al. Nature, 503(7477), 548-551, (2013). Examples of covalent KRAS inhibitors include adagrasib which is being developed by Mirati Therapeutics, sotorasib which is being developed by Amgen, and ARS-3248 and ARS-1620 which are being developed by Johnson and Johnson / Wellspring Bioscience. (Gilson et al. Cancers 12(5), 1341 (2020)). These inhibitors react irreversibly with cysteine in KRAS G12C (Goebel et al. RSC Medicinal Chemistry 11, 260 (2020)). In May of 2021, the FDA approved sotorasib for patients with KRAS G12C mutated advanced or metastatic non-small cell lung cancer. However, escape mutations have already been observed clinically in patients treated with sotorasib (Li et al. American Society of Clinical Oncology Annual Meeting Abstracts, 2022). In addition to KRAS G12C, a second clinically relevant mutant of the protein is KRAS G12D. Indeed, in a population of patients who had been treated with the KRAS G12C inhibitor adagrasib, several patients who initially responded but then progressed carried the G12D mutant (Awad et al. NEJM 384, 2382 (2021)). Despite several decades of research to discover inhibitors of KRAS and its mutant forms, the only approved therapeutic option suffers from acquired resistance. The Scripps Research Institute filed three PCT Applications, WO2015 / 188120, WO2018 / 102433, and WO2019 / 139979 describing fluorosulfur(VI) compounds and uses thereof via reactions with phenols. This chemistry, known as SuFEx (Sulfur-Fluoride Exchange), has also been studied by the Sharpless lab at the Scripps Research Institute, which has published a number of papers on the topic (Dong et al. Angew. Chem. Int. Ed. Engl.53(36), 9466-9470 (2014); Qin et al. Angew. Chem. Int. Ed. 55(45), 14155-14158 (2016); Gao et al. Angew. Chem. Int. Ed.57(7), 1939-1943 (2018); Guo et al. Angew. Chem. Int. Ed. 57(10), 2605-2610 (2017); Gahtory et al. Chemistry 24(41), 10550-10556, (2018); Smedley et al. Angew. Chem. Int. Ed.58(14), 4552-4556 (2019); Liu et al. Angew. Chem. Int. Ed.58(24), 8029-8033 (2019); Dong et al. Angew. Chem. Int. Ed.53(36), 9430-9448 (2014); Li et al. Angew. Chem. Int. Ed.56(11), 2903-2908 (2017); Zheng et al. PNAS 116(38) 18808-18814 (2019); Wang et al. Angew. Chem. Int. Ed.56(37), 11203-11208 (2017); Liu et al. J. Am. Chem. Soc. 140, 2919-2925 (2018); and Chen et al. J. Am. Chem. Soc. 138, 7353-7364 (2016)). Similar sulfonyl fluoride chemistries have been developed for the purpose of biorthogonal protein labelling (Narayanan et al. Chem. Sci.6(5): 2650-2659 (2015) and Gu et al. J. Chem. Biol. 20(4), 541-548 (2013)) These strategies employ electrophilic sulfonyl compounds with a fluoride leaving group to react with a variety of nucleophiles. Ku-Lung Hsu, et al., at University of Virginia have described sulfonyl-containing heteroaryl compound which have been named SuTEx compounds (Sulfur-Triazole Exchange)(Hahm et al. Nat. Chem. Bio. 16, 150–159 (2020); Brulet et al. J. Am. Chem. Soc. 142(18), 8270-8280 (2020); Borne et al. Development and biological applications of sulfur- triazole exchange (SuTEx) chemistry RSC Chem. Biol. (2021); and Huang et al. Chemoproteomic profiling of kinases in live cells using electrophilic sulfonyl triazole probes Chem. Sci. (2021)). See also WO 2020 / 214336 (Sulfur-heterocycle exchange chemistry) and WO 2021 / 016263 (Cysteine Binding Compositions and Methods of Use Thereof), filed by University of Virginia as assignee, and Hsu, et al. as inventors. Additional publications on the use of SuTEx molecules include Grams et al. Reactive chemistry for covalent probe and therapeutic development Trends in Pharmacological Sciences (2022) and Toroitich et al. Discovery off a cell-active SuTEx ligand of prostaglandin reductase 2 ChemBioChem (2021). Umbra Therapeutics Inc. filed three PCT Applications, WO 2022 / 187688, WO 2022 / 187690, and WO 2022 / 187693 on March 5, 2021, describing new SuTEx compounds for covalent modification of proteins. The ‘998 application describes SuTEx compounds that covalently modify KRAS. It is an object of the present invention to provide new compositions of matter, including pharmaceutical compositions, and their methods of use and manufacture to treat diseases mediated by KRAS. SUMMARY OF THE INVENTION Heteroaryl sulfonyl compounds and their uses and manufacture are provided that covalently modify KRAS to treat a disease mediated by KRAS, for example a mutant KRAS, in a host, typically a human. The heteroaryl sulfonyl compound is first typically selectively non- covalently bound to KRAS by association of KRAS with a KRAS Recognition Moiety in the heteroaryl sulfonyl compound. In a typical second step, a reactive tyrosine residue on KRAS attacks the sulfonyl moiety in the heteroaryl sulfonyl compound of the present invention to form a covalent bond between the tyrosine and the compound and force the elimination of a Leaving Group from the compound. In another aspect a reactive lysine or histidine residue on KRAS attacks the heteroaryl sulfonyl compound of the present invention to form a covalent bond between the lysine or histidine and the compound, forcing the elimination of a Leaving Group from the compound. In a principal aspect of the invention the heteroaryl sulfonyl compound covalently modifies a mutant KRAS. Non-limiting examples of mutant KRAS include codon 12 mutations such as KRAS G12D, KRAS G12C, or KRAS G12V; codon 13 mutations such as KRAS G13C or KRAS G13D; codon 18 mutations such as KRAS A18D; codon 61 mutations such as KRAS Q61H; and codon 117 mutations such as KRAS K117N. In certain embodiments a compound of the present invention covalently binds G12D mutant KRAS. The heteroaryl sulfonyl compounds of the present invention are uniquely designed for KRAS specificity, for example mutant KRAS, to maximize therapeutic effect and minimize off- target toxicity, by inclusion of a specific KRAS Recognition Moiety and Linker as described further herein that selectively bind KRAS, for example mutant KRAS, for further covalent linkage. In this way, the heteroaryl sulfonyl compound of the present invention exerts precise control over the targeted silencing, destruction or inactivation of KRAS, for example mutant KRAS, while limiting unacceptable off-target effects. In some embodiments, the heteroaryl sulfonyl compound of the present invention binds to KRAS, for example mutant KRAS, with high affinity. The high affinity binding confers one or more advantages, such as lower dose or reduced off-target effects. The heteroaryl sulfonyl compounds described herein can take advantage of the variable electrophilic properties of heteroaryl sulfonyl compounds to covalently modify KRAS, resulting in a decrease or termination of its biological activity.

[0002] The covalent-binding heteroaryl sulfonyl compounds of the present invention include a KRAS Recognition Moiety, a Leaving Group, and an Attaching Group. The heteroaryl sulfonyl compounds are oriented such that the Leaving Group is on one side of the S(O)2electrophile and the Attaching Group is on the other. The KRAS Recognition Moiety is located either on the Leaving Group or the Attaching Group in a manner that allows it to associate with KRAS as described herein. In some embodiments, the Leaving Group is a monocyclic or bicyclic heteroaryl group bound to the sulfur atom through a S-N bond. For example, as used herein, R1and R16are typically Leaving Groups. The Leaving Group is eliminated when the heteroaryl sulfonyl compound undergoes nucleophilic attack by an amino acid, for example a tyrosine or lysine, of KRAS. The Attaching Group, along with the S(O)2group to which it is bound, remains on KRAS after covalent modification. For example, as used herein, Linker is an Attaching Group. Non-limiting examples of the covalent modification of KRAS via a tyrosine that reacts with the heteroaryl sulfonyl compound of the present invention is provided below: wherein KRAS Recognition Moiety is selected from structures described herein. Additional non-limiting examples of the covalent modification of KRAS via a lysine that reacts with the heteroaryl sulfonyl compound of the present invention is provided below: wherein KRAS Recognition Moiety is selected from structures described herein. Additional non-limiting examples of the covalent modification of KRAS via a histidine that reacts with the heteroaryl sulfonyl compound of the present invention is provided below:

[0003] wherein KRAS Recognition Moiety is selected from structures described herein. The KRAS Recognition Moiety brings the activated heteroaryl sulfonyl into close proximity with a reactive amino acid of KRAS, for example mutant KRAS, resulting in covalent modification of KRAS and resultant amelioration or elimination of a disease or KRAS-mediated disorder. The heteroaryl sulfonyl compound of the present invention is used to modulate KRAS’s biological activity by covalently modifying the protein, for example, by covalently modifying a tyrosine, lysine, or histidine moiety in or near an allosteric binding pocket, for example the Switch- II Pocket. In certain aspects, a heteroaryl sulfonyl compound of Formula A or Formula B is provided: or a pharmaceutically acceptable salt thereof; wherein: KRAS Recognition Moiety is selected from the group consisting of R1is selected from the group consisting of: in certain embodiments R1is R6is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R18; R7, R7a, R7b, R7c, and R7dare independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17; R13is selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, aryl, -OR6, -N(R6)2, -C(O)R6, -NR6C(O)R6, -C(O)N(R6)2, and -NR6C(O)N(R6)2, each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R16is a heteroaryl group, where the bond to the sulfur atom is through one of the nitrogen atoms present in the cycle, and R16is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R17is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6; R18is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R19, -OC(O)R19, -NR19C(O)R19, -C(O)OR19, -OC(O)OR19, -NR19C(O)OR19, -C(O)N(R19)2, -OC(O)N(R19)2, -NR19C(O)N(R19)2, -OR19, -N(R19)2, -S(O)R19, -S(O)2R19, -S(O)OR19, -S(O)2OR19, -S(O)N(R19)2, S(O)2N(R19)2, and -SR19; R19is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; R27, R27a, R27b, R27c, R27d, R27e, and R27fare independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R18; R28, R28a, R28b, R28c, and R28dis independently selected at each instance from hydrogen, F, Br, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, - OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R18; R29is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, halogen and heteroaryl each of which is optionally substituted with 1 or 2 substituents independently selected from R17; in certain embodiments R29is a bicyclic heterocycle; R31is selected from the group consisting of -O-, -S-, -S(O)-, -S(O)2-, -NR6-, -C(O)NR6- and -CF2- wherein one bond is to the KRAS Recognition Moiety and other bond is to the rest of the molecule, for example a bond to Linker; R33is an aryl, heteroaryl, or bicycle optionally substituted with q substituents independently selected at each instance from R27; R33Bis an aryl, heteroaryl, or bicycle optionally substituted with q substituents independently selected at each instance from R28; R35is independently selected from hydrogen, alkyl, cycloalkyl, -alkyl-cycloalkyl, -alkyl- aryl, aryl, heterocycle, -alkyl-heterocycle, and heteroaryl each of which is optionally substituted with 1 or 2 substituents independently selected from R17; R43is an heteroaryl, aryl, or bicycle substituted with R41and optionally substituted with q substituents independently selected at each instance from R27; each q is independently 0, 1, 2, or 3; R41is a bivalent moiety selected from -alkyl-, -alkenyl-, -alkynyl-, -cycloalkyl-, -heterocycle-, -aryl-, -heteroaryl-, -O-, -S-, -S(O)-, -S(O)2-, -NR6-, -C(O)NR6- and -CF2- wherein one bond is to the KRAS Recognition Moiety and other bond is to the rest of the molecule, for example a bond to Linker; and Linker is a bond or a moiety that covalently links the KRAS Recognition Moiety to the rest of the molecule. In certain embodiments Linker is of Formula: wherein: X1, X2, X3, X4, X5, and X6are bivalent moieties independently selected from the group consisting of bond, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocycle, heteroaryl, bicycle, tricycle, -S-, -O-, -NR6-, -C(O)-, -C(O)-NR6-, -C(O)-O-, –(CH2CH2O)p–, -S(O)2-, -S(O)2NR6-, and -S(O)2O-, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; wherein X1, X2, X3, X4, X5, and X6are selected in a way that avoids undesired repetition of atoms or moieties, such as in nonlimiting examples, S, O, or a combination thereof (e.g., that would otherwise form a disulfide or peroxide bond), as well known to skilled artisans. In certain embodiments KRAS has a reactive tyrosine which covalently binds to the heteroaryl sulfonyl compounds of the present invention. In certain embodiments the reactive tyrosine is in an allosteric site, for example the Switch-II Pocket. In certain embodiments KRAS has a reactive lysine which covalently binds to the heteroaryl sulfonyl compounds of the present invention. In certain embodiments the reactive lysine is in an allosteric site, for example the Switch-II Pocket. In certain embodiments KRAS has a reactive histidine which covalently binds to the heteroaryl sulfonyl compounds of the present invention. In certain embodiments the reactive histidine is in an allosteric site, for example the Switch-II Pocket. In certain embodiments KRAS has a reactive cysteine which covalently binds to the heteroaryl sulfonyl compounds of the present invention. In certain embodiments the reactive cysteine is in an allosteric site, for example the Switch-II Pocket. Assays and / or spectroscopic techniques to confirm covalent binding are described in the paper by Brulet et. al. titled “Liganding Functional Tyrosine Sites on Proteins Using Sulfur- Triazole Exchange Chemistry” JACS 2020, 142, 8270-8280 or the paper by Hahm et. al. titled “Global targeting of functional tyrosines using sulfur triazole exchange chemistry” Nature Chem. Biol.2020, 16(2), 150-159. In certain embodiments the heteroaryl sulfonyl compound of the present invention primarily covalently modifies a specific tyrosine or lysine in KRAS. In other embodiments, a selected heteroaryl sulfonyl compound of the present invention reacts with two or more different tyrosines and / or lysines in KRAS. In certain embodiments the heteroaryl sulfonyl compound of the present invention is more than about 5-, 10-, 15-, 20-, 25-, 50-, 75-, or 100-fold more selective for one specific amino acid, for example a specific tyrosine, than other amino acids of KRAS. In certain embodiments one or more amino acid other than tyrosine or lysine is covalently modified by a heteroaryl sulfonyl compound of the present invention. For example, the amino acid that is covalently modified is cysteine, arginine, histidine, serine, threonine, or tryptophan. The present invention focuses on the covalent modification of KRAS to treat diseases, for example, abnormal cellular proliferation such as tumors and cancer. In certain embodiments, a method of treating a disorder mediated by a KRAS is provided comprising administering an effective amount of a heteroaryl sulfonyl compound of the present invention to a patient in need thereof, for example a human, or a pharmaceutically acceptable salt thereof optionally in a pharmaceutically acceptable carrier. For example, In certain embodiments, a heteroaryl sulfonyl compound of the present invention is administered to a human to treat a cancer or tumor where the heteroaryl sulfonyl compound has a KRAS Recognition Moiety and the tumor or cancer is mediated by KRAS. In certain embodiments, the heteroaryl sulfonyl compound described herein does not have to be administered in as high of a dose or as frequently as the classic KRAS inhibitor corresponding to the KRAS Recognition Moiety incorporated into the heteroaryl sulfonyl compound alone for treatment of a disorder. In certain embodiments, a heteroaryl sulfonyl compound of the present invention has fewer or less severe side-effects in the treatment of a disorder mediated by KRAS, than the classic KRAS inhibitor corresponding to the KRAS Recognition Moiety incorporated into the heteroaryl sulfonyl compound alone. In certain embodiments, the heteroaryl sulfonyl compound of the present invention is more efficacious in the treatment of a disorder mediated by KRAS than the classic KRAS inhibitor corresponding to the KRAS Recognition Moiety incorporated into the heteroaryl sulfonyl compound alone. In principal embodiments, a heteroaryl sulfonyl compound described herein is useful to treat a disorder, for example abnormal cellular proliferation, such as a tumor or cancer, wherein KRAS is mutated. In other embodiments a heteroaryl sulfonyl compound described herein is useful to treat a disorder wherein KRAS is not mutated. In certain embodiments a heteroaryl sulfonyl compound described herein is at least about 2-, 3-, 4-, 5-, 10-, 50-, 100-, 200-, 300-, 400-, 500-, or 1,000-fold more selective for a mutated KRAS than the wild-type KRAS. In certain embodiments, a heteroaryl sulfonyl compound of the present invention is useful as a therapeutic agent, when administered in an effective amount to a patient, for the treatment of a medical disorder that can be treated with the KRAS Recognition Moiety. The heteroaryl sulfonyl compounds of the present invention can be administered in any manner that allows the heteroaryl sulfonyl compound to covalently modify KRAS. As such, examples of methods to deliver the heteroaryl sulfonyl compounds of the present invention include, but are not limited to, systemic, parenteral, topical, oral, intravenous, buccal, sublingual, subcutaneous, or transnasal administration. In certain embodiments, the heteroaryl sulfonyl compound of the present invention has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. In certain embodiments, the heteroaryl sulfonyl compound of the present invention includes a deuterium or multiple deuterium atoms. Deuterium is not considered or used herein as a detectable labeling group. Another aspect of the present invention provides a heteroaryl sulfonyl 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 or preventing a disease in which KRAS, for example mutant KRAS, plays a role. In certain embodiments, the heteroaryl sulfonyl compound of the present invention is not fluorescent, including but not limited to not a fluorophore. Additional features and advantages of the present application will be apparent from the following detailed description. The present invention thus includes at least the following features: (a) A heteroaryl sulfonyl compound of the present invention, as described herein, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof; (b) A means for covalently modifying KRAS and mutant forms thereof; (c) A method for treating a disorder mediated by KRAS, for example mutant KRAS, comprising administering an effective amount of a heteroaryl sulfonyl compound of the present invention, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof; (d) A heteroaryl sulfonyl compound of the present invention, or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder that is mediated by KRAS, for example mutant KRAS; (e) Use of a heteroaryl sulfonyl compound of the present invention, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment of a patient in need thereof, typically a human, with disorder mediated by KRAS, for example mutant KRAS; (f) Use of a heteroaryl sulfonyl compound of the present invention, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disorder mediated by KRAS, for example mutant KRAS; (g) A pharmaceutical composition comprising an effective patient-treating amount of a heteroaryl sulfonyl compound of the present invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent; (h) A heteroaryl sulfonyl compound of the present invention, as described herein as a mixture of enantiomers or diastereomers (as relevant), including as a racemate; (i) A heteroaryl sulfonyl compound of the present invention, as described herein in enantiomerically or diastereomerically (as relevant) enriched form, including an isolated enantiomer or diastereomer (i.e., greater than 85, 90, 95, 97, or 99% pure); and (j) A process for the preparation of therapeutic products that contain an effective amount of a heteroaryl sulfonyl compound of the present invention, or a pharmaceutically acceptable salt thereof, as described herein. DETAILED DESCRIPTION OF THE INVENTION Heteroaryl sulfonyl compounds and their use and manufacture are provided that covalently modify KRAS, for example mutant KRAS, to treat a disease that is mediated by KRAS in a host, typically a human. In one aspect of the invention a heteroaryl sulfonyl compound described herein reacts with a tyrosine residue on KRAS, for example mutant KRAS, to form a covalent bond. In another aspect a heteroaryl sulfonyl compound described herein reacts with a lysine or histidine residue on KRAS, for example mutant KRAS, to form a covalent bond. The invention provides a heteroaryl sulfonyl compound of the present invention, or a pharmaceutically acceptable salt thereof that includes a KRAS Recognition Moiety that provides specificity to the heteroaryl sulfonyl compound, and an electrophilic sulfonyl (SO2) that reacts with the target tyrosine or lysine to create a covalent bond between KRAS and the presently described inhibitor. The heteroaryl sulfonyl compound as described herein in principle embodiments has a stable shelf life for at least 2 months, 3 months, 6 months or 1 year or more neat or as part of a pharmaceutically acceptable dosage form, and itself is pharmaceutically acceptable. Terminology As used herein, “Anchor Bond” or “bond to KRAS Recognition Moiety” is defined as the chemical bond between the KRAS Recognition Moiety and the rest of the molecule for example a bond to R3, R9, or R16, as appropriate. Non-limiting examples of Anchor Bonds are shown in bold in the following structures: where R3is methylene, where R3is bond and R2is phenyl, where R9is difluoromethylene, and where R16is 1,2,4-triazole. Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. The heteroaryl sulfonyl compounds in any of the Formulas described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, such as rotamers, as if each is specifically described, unless otherwise indicated or otherwise excluded by context. The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and / or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. In certain embodiments the present invention includes heteroaryl sulfonyl compounds with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. In certain embodiments the heteroaryl sulfonyl compounds of the present invention are not isotopically enriched. Examples of isotopes that can be incorporated into heteroaryl sulfonyl compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as2H,3H,11C,13C,14C,15N,17O,18O,18F31P,32P,35S,36CI, and125I respectively. In certain embodiments, isotopically labelled heteroaryl sulfonyl compounds can be used in metabolic studies (with, for example14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. For example, a18F labeled heteroaryl sulfonyl compound may be desirable for PET or SPECT studies. Isotopically labeled heteroaryl sulfonyl 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. By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H) may optionally be used anywhere in described structures that achieves the desired result. Alternatively, or in addition, isotopes of carbon, e.g.,13C and14C, may be used. In certain embodiments, the isotopic substitution is replacing hydrogen with a deuterium at one or more locations on the molecule to improve the performance of the drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, the deuterium can be bound to carbon in a location of bond breakage during metabolism (an α-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a β-deuterium kinetic isotope effect). Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 80, 85, 90, 95 or 99% or more enriched in an isotope at any location of interest. In certain embodiments deuterium is 80, 85, 90, 95 or 99% enriched at a desired location. Unless otherwise stated, the enrichment at any point is above natural abundance, and in an embodiment is enough to alter a detectable property of the drug in a human. In certain embodiments, the substitution of a hydrogen atom for a deuterium atom occurs within any variable group. For example, when any variable group is, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in nonlimiting embodiments, CDH2, CD2H, CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc.). The heteroaryl sulfonyl compound of the present invention may form a solvate with solvents (including water). Therefore, In certain embodiments, the invention includes a solvated form of the active heteroaryl sulfonyl compound. The term "solvate" refers to a molecular complex of a heteroaryl sulfonyl compound of the present invention (including a salt thereof) with one or more solvent molecules. Nonlimiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a heteroaryl sulfonyl compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO. A solvate can be in a liquid or solid form. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH2is attached through carbon of the keto (C=O) group. The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom's normal valence is not exceeded and the resulting heteroaryl sulfonyl compound is stable. For example, when the substituent is oxo (i.e., =O) then two hydrogens on the atom are replaced. For example a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and / or variables are permissible only if such combinations result in stable heteroaryl sulfonyl compounds or useful synthetic intermediates. “Alkyl” is a branched, straight chain, or cyclic saturated aliphatic hydrocarbon group, which unless otherwise referred to in context, is one to eight carbon atoms. In certain embodiments, the alkyl contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms, from 1 to about 4 carbon atoms, or from 1 to 3 carbon atoms. In certain embodiments, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1- C4, C1-C5or C1-C6.The specified ranges as used herein indicate an alkyl group which is considered to explicitly disclose as individual species each member of the range described as a unique species. For example, the term C1-C6 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and also a carbocyclic alkyl group of 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. When C0-Cn alkyl is used herein in conjunction with another group, for example, (C3- C7cycloalkyl)C0-C4 alkyl, or –C0-C4alkyl(C3-C7cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C0alkyl), or attached by an alkyl chain in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms as in –O-C0-C4alkyl(C3-C7cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert- pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3- dimethylbutane, and hexyl. When a term is used that includes “alk” it should be understood that “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example and without limitation, the terms alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenloxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context. “Alkenyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at a stable point along the chain, which unless referred to in context is two to eight carbon atoms. Nonlimiting examples are C2-C8alkenyl, C2-C7alkenyl, C2-C6alkenyl, C2-C5alkenyl and C2-C4alkenyl. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. “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, for example, C2- C8alkynyl or C2-C6alkynyl. Unless otherwise defined in context, “alkynyl” is C2-C8alkynyl. The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. “Alkoxy” is an alkyl group as defined above covalently bound through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n- hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly an “alkylthio” or a “thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound through a sulfur bridge (-S-). In certain embodiments, the alkoxy group is optionally substituted as described above. “Haloalkyl” indicates both branched and straight-chain alkyl groups substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2- fluoroethyl, and penta-fluoroethyl. “Aryl" indicates an aromatic group containing only carbon in the aromatic ring or rings. In certain embodiments, the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members. The term “aryl” includes groups where a saturated or partially unsaturated carbocycle group is fused with an aromatic ring. The term “aryl” also includes groups where a saturated or partially unsaturated heterocycle group is fused with an aromatic ring so long as the attachment point is the aromatic ring. Such heteroaryl sulfonyl compounds may include aryl rings fused to a 4 to 7 or a 5 to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2 or 3 heteroatoms independently selected from N, O, B, P, Si and S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In certain embodiments, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. The term “heterocycle” refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, S, and O. The term “heterocycle” includes monocyclic 3-12 membered rings, as well as bicyclic 5-16 membered ring systems (which can include fused, bridged, or spiro, bicyclic ring systems). It does not include rings containing - O-O- or -S-S- portions. Examples of saturated heterocycle groups include saturated 4- to 7- membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]; saturated 4 to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocycle groups include but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4- tetrahydro-isoquinolyl, 1 ,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a- hexahydro-lH-3-aza-fluorenyl, 5,6,7- trihydro-l,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H- benzo[l,4]oxazinyl, benzo[l,4]dioxanyl, 2,3- dihydro-lH-lλ’-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl. “Bicyclic heterocycle” includes groups wherein the heterocyclic radical is fused with an aryl radical wherein the point of attachment is the heterocycle ring. “Bicyclic heterocycle” also includes heterocyclic radicals that are fused or bridged with a carbocycle radical. For example partially unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indoline, isoindoline, partially unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms. Non-limiting examples of bicyclic heterocycles include: , Unless otherwise drawn or clear from the context, the term “bicyclic heterocycle” includes cis and trans diastereomers. Non-limiting examples of chiral bicyclic heterocycles include: In certain alternative embodiments the term “heterocycle” refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, S, O, B, Si, and P. The term “bicycle” refers to a ring system wherein two rings are fused together and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Non-limiting examples of bicycle groups include: , When the term “bicycle” is used in the context of a bivalent residue such as R2, R3, or R5, the attachment points can be on separate rings or on the same ring. In certain embodiments both attachment points are on the same ring. In certain embodiments both attachment points are on different rings. Non-limiting examples of bivalent bicycle groups include: The term “tricycle” refers to a ring system wherein three rings are fused together and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Non-limiting examples of tricycle groups include: , When the term “tricycle” is used in the context of a bivalent residue such as R2, R3, or R5, the attachment points can be on separate rings or on the same ring. In certain embodiments both attachment points are on the same ring. In certain embodiments both attachment points are on different rings. Non-limiting examples of bivalent tricycle groups include: . “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring which contains from 1 to 5, or in some embodiments from 1, 2, 3, 4, or 5 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms selected from N, O, S, B or P with remaining ring atoms being carbon. In certain embodiments, the only heteroatom is nitrogen. In certain embodiments, the only heteroatom is oxygen. In certain embodiments, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have from 5 or 6 ring atoms. In some embodiments bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is, groups containing 8 or 10 ring atoms in which one 5, 6, or 7-member aromatic ring is fused to a second aromatic or non-aromatic ring wherein the point of attachment is the aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In another embodiment, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. A “dosage form” means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like. A “dosage form” can also include an implant, for example an optical implant. “Pharmaceutical compositions” are compositions comprising at least one active agent, and at least one other substance, such as a carrier. The present invention includes pharmaceutical compositions of the described heteroaryl sulfonyl compounds. “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein. A “pharmaceutically acceptable salt” is a derivative of the disclosed heteroaryl sulfonyl compound in which the parent heteroaryl sulfonyl compound is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof. The salts of the present heteroaryl sulfonyl compounds can be synthesized from a parent heteroaryl sulfonyl compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these heteroaryl sulfonyl 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 heteroaryl sulfonyl compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Salts of the present heteroaryl sulfonyl compounds further include solvates of the heteroaryl sulfonyl compounds and of the heteroaryl sulfonyl 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 salts which are acceptable for human consumption and the quaternary ammonium salts of the parent heteroaryl sulfonyl compound formed, for example, from inorganic or organic acids. Examples, of such salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)1-4- COOH, and the like, or using a different acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p.1418 (1985). The term “carrier” applied to pharmaceutical compositions / combinations of the invention refers to a diluent, excipient, or vehicle with which an active heteroaryl sulfonyl compound is provided. A “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition / combination that is generally safe, acceptable for human consumption, and neither biologically nor otherwise inappropriate for administration to a host, typically a human. In certain embodiments, an excipient is used that is acceptable for veterinary use. A “patient” or “host” or “subject” is a human or non-human animal in need of treatment or prevention of any of the disorders as specifically described herein. Typically, the host is a human. A “patient” or “host” or “subject” also refers to for example, a mammal, primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mice, bird and the like. A “therapeutically effective amount” of a compound, pharmaceutical composition, or combination of this invention means an amount effective, when administered to a host, provides a therapeutic benefit such as an amelioration of symptoms or reduction or diminution of the disease itself. KRAS Recognition Moiety As used herein codes referring to crystal structures correspond to the crystal structure available on the Protein Data Bank (PDB, https: / / www.rcsb.org). For example, non-limiting examples of crystal structures of KRAS include 6OIM, 5V9U, 6FA2, 6GQX, 6TAM, 7ACQ, 4EPW, 6VC8, 6ZL5, 5KYK, 6MTA, 4LDJ, 4TQ9, 4DSN, 4QL3, 3GFT, and 5YY1, where these codes correspond to crystal structures in the PDB database and are available online at https: / / www.rcsb.org. Non-limiting examples of KRAS Recognition Moieties are provided below. In certain embodiments the KRAS Recognition Moiety is wherein R29is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, halogen and heteroaryl each of which is optionally substituted with 1 or 2 substituents independently selected from R17; R31is selected from the group consisting of -O-, -S-, -S(O)-, -S(O)2-, -NR6-, -C(O)NR6- and -CF2- wherein one bond is to the KRAS Recognition Moiety and other bond is to the rest of the molecule, for example a bond to R3, R9, or R16, as appropriate; q is 0, 1, 2, 3, 4, or 5; R33is an aryl or bicycle optionally substituted with q substituents independently selected at each instance from R27; R33Bis an aryl or bicycle optionally substituted with q substituents independently selected at each instance from R28; R35is independently selected from hydrogen, alkyl, cycloalkyl, -alkyl-cycloalkyl, -alkyl- aryl, aryl, heterocycle, -alkyl-heterocycle, and heteroaryl each of which is optionally substituted with 1 or 2 substituents independently selected from R17; R41is a bivalent moiety including but not limited to -alkyl-, -alkenyl-, -alkynyl-, -cycloalkyl-, -heterocycle-, -aryl-, -heteroaryl-, bond, -O-, -S-, -S(O)-, -S(O)2-, -NR6-, -C(O)NR6- and -CF2- wherein one bond is to the KRAS Recognition Moiety and other bond is to the rest of the molecule, for example a bond to R3, R9, or R16, as appropriate; and wherein all other variables are as defined herein. In alternative embodiments, the KRAS Recognition Moiety is wherein R29Bis cycloalkyl, heterocycle, or heteroaryl each of which is substituted with R41and is optionally substituted with 1 or 2 substituents independently selected from R17; R41is selected from the group consisting of bond, -O-, -S-, -S(O)-, -S(O)2-, -NR6-, - C(O)NR6- and -CF2- wherein one bond is to the KRAS Recognition Moiety and other bond is to the rest of the molecule, for example a bond to Linker; R51is independently selected from the group consisting of bond, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocycle, heteroaryl, bicycle, tricycle, -S-, -O-, -NR6-, -C(O)-, - C(O)-NR6-, -C(O)-O-, –(CH2CH2O)p–, -S(O)2-, -S(O)2NR6-, and -S(O)2O-, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and R52is C0-6alkyl-N(R6)2 or C0-6alkyl-heterocycle.

[0004] In certain embodiments q is 0, 1, 2, or 3. In certain embodiments q is 0. In certain embodiments q is 1. In certain embodiments q is 2. In certain embodiments R29is a bicyclic heterocycle; In certain embodiments R30is -C(O)R6. In certain embodiments R30is -C(O)OR6. In certain embodiments R30is -C(O)N(R6)2. In certain embodiments R29is selected from the group consisting of:

[0005] In certain embodiments, R29is selected from the group consisting of In certain embodiments, R29is selected from the group consisting of . In certain embodiments, R33is selected from the group consisting of

[0006] In certain embodiments, R33is selected from the group consisting of In certain embodiments, R33Bis selected from the group consisting of

[0007] In certain embodiments, R33Bis selected from the group consisting of In certain embodiments, R33or R33Bis selected from the group consisting of In certain embodiments, R35is -alkyl-heterocycle. In certain embodiments, R35is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is . In certain embodiments the KRAS Recognition Moiety is In alternative embodiments R29Bis selected from the group consisting of: . In certain embodiments, the KRAS Recognition Moiety is

[0008] In certain embodiments, the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is . In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments the KRAS Recognition Moiety is In certain embodiments, the compound of the present invention is ; or a pharmaceutically acceptable salt thereof. In alternative embodiments, the compound of the present invention is or a pharmaceutically acceptable salt thereof. In certain embodiments R27ais halogen. In certain embodiments R27ais haloalkyl. In certain embodiments R27ais alkyl. In certain embodiments R27ais hydrogen. In certain embodiments R27bis halogen. In certain embodiments R27bis haloalkyl. In certain embodiments R27bis alkyl. In certain embodiments R27dis alkynyl. In certain embodiments R27dis halogen. In certain embodiments R27dis fluoro. In certain embodiments R27dis chloro. In certain embodiments R27dis hydroxyl. In certain embodiments R27dis alkyl. In certain embodiments R27eis halogen. In certain embodiments R27eis fluoro. In certain embodiments R27eis chloro. In certain embodiments R27eis hydroxyl. In certain embodiments R27eis alkyl. In certain embodiments there is one R27and it is halogen. In certain embodiments there is one R27and it is haloalkyl. In certain embodiments there is one R27and it is alkyl. In certain embodiments there is one R27and it is hydrogen. In certain embodiments, the KRAS recognition moiety is wherein R43is a bivalent aryl or bicycle substituted with R41and optionally substituted with q substituents independently selected at each instance from R27; In certain embodiments, R43is selected from the group consisting of the asterisk indicates the attachment point to the KRAS Recognition Moiety (for example, the KRAS recognition moiety of formula43 wherein R is means a compound of structure In certain embodiments, R43is . In certain embodiments, the KRAS Recognition Moiety is In certain embodiments, the KRAS Recognition Moiety is

[0009] In certain embodiments, the KRAS Recognition Moiety is In certain embodiments, the KRAS Recognition Moiety is

[0010] . In certain embodiments, the KRAS Recognition Moiety is In certain embodiments, the KRAS Recognition Moiety is

[0011] . In certain embodiments, the KRAS Recognition Moiety is . Additional Embodiments In certain aspects a heteroaryl sulfonyl compound of the present invention, or a pharmaceutically acceptable salt thereof, is provided of Formula:

[0012] or a pharmaceutically acceptable salt thereof; wherein: R1is selected from: b) a bicyclic heteroaryl or tricyclic heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R2is a bivalent moiety independently selected at each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, aryl-C(O)-NR6-, heteroaryl-C(O)-NR6-, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; in principal embodiments R2is selected from alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R3is a bivalent moiety independently selected at each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, aryl-C(O)-NR6-, heteroaryl-C(O)-NR6-, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; or R3is a bivalent moiety independently selected at each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -S-alkyl-, -O-alkyl-, -NR6-alkyl-, -alkyl- C(O)-, -alkyl-C(O)-alkyl-, -alkyl-C(O)-NR6-alkyl-, -C(O)-NR6-alkyl-, -alkyl-C(O)-NR6-, -alkyl- C(O)-O-alkyl-, -C(O)-O-alkyl-, -alkyl-C(O)-O-, -C(O)-, -NR6C(O)NR6-, -C(O)NR6-, - OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and wherein R2and R3are selected such that a suitably stable and suitably nontoxic compound for in vivo administration in a host is achieved, and in certain embodiments, in a way that avoids undesired repetition of atoms or moieties, such as in nonlimiting examples, S, O, or a combination thereof (i.e., that would otherwise form a disulfide or peroxide bond), as well known to skilled artisans; p is independently selected from 1, 2, 3, 4, 5, and 6; R4is a heteroaryl group, where the bond to the sulfur atom is through one of the nitrogen atoms present in the cycle, and each heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R5is a bivalent moiety selected from alkyl, alkenyl, haloalkyl, cycloalkyl, naphthyl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, heteroaryl-C(O)-NR6-, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; in principal embodiments R5is selected from alkyl, alkenyl, haloalkyl, cycloalkyl, naphthyl, heterocycle, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and wherein R3and R5are selected such that a suitably stable and suitably nontoxic compound for in vivo administration in a host is achieved, and in certain embodiments, in a way that avoids undesired repetition of atoms or moieties, such as in nonlimiting examples, S, O, or a combination thereof (i.e., that would otherwise form a disulfide or peroxide bond), as well known to skilled artisans; R6is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R18; R7, R7a, R7b, R7c, and R7dare independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, =O, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17; R17is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, =O, and -SR6; R18is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R19, -OC(O)R19, -NR19C(O)R19, -C(O)OR19, -OC(O)OR19, -NR19C(O)OR19, -C(O)N(R19)2, -OC(O)N(R19)2, -NR19C(O)N(R19)2, -OR19, -N(R19)2, -S(O)R19, -S(O)2R19, -S(O)OR19, -S(O)2OR19, -S(O)N(R19)2, S(O)2N(R19)2, =O, and -SR19; R19is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; R8a, R8b, R8c, and R8dare independently selected at each instance from R7and R12wherein at least one of R8a, R8b, R8c, and R8dis R12; R9is a bivalent moiety selected from alkyl, alkenyl, haloalkyl, cycloalkyl, heterocycle, -alkyl-C(O)-NR6-alkyl-, -C(O)-NR6-alkyl-, -alkyl-C(O)-NR6-, -alkyl-C(O)-O-alkyl-, -C(O)-O-alkyl-, -alkyl-C(O)-O-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R11is selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, naphthyl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17; and R12is independently selected from halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, =O, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17; and wherein all other variables are as defined herein. In another aspect a heteroaryl sulfonyl compound of Formula VIII is provided: or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; wherein: R13is selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, aryl, -OR6, -N(R6)2, -C(O)R6, -NR6C(O)R6, -C(O)N(R6)2, and -NR6C(O)N(R6)2, each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R16is a heteroaryl group, where the bond to the sulfur atom is through one of the nitrogen atoms present in the cycle, and R16is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and all other variables are as defined herein. Embodiments of Formula I In certain embodiments the heteroaryl sulfonyl compound of Formula I is selected from: or a pharmaceutically acceptable salt thereof. Embodiments of Formula II In certain embodiments the heteroaryl sulfonyl compound of Formula II is selected from: or a pharmaceutically acceptable salt thereof. Embodiments of Formula III In certain embodiments the heteroaryl sulfonyl compound of Formula III is selected from: or a pharmaceutically acceptable salt thereof.

[0013] Embodiments of Formula IV In certain embodiments the heteroaryl sulfonyl compound of Formula IV is selected from: or a pharmaceutically acceptable salt thereof.

[0014] Embodiments of Formula V In certain embodiments the heteroaryl sulfonyl compound of Formula V is selected from: or a pharmaceutically acceptable salt thereof. Embodiments of Formula VI In certain embodiments the heteroaryl sulfonyl compound of Formula VI is selected from:

[0015] or a pharmaceutically acceptable salt thereof. Embodiments of Formula VII In certain embodiments the heteroaryl sulfonyl compound of Formula VII is selected from:

[0016] or a pharmaceutically acceptable salt thereof. Embodiments of Formula VIII In certain embodiments the heteroaryl sulfonyl compound of Formula VIII is selected from: ; or a pharmaceutically acceptable salt thereof. In certain embodiments the heteroaryl sulfonyl compound of Formula VIII is selected from: ; or a pharmaceutically acceptable salt thereof. In other aspects a heteroaryl sulfonyl compound of Formula I’, Formula II’, Formula III’, Formula IV’, Formula V’, Formula VI’, Formula VII’, or Formula VIII’, is provided: or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition; wherein R15is a bivalent moiety selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -S-alkyl-, -O-alkyl-, -NR6-alkyl-, -alkyl- C(O)-, -alkyl-C(O)-alkyl-, -alkyl-C(O)-NR6-alkyl-, -C(O)-NR6-alkyl-, -alkyl-C(O)-NR6-, -alkyl-C(O)-O-alkyl-, -C(O)-O-alkyl-, -alkyl-C(O)-O-, -C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R7; and wherein all other variables are as defined herein. Embodiments of Formula I’ In certain embodiments the heteroaryl sulfonyl compound of Formula I’ is selected from: or a pharmaceutically acceptable salt thereof. Embodiments of Formula II’ In certain embodiments the heteroaryl sulfonyl compound of Formula II’ is selected from: or a pharmaceutically acceptable salt thereof. Embodiments of Formula III’ In certain embodiments the heteroaryl sulfonyl compound of Formula III’ is selected from: or a pharmaceutically acceptable salt thereof. Embodiments of Formula IV’ In certain embodiments the heteroaryl sulfonyl compound of Formula IV’ is selected from: or a pharmaceutically acceptable salt thereof. Embodiments of Formula V’ In certain embodiments the heteroaryl sulfonyl compound of Formula V’ is selected from: or a pharmaceutically acceptable salt thereof. Embodiments of Formula VI’ In certain embodiments the heteroaryl sulfonyl compound of Formula VI’ is selected from:

[0017] or a pharmaceutically acceptable salt thereof. Embodiments of Formula VII’ In certain embodiments the heteroaryl sulfonyl compound of Formula VII’ is selected from:

[0018] or a pharmaceutically acceptable salt thereof. Embodiments of Formula VIII’ In certain embodiments the heteroaryl sulfonyl compound of Formula VIII’ is selected from: ; or a pharmaceutically acceptable salt thereof. In certain embodiments the heteroaryl sulfonyl compound of Formula VIII’ is selected from: or a pharmaceutically acceptable salt thereof. Additional Embodiments In certain embodiments the heteroaryl sulfonyl compound of the present invention is selected from:

[0019] . In certain embodiments the heteroaryl sulfonyl compound of the present invention is selected from: and

[0020] Į In certain embodiments the heteroaryl sulfonyl compound of the present invention is selected from: . In certain embodiments the heteroaryl sulfonyl compound of the present invention is selected from:

[0021] . In certain embodiments the heteroaryl sulfonyl compound of the present invention is selected from:

[0022] In certain embodiments the heteroaryl sulfonyl compound of the present invention is selected from:

[0023] In certain embodiments the heteroaryl sulfonyl compound of the present invention is selected from:

[0024] In certain embodiments the heteroaryl sulfonyl compound of the present invention is selected from:

[0025] . In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from: In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from:

[0026] . In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from:

[0027]  In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from: . In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from: In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from: . In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from: . In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from:

[0028] In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from: In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from: In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from: In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from: . In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from:

[0029] In certain embodiments, the heteroaryl sulfonyl compound of the present invention is selected from: Embodiments of R1In certain embodiments In certain embodiments In certain embodiments In certain embodiments . In certain embodiments In certain embodiments In certain embodiments In certain embodiments In certain embodiments R1is a fused bicyclic heteroaryl. Embodiments of R2and R3Bivalent substituents described herein can be either attached in a left to right fashion or a right to left fashion except as excluded by context. For example, where R2is -aryl-C(O)-NR6- either the aryl or nitrogen side is attached to the sulfonyl group. For example, when R2is -aryl-C(O)-NR6-, Formula I can be similarly, when -R3- is , Formula I can be In certain embodiments -R2-R3- and -R3-R2- are selected from: In certain embodiments -R2-R3- and -R3-R2- are selected from: In certain embodiments -R2-R3- and -R3-R2- are selected from:

[0030] In certain embodiments R2is selected from: In certain embodiments R2is selected from In certain embodiments R2is selected from: In certain embodiments R2is selected from: In certain embodiments R3is selected from In certain embodiments R3is selected from: In certain embodiments R3is selected from: In certain embodiments R3is selected from:

[0031] In certain embodiments R3is selected from: In certain embodiments R3is selected from: In certain embodiments R3is selected from: In certain embodiments R2is bond. In certain embodiments R3is bond. In certain embodiments R2and R3are both bond. In certain embodiments one of R2and R3is bond and the other is selected from alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, heteroaryl, aryl-C(O)-NR6-, heteroaryl-C(O)-NR6-, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7. In certain embodiments p is 1. In certain embodiments p is 2. In certain embodiments p is 3. In certain embodiments p is 4. In certain embodiments p is 5. In certain embodiments p is 6. In certain embodiments R2is phenyl. In certain embodiments R2is phenyl substituted with 1 substituent selected from R7. In certain embodiments R2is phenyl substituted with 2 substituents selected from R7. In certain embodiments R2is phenyl substituted with 3 substituents selected from R7. In certain embodiments R2is phenyl substituted with 4 substituents selected from R7. In certain embodiments R2is phenyl substituted with 1 substituent selected from R7EWG. In certain embodiments R2is phenyl substituted with 2 substituents selected from R7EWG. In certain embodiments R2is phenyl substituted with 3 substituents selected from R7EWG. In certain embodiments R2is phenyl substituted with 4 substituents selected from R7EWG. R7EWGis independently selected at each instance from halogen, haloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, with each haloalkyl, heterocycle, aryl, and heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R3is phenyl substituted with 1 substituent selected from R7. In certain embodiments R3is phenyl substituted with 2 substituents selected from R7. In certain embodiments R3is phenyl substituted with 3 substituents selected from R7. In certain embodiments R3is phenyl substituted with 4 substituents selected from R7. In certain embodiments R2is heteroaryl. In certain embodiments R2is heteroaryl substituted with 1 substituent selected from R7. In certain embodiments R2is heteroaryl substituted with 2 substituents selected from R7. In certain embodiments R2is heteroaryl substituted with 3 substituents selected from R7. In certain embodiments R2is heteroaryl substituted with 4 substituents selected from R7. Embodiments of R4In certain embodiments In certain embodiments In certain embodiments In certain embodiments . In certain embodiments In certain embodiments In certain embodiments In certain embodiments In certain embodiments R4is a 5-membered heteroaryl. In certain embodiments R4is a fused bicyclic heteroaryl. In certain embodiments each R7is independently selected from R7a, R7b, R7cand R7d. In certain embodiments R4is a bicyclic heteroaryl optionally substituted with 1, 2, 3, or 4 R7substituents. Embodiments of R5 In certain embodiments R5is selected from In certain embodiments R5is selected from: In certain embodiments R5is bond. In certain embodiments R5and R3are both bond. In certain embodiments one of R5and R3is bond and the other is selected from alkyl, alkenyl, haloalkyl, cycloalkyl, heterocycle, naphthyl, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, heteroaryl, heteroaryl-C(O)-NR6-, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7. Embodiments of R6In certain embodiments one R6is hydrogen. In certain embodiments one R6is alkyl. In certain embodiments one R6is haloalkyl. In certain embodiments one R6is cycloalkyl. In certain embodiments one R6is aryl. In certain embodiments one R6is heterocycle. In certain embodiments one R6is heteroaryl. Embodiments of R7In certain embodiments R7is independently selected at each instance from R7EWG. In certain embodiments R7ais independently selected at each instance from R7EWG. In certain embodiments R7bis independently selected at each instance from R7EWG. In certain embodiments R7cis independently selected at each instance from R7EWG. In certain embodiments R7dis independently selected at each instance from R7EWG. R7EWGis independently selected at each instance from halogen, haloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, with each haloalkyl, heterocycle, aryl, and heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R7ais hydrogen. In certain embodiments R7ais cyano. In certain embodiments R7ais halogen. In certain embodiments R7ais fluoro. In certain embodiments R7ais haloalkyl. In certain embodiments R7ais -CF3. In certain embodiments R7ais aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R7ais phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R7ais aryl. In certain embodiments R7ais phenyl. In certain embodiments R7bis hydrogen. In certain embodiments R7bis cyano. In certain embodiments R7bis halogen. In certain embodiments R7bis fluoro. In certain embodiments R7bis haloalkyl. In certain embodiments R7bis -CF3. In certain embodiments R7bis aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R7bis phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R7bis aryl. In certain embodiments R7bis phenyl. In certain embodiments R7cis hydrogen. In certain embodiments R7cis cyano. In certain embodiments R7cis halogen. In certain embodiments R7cis fluoro. In certain embodiments R7cis haloalkyl. In certain embodiments R7cis -CF3. In certain embodiments R7cis aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R7cis phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R7cis aryl. In certain embodiments R7cis phenyl. In certain embodiments R7dis hydrogen. In certain embodiments R7dis cyano. In certain embodiments R7dis halogen. In certain embodiments R7dis fluoro. In certain embodiments R7dis haloalkyl. In certain embodiments R7dis -CF3. In certain embodiments R7dis aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R7dis phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R7dis aryl. In certain embodiments R7dis phenyl. Embodiments of R8a, R8b, R8c, and R8dIn certain embodiments R8ais R12. In certain embodiments R8bis R12. In certain embodiments R8cis R12. In certain embodiments R8dis R12. In certain embodiments R8ais R12and R8b, R8c, and R8dare hydrogen. In certain embodiments R8bis R12and R8c, R8d, and R8aare hydrogen. In certain embodiments R8cis R12and R8b, R8d, and R8aare hydrogen. In certain embodiments R8dis R12and R8b, R8c, and R8aare hydrogen. In certain embodiments R8ais cyano. In certain embodiments R8ais halogen. In certain embodiments R8ais fluoro. In certain embodiments R8ais haloalkyl. In certain embodiments R8ais -CF3. In certain embodiments R8ais aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R8ais phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R8ais aryl. In certain embodiments R8ais phenyl. In certain embodiments R8ais OR6. In certain embodiments R8ais N(R6)2. In certain embodiments R8bis cyano. In certain embodiments R8bis halogen. In certain embodiments R8bis fluoro. In certain embodiments R8bis haloalkyl. In certain embodiments R8bis -CF3. In certain embodiments R8bis aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R8bis phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R8bis aryl. In certain embodiments R8bis phenyl. In certain embodiments R8bis OR6. In certain embodiments R8bis N(R6)2. In certain embodiments R8cis cyano. In certain embodiments R8cis halogen. In certain embodiments R8cis fluoro. In certain embodiments R8cis haloalkyl. In certain embodiments R8cis -CF3. In certain embodiments R8cis aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R8cis phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R8cis aryl. In certain embodiments R8cis phenyl. In certain embodiments R8cis OR6. In certain embodiments R8cis N(R6)2. In certain embodiments R8dis cyano. In certain embodiments R8dis halogen. In certain embodiments R8dis fluoro. In certain embodiments R8dis haloalkyl. In certain embodiments R8dis -CF3. In certain embodiments R8dis aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R8dis phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R8dis aryl. In certain embodiments R8dis phenyl. In certain embodiments R8dis OR6. In certain embodiments R8dis N(R6)2.

[0032] Embodiments of R9In certain embodiments -R2-R9- and -R9-R2- are selected from: In certain embodiments -R2-R9- and -R9-R2- are selected from:

[0033] In certain embodiments -R9-R3- and -R9-R2- are selected from: In certain embodiments R9is selected from In certain embodiments R9is selected from: In certain embodiments R9is selected from: In certain embodiments R9is selected from: In certain embodiments R9is selected from: In certain embodiments R2is bond and R9is selected from alkyl, alkenyl, haloalkyl, cycloalkyl, heterocycle, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7. Embodiments of R11In certain embodiments R11is hydrogen. In certain embodiments R11is cyano. In certain embodiments R11is halogen. In certain embodiments R11is fluoro. In certain embodiments R11is haloalkyl. In certain embodiments R11is -CF3. In certain embodiments R11is naphthyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R11is naphthyl. Embodiments of R12In certain embodiments R12is cyano. In certain embodiments R12is halogen. In certain embodiments R12is fluoro. In certain embodiments R12is haloalkyl. In certain embodiments R12is -CF3. In certain embodiments R12is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R12is aryl. In certain embodiments R12is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. In certain embodiments R12is phenyl. Embodiments of R13In certain embodiments R13is cycloalkyl. In certain embodiments R13is cyclopropyl. In certain embodiments R13is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. In certain embodiments R13is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. In certain embodiments R13is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. In certain embodiments R13is aryl. In certain embodiments R13is phenyl. In certain embodiments R13is heteroaryl. In certain embodiments R13is haloalkyl. Embodiments of R15In certain embodiments R15is selected from In certain embodiments R15is selected from: In certain embodiments R15is selected from: In certain embodiments R15is selected from: In certain embodiments R15is selected from: In certain embodiments R15is selected from: In certain embodiments R15is phenyl. In certain embodiments R15is phenyl substituted with 1 substituent selected from R7. In certain embodiments R15is phenyl substituted with 2 substituents selected from R7. In certain embodiments R15is phenyl substituted with 3 substituents selected from R7. In certain embodiments R15is phenyl substituted with 4 substituents selected from R7. In certain embodiments R15is heteroaryl. In certain embodiments R15is heteroaryl substituted with 1 substituent selected from R7. In certain embodiments R15is heteroaryl substituted with 2 substituents selected from R7. In certain embodiments R15is heteroaryl substituted with 3 substituents selected from R7. In certain embodiments R15is heteroaryl substituted with 4 substituents selected from R7. Embodiments of R16In certain embodiments In certain embodiments In certain embodiments R16is . In certain embodiments In certain embodiments . In certain embodiments In certain embodiments In certain embodiments In certain embodiments In certain embodiments R16is a fused bicyclic heteroaryl. Embodiments of R17In certain embodiments R17is hydrogen. In certain embodiments R17is cyano. In certain embodiments R17is halogen. In certain embodiments R17is fluoro. In certain embodiments R17is haloalkyl. In certain embodiments R17is -CF3. In certain embodiments R17is aryl. In certain embodiments R17is phenyl. In certain embodiments one R17is hydrogen. In certain embodiments one R17is cyano. In certain embodiments one R17is halogen. In certain embodiments one R17is fluoro. In certain embodiments one R17is haloalkyl. In certain embodiments one R17is -CF3. In certain embodiments one R17is aryl. In certain embodiments one R17is phenyl. Embodiments of R18In certain embodiments R18is hydrogen. In certain embodiments R18is cyano. In certain embodiments R18is halogen. In certain embodiments R18is fluoro. In certain embodiments R18is haloalkyl. In certain embodiments R18is -CF3. In certain embodiments R18is aryl. In certain embodiments R18is phenyl. Embodiments of R19In certain embodiments one R19is hydrogen. In certain embodiments one R19is alkyl. In certain embodiments one R19is haloalkyl. In certain embodiments one R19is cycloalkyl. In certain embodiments one R19is aryl. In certain embodiments one R19is heterocycle. In certain embodiments one R19is heteroaryl. Embodiments of R27In certain embodiments R27is hydrogen. In certain embodiments R27is cyano. In certain embodiments R27is halogen. In certain embodiments R27is fluoro. In certain embodiments R27is haloalkyl. In certain embodiments R27is -CF3. In certain embodiments R27is aryl. In certain embodiments R27is phenyl. In certain embodiments one R27is hydrogen. In certain embodiments one R27is cyano. In certain embodiments one R27is halogen. In certain embodiments one R27is fluoro. In certain embodiments one R27is haloalkyl. In certain embodiments one R27is -CF3. In certain embodiments one R27is aryl. In certain embodiments one R27is phenyl. Embodiments of “alkyl” In certain embodiments “alkyl” is a C1-C10alkyl, C1-C9alkyl, C1-C8alkyl, C1-C7alkyl, C1-C6alkyl, C1-C5alkyl, C1-C4alkyl, C1-C3alkyl, or C1-C2alkyl. In certain embodiments “alkyl” has one carbon. In certain embodiments “alkyl” has two carbons. In certain embodiments “alkyl” has three carbons. In certain embodiments “alkyl” has four carbons. In certain embodiments “alkyl” has five carbons. In certain embodiments “alkyl” has six carbons. Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl. Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl. Additional non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl. Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl. Additional non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl. In an alternative embodiment the “alkyl” group is optionally substituted. In an alternative embodiment the “alkenyl” group is optionally substituted. Embodiments of “haloalkyl” In certain embodiments “haloalkyl” is a C1-C10haloalkyl, C1-C9haloalkyl, C1-C8haloalkyl, C1-C7haloalkyl, C1-C6haloalkyl, C1-C5haloalkyl, C1-C4haloalkyl, C1-C3haloalkyl, and C1- C2haloalkyl. In certain embodiments “haloalkyl” has one carbon. In certain embodiments “haloalkyl” has one carbon and one halogen. In certain embodiments “haloalkyl” has one carbon and two halogens. In certain embodiments “haloalkyl” has one carbon and three halogens. In certain embodiments “haloalkyl” has two carbons. In certain embodiments “haloalkyl” has three carbons. In certain embodiments “haloalkyl” has four carbons. In certain embodiments “haloalkyl” has five carbons. In certain embodiments “haloalkyl” has six carbons. Non-limiting examples of “haloalkyl” include: , , . Additional non-limiting examples of “haloalkyl” include: Additional non-limiting examples of “haloalkyl” include: Additional non-limiting examples of “haloalkyl” include: Embodiments of “heteroaryl” Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole. Additional non-limiting examples of 5 membered “heteroaryl” groups include: In certain embodiments “heteroaryl” is a 6 membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl). Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include: , In certain embodiments “heteroaryl” is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: In certain embodiments “heteroaryl” is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: Embodiments of “heterocycle” In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of “heterocycle” include aziridine, oxirane, thiirane, azetidine, 1,3- diazetidine, oxetane, and thietane. Additional non-limiting examples of “heterocycle” include pyrrolidine, 3-pyrroline, 2- pyrroline, pyrazolidine, and imidazolidine. Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane. Additional non-limiting examples of “heterocycle” include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine. Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocyclic ring. For example, group. However, group. Non-limiting examples of “heterocycle” also include: Additional non-limiting examples of “heterocycle” include: . Additional non-limiting examples of “heterocycle” include: Non-limiting examples of “heterocycle” also include: Non-limiting examples of “heterocycle” also include: Additional non-limiting examples of “heterocycle” include: Additional non-limiting examples of “heterocycle” include: Embodiments of “aryl” In certain embodiments “aryl” is a 6 carbon aromatic group (phenyl). In certain embodiments “aryl” is a 10 carbon aromatic group (naphthyl). In certain embodiments “aryl” is a 6 carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring. For example is an “aryl” group. However, is a “heterocycle” group. 1. In certain embodiments a compound selected from Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, and Formula VIII is provided:

[0034] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof; wherein: R1is selected from: b) a bicyclic heteroaryl or tricyclic heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R2is independently selected at each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, aryl-C(O)-NR6-, heteroaryl-C(O)-NR6-, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R3is independently selected at each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, aryl-C(O)-NR6-, heteroaryl-C(O)-NR6-, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and wherein R2and R3are selected such that a suitably stable and suitably nontoxic compound for in vivo administration in a host is achieved, and in certain embodiments, in a way that avoids undesired repetition of atoms or moieties, such as in nonlimiting examples, S, O, or a combination thereof (i.e., that would otherwise form a disulfide or peroxide bond), as well known to skilled artisans; p is independently selected from 1, 2, 3, 4, 5, and 6; R4is a heteroaryl group, where the bond to the sulfur atom is through one of the nitrogen atoms present in the cycle, and each heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R5is selected from alkyl, alkenyl, haloalkyl, cycloalkyl, naphthyl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, heteroaryl-C(O)-NR6-, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and wherein R3and R5are selected such that a suitably stable and suitably nontoxic compound for in vivo administration in a host is achieved, and in certain embodiments, in a way that avoids undesired repetition of atoms or moieties, such as in nonlimiting examples, S, O, or a combination thereof (i.e., that would otherwise form a disulfide or peroxide bond), as well known to skilled artisans; R6is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R18; R7, R7a, R7b, R7c, and R7dare independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17; R17is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6; R18is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R19, -OC(O)R19, -NR19C(O)R19, -C(O)OR19, -OC(O)OR19, -NR19C(O)OR19, -C(O)N(R19)2, -OC(O)N(R19)2, -NR19C(O)N(R19)2, -OR19, -N(R19)2, -S(O)R19, -S(O)2R19, -S(O)OR19, -S(O)2OR19, -S(O)N(R19)2, S(O)2N(R19)2, and -SR19; R19is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; R8a, R8b, R8c, and R8dare independently selected at each instance from R7and R12wherein at least one of R8a, R8b, R8c, and R8dis R12; R9is selected from alkyl, alkenyl, haloalkyl, cycloalkyl, heterocycle, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R11is selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, naphthyl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17; and R12is independently selected from halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17; and R13is selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, aryl, -OR6, -N(R6)2, -C(O)R6, -NR6C(O)R6, -C(O)N(R6)2, and -NR6C(O)N(R6)2, each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R16is a heteroaryl group, where the bond to the sulfur atom is through one of the nitrogen atoms present in the cycle, and R16is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; KRAS Recognition Moiety is a molecule which can bind to or otherwise anchors too KRAS. 2. The compound of embodiment 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 3. The compound of embodiment 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 4. The compound of embodiment 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 5. The compound of embodiment 4, wherein R13is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 6. The compound of embodiment 4, wherein R13is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 7. The compound of embodiment 4, wherein R13is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 8. The compound of embodiment 4, wherein R13is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 9. The compound of embodiment 4, wherein R13is cyclopropyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 10. The compound of embodiment 4, wherein R13is heterocycle optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 11. The compound of embodiment 4, wherein R13is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 12. The compound of any one of embodiments 5-11, wherein R16is a triazole. 13. The compound of any one of embodiments 5-12, wherein R16is . 14. The compound of any one of embodiments 5-12, wherein R16is . 15. The compound of any one of embodiments 5-11, wherein R16is . 16. The compound of any one of embodiments 5-11, wherein R16is . 17. The compound of any one of embodiments 5-12, wherein R16is . 18. The compound of any one of embodiments 5-11, wherein R16is . 19. The compound of any one of embodiments 5-11, wherein R16is . 20. The compound of any one of embodiments 5-11, wherein 21. The compound of embodiment 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 22. The compound of embodiment 21, wherein R9is selected alkyl, alkenyl, haloalkyl, cycloalkyl, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 23. The compound of embodiment 22, wherein R9is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 24. The compound of embodiment 22, wherein R9is alkenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 25. The compound of embodiment 22, wherein R9is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 26. The compound of embodiment 22, wherein R9is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 27. The compound of embodiment 22, wherein R9is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 28. The compound of embodiment 22, wherein R9is bicycle optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 29. The compound of any one of embodiments 1-20, wherein R3is bond. 30. The compound of any one of embodiments 1-20, wherein R3is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 31. The compound of any one of embodiments 1-20, wherein R3is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 32. The compound of any one of embodiments 1-20, wherein R3is alkenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 33. The compound of any one of embodiments 1-20, wherein R3is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 34. The compound of any one of embodiments 1-20, wherein R3is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 35. The compound of any one of embodiments 1-20, wherein R3is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 36. The compound of any one of embodiments 1-20, wherein R3is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 37. The compound of any one of embodiments 1-20, wherein R3is bicycle optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 38. The compound of any one of embodiments 1-37, wherein R2is selected from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 39. The compound of any one of embodiments 1-38, wherein R2is bond. 40. The compound of any one of embodiments 1-38, wherein R2is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 41. The compound of any one of embodiments 1-38, wherein R2is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 42. The compound of any one of embodiments 1-38, wherein R2is alkenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 43. The compound of any one of embodiments 1-38, wherein R2is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 44. The compound of any one of embodiments 1-38, wherein R2is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 45. The compound of any one of embodiments 1-38, wherein R2is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 46. The compound of any one of embodiments 1-38, wherein R2is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 47. The compound of any one of embodiments 1-38, wherein R2is bicycle optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 48. The compound of any one of embodiments 1-47, wherein R2is not substituted. 49. The compound of any one of embodiments 1-47, wherein R2is substituted with 1 substituent selected from R7. 50. The compound of any one of embodiments 1-47, wherein R2is substituted with 2 substituents selected from R7. 51. The compound of any one of embodiments 1-47, wherein R2is substituted with 3 substituents selected from R7. 52. The compound of embodiment 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 53. The compound of embodiment 1 wherein the compound is Formula: (III); or a pharmaceutically acceptable salt thereof. 54. The compound of embodiment 1 wherein the compound is Formula: (IV); or a pharmaceutically acceptable salt thereof. 55. The compound of embodiment 1 wherein the compound is Formula: or a pharmaceutically acceptable salt thereof. 56. The compound of any one of embodiments 52-55, wherein R3is bond. 57. The compound of any one of embodiments 52-55, wherein R3is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 58. The compound of any one of embodiments 52-55, wherein R3is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 59. The compound of any one of embodiments 52-55, wherein R3is alkenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 60. The compound of any one of embodiments 52-55, wherein R3is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 61. The compound of any one of embodiments 52-55, wherein R3is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 62. The compound of any one of embodiments 52-55, wherein R3is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 63. The compound of any one of embodiments 52-55, wherein R3is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 64. The compound of any one of embodiments 52-55, wherein R3is bicycle optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 65. The compound of any one of embodiments 1-3, or 21-64, wherein R1and R4are . 66. The compound of any one of embodiments 1-3, or 21-64, wherein R1and R4are . 67. The compound of any one of embodiments 1-3, or 21-64, wherein R1and R4are . 68. The compound of any one of embodiments 1-3, or 21-64, wherein R1and R4are . 69. The compound of any one of embodiments 1-3, or 21-64, wherein R1and R4are . 70. The compound of any one of embodiments 1-3, or 21-64, wherein R1and R4are . 71. The compound of any one of embodiments 1-3, or 21-64, wherein R1and R4are . 72. The compound of any one of embodiments 1-3, or 21-64, wherein R1and R4are . 73. The compound of any one of embodiments 1-3, or 21-64, wherein R1and R4are a bicyclic heteroaryl which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 74. The compound of any one of embodiments 1-3, or 21-64, wherein R4is a heteroaryl group, where the bond to the sulfur atom is through the nitrogen present in the cycle, and each heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 75. The compound of any one of embodiments 1-74, wherein R6is independently selected at each instance from alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 76. The compound of embodiment 75, wherein R6is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 77. The compound of embodiment 75, wherein R6is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 78. The compound of embodiment 75, wherein R6is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 79. The compound of embodiment 75, wherein R6is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 80. The compound of embodiment 75, wherein R6is heterocycle optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 81. The compound of embodiment 75, wherein R6is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 82. The compound of any one of embodiments 75-81, wherein R6is not substituted with R18. 83. The compound of any one of embodiments 75-81, wherein R6is substituted with 1 substituent selected from R18. 84. The compound of any one of embodiments 75-81, wherein R6is substituted with 2 substituents independently selected from R18. 85. The compound of any one of embodiments 75-81, wherein R6is substituted with 3 substituents independently selected from R18. 86. The compound of any one of embodiments 1-85, wherein R7, R7a, R7b, R7c, and R7dare independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, and nitro, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R1787. The compound of any one of embodiments 1-86, wherein one of R7, R7a, R7b, R7c, and R7dis alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 88. The compound of any one of embodiments 1-86, wherein one of R7, R7a, R7b, R7c, and R7dis haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 89. The compound of any one of embodiments 1-86, wherein one of R7, R7a, R7b, R7c, and R7dis phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 90. The compound of any one of embodiments 1-86, wherein one of R7, R7a, R7b, R7c, and R7dis heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 91. The compound of any one of embodiments 1-86, wherein one of R7, R7a, R7b, R7c, and R7dis haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 92. The compound of any one of embodiments 1-86, wherein one of R7, R7a, R7b, R7c, and R7dis heterocycle optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 93. The compound of any one of embodiments 1-86, wherein one of R7, R7a, R7b, R7c, and R7dis cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 94. The compound of any one of embodiments 87-93, wherein R7, R7a, R7b, R7c, and R7dare not substituted. 95. The compound of any one of embodiments 87-93, wherein R7, R7a, R7b, R7c, and R7dare optionally substituted with 1 or 2 substituents selected from R17. 96. The compound of any one of embodiments 1-86, wherein one of R7, R7a, R7b, R7c, and R7dis halogen. 97. The compound of any one of embodiments 1-86, wherein one of R7, R7a, R7b, R7c, and R7dis -OR6. 98. The compound of any one of embodiments 1-86, wherein one of R7, R7a, R7b, R7c, and R7dis H. 99. The compound of any one of embodiments 1-86, wherein one of R7, R7a, R7b, R7c, and R7dis cyano. 100. The compound of any one of embodiments 1-86, wherein one of R7, R7a, R7b, R7c, and R7dis nitro. 101. The compound of any one of embodiments 1-100, wherein R17is selected in each instance from halogen, alkyl, haloalkyl, alkenyl, and cyano. 102. In certain embodiments a pharmaceutical composition comprising a compound of any one of embodiments 1-101 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided. 103. In certain embodiments a method of treating a disorder mediated by KRAS comprising administering an effective amount of a compound of any one of embodiments 1-102 or a pharmaceutically acceptable salt thereof to a patient in need thereof is provided. 104. The method of embodiment 103 wherein the patient is a human. In other embodiments a compound, pharmaceutical composition, or method is provided as described below: 1. A compound of Formula:

[0035] or a pharmaceutically acceptable salt thereof; wherein: R1is selected from: b) a bicyclic heteroaryl or tricyclic heteroaryl, optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R2is a bivalent moiety independently selected at each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, aryl-C(O)-NR6-, heteroaryl-C(O)-NR6-, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R3is a bivalent moiety independently selected at each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -S-alkyl-, -O-alkyl-, -NR6-alkyl-, -alkyl-C(O)-, -alkyl-C(O)-alkyl-, -alkyl-C(O)-NR6-alkyl-, -C(O)-NR6-alkyl-, -alkyl-C(O)-NR6-, -alkyl-C(O)-O-alkyl-, -C(O)-O-alkyl-, -alkyl-C(O)-O-, -C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and wherein R2and R3are selected such that a suitably stable and suitably nontoxic compound for in vivo administration in a host is achieved; each p is independently selected from 1, 2, 3, 4, 5, and 6; R4is a heteroaryl group, where the bond to the sulfur atom is through one of the nitrogen atoms present in the cycle, and each heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R5is a bivalent moiety selected from alkyl, alkenyl, haloalkyl, cycloalkyl, naphthyl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, heteroaryl-C(O)-NR6-, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and wherein R3and R5are selected such that a suitably stable and suitably nontoxic compound for in vivo administration in a host is achieved; R6is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R18; R7, R7a, R7b, R7c, and R7dare independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17; R15is a bivalent moiety selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -S-alkyl-, -O-alkyl-, -NR6-alkyl-, -alkyl-C(O)-, -alkyl-C(O)-alkyl-, -alkyl-C(O)-NR6-alkyl-, -C(O)-NR6-alkyl-, -alkyl-C(O)-NR6-, -alkyl-C(O)-O-alkyl-, -C(O)-O-alkyl-, -alkyl-C(O)-O-, -C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R7; R17is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6; R18is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R19, -OC(O)R19, -NR19C(O)R19, -C(O)OR19, -OC(O)OR19, -NR19C(O)OR19, -C(O)N(R19)2, -OC(O)N(R19)2, -NR19C(O)N(R19)2, -OR19, -N(R19)2, -S(O)R19, -S(O)2R19, -S(O)OR19, -S(O)2OR19, -S(O)N(R19)2, S(O)2N(R19)2, and -SR19; R19is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; R8a, R8b, R8c, and R8dare independently selected at each instance from R7and R12wherein at least one of R8a, R8b, R8c, and R8dis R12; R9is a bivalent moiety selected from alkyl, alkenyl, haloalkyl, cycloalkyl, heterocycle, -alkyl-C(O)-NR6-alkyl-, -C(O)-NR6-alkyl-, -alkyl-C(O)-NR6-, -alkyl-C(O)-O-alkyl-, -C(O)-O-alkyl-, -alkyl-C(O)-O-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R11is selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, naphthyl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17; and R12is independently selected from halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17; R13is selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, aryl, -OR6, -N(R6)2, -C(O)R6, -NR6C(O)R6, -C(O)N(R6)2, and -NR6C(O)N(R6)2, each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R16is a heteroaryl group, where the bond to the sulfur atom is through one of the nitrogen atoms present in the cycle, and R16is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and KRAS Recognition Moiety is a molecule which can bind to or otherwise anchors too KRAS. 2. A compound of Formula:

[0036] or a pharmaceutically acceptable salt thereof; wherein: R1is selected from: b) a bicyclic heteroaryl or tricyclic heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R2is a bivalent moiety independently selected at each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, aryl-C(O)-NR6-, heteroaryl-C(O)-NR6-, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R3is a bivalent moiety independently selected at each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, aryl-C(O)-NR6-, heteroaryl-C(O)-NR6-, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and wherein R2and R3are selected such that a suitably stable and suitably nontoxic compound for in vivo administration in a host is achieved; p is independently selected from 1, 2, 3, 4, 5, and 6; R4is a heteroaryl group, where the bond to the sulfur atom is through one of the nitrogen atoms present in the cycle, and each heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R5is a bivalent moiety selected from alkyl, alkenyl, haloalkyl, cycloalkyl, naphthyl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, heteroaryl-C(O)-NR6-, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and wherein R3and R5are selected such that a suitably stable and suitably nontoxic compound for in vivo administration in a host is achieved; R6is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R18; R7, R7a, R7b, R7c, and R7dare independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17; R17is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6; R18is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R19, -OC(O)R19, -NR19C(O)R19, -C(O)OR19, -OC(O)OR19, -NR19C(O)OR19, -C(O)N(R19)2, -OC(O)N(R19)2, -NR19C(O)N(R19)2, -OR19, -N(R19)2, -S(O)R19, -S(O)2R19, -S(O)OR19, -S(O)2OR19, -S(O)N(R19)2, S(O)2N(R19)2, and -SR19; R19is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; R8a, R8b, R8c, and R8dare independently selected at each instance from R7and R12wherein at least one of R8a, R8b, R8c, and R8dis R12; R9is a bivalent moiety selected from alkyl, alkenyl, haloalkyl, cycloalkyl, heterocycle, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R11is selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, naphthyl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17; and R12is independently selected from halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17; and R13is selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, aryl, -OR6, -N(R6)2, -C(O)R6, -NR6C(O)R6, -C(O)N(R6)2, and -NR6C(O)N(R6)2, each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R16is a heteroaryl group, where the bond to the sulfur atom is through one of the nitrogen atoms present in the cycle, and R16is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; KRAS Recognition Moiety is a molecule which can bind to or otherwise anchors to KRAS. 3. The compound of embodiment 1 or embodiment 2, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 4. The compound of embodiment 1 or embodiment 2, wherein the compound is of Formula: , or a pharmaceutically acceptable salt thereof. 5. The compound of embodiment 1 or embodiment 2, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 6. The compound of embodiment 5, wherein R13is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 7. The compound of embodiment 5, wherein R13is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 8. The compound of embodiment 5, wherein R13is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 9. The compound of embodiment 5, wherein R13is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 10. The compound of embodiment 5, wherein R13is cyclopropyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 11. The compound of embodiment 5, wherein R13is heterocycle optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 12. The compound of embodiment 5, wherein R13is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 13. The compound of any one of embodiments 5-12, wherein R16is a triazole. 14. The compound of any one of embodiments 5-12, wherein R16is . 15. The compound of any one of embodiments 5-12, wherein R16is . 16. The compound of any one of embodiments 5-12, wherein R16is . 17. The compound of any one of embodiments 5-12, wherein R16is . 18. The compound of any one of embodiments 5-12, wherein R16is . 19. The compound of any one of embodiments 5-12, wherein R16is . 20. The compound of any one of embodiments 5-12, wherein R16is . 21. The compound of any one of embodiments 5-12, wherein 22. The compound of embodiment 1 or 2, wherein the compound is of Formula: , or a pharmaceutically acceptable salt thereof. 23. The compound of embodiment 22, wherein R9is selected from alkyl, alkenyl, haloalkyl, cycloalkyl, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 24. The compound of embodiment 22, wherein R9is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 25. The compound of embodiment 22, wherein R9is alkenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 26. The compound of embodiment 22, wherein R9is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 27. The compound of embodiment 22, wherein R9is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 28. The compound of embodiment 22, wherein R9is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 29. The compound of embodiment 22, wherein R9is bicycle optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 30. The compound of any one of embodiments 1-29, wherein R3is bond. 31. The compound of any one of embodiments 1-29, wherein R3is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 32. The compound of any one of embodiments 1-29, wherein R3is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 33. The compound of any one of embodiments 1-29, wherein R3is alkenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 34. The compound of any one of embodiments 1-29, wherein R3is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 35. The compound of any one of embodiments 1-29, wherein R3is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 36. The compound of any one of embodiments 1-29, wherein R3is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 37. The compound of any one of embodiments 1-29, wherein R3is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 38. The compound of any one of embodiments 1-29, wherein R3is bicycle optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 39. The compound of any one of embodiments 1-38, wherein R2is selected from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 40. The compound of any one of embodiments 1-38, wherein R2is bond. 41. The compound of any one of embodiments 1-38, wherein R2is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 42. The compound of any one of embodiments 1-38, wherein R2is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 43. The compound of any one of embodiments 1-38, wherein R2is alkenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 44. The compound of any one of embodiments 1-38, wherein R2is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 45. The compound of any one of embodiments 1-38, wherein R2is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 46. The compound of any one of embodiments 1-38, wherein R2is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 47. The compound of any one of embodiments 1-38, wherein R2is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 48. The compound of any one of embodiments 1-38, wherein R2is bicycle optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 49. The compound of any one of embodiments 1-48, wherein R2is not substituted. 50. The compound of any one of embodiments 1-48, wherein R2is substituted with 1 substituent selected from R7. 51. The compound of any one of embodiments 1-48, wherein R2is substituted with 2 substituents selected from R7. 52. The compound of any one of embodiments 1-48, wherein R2is substituted with 3 substituents selected from R7. 53. The compound of embodiment 1, wherein the compound is of Formula: , or a pharmaceutically acceptable salt thereof. 54. The compound of embodiment 1, wherein the compound is Formula: or a pharmaceutically acceptable salt thereof. 55. A compound of Formula or a pharmaceutically acceptable salt thereof; wherein: R2is independently selected at each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -(CH2)p-C(O)-, -(CH2)p-C(O)-NR6-, –(CH2CH2O)p–, –(OCH2CH2)p–, -C(O)-, -NR6C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, aryl-C(O)-NR6-, heteroaryl-C(O)-NR6-, bicycle, tricycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R3is independently selected at each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -S-alkyl-, -O-alkyl-, -NR6-alkyl-, -alkyl-C(O)-, -alkyl-C(O)-alkyl-, -alkyl-C(O)-NR6-alkyl-, -C(O)-NR6-alkyl-, -alkyl-C(O)-NR6-, -alkyl-C(O)-O-alkyl-, -C(O)-O-alkyl-, -alkyl-C(O)-O-, -C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and wherein R2and R3are selected such that a suitably stable and suitably nontoxic compound for in vivo administration in a host is achieved; each p is independently selected from 1, 2, 3, 4, 5, and 6; R4is a heteroaryl group, where the bond to the sulfur atom is through one of the nitrogen atoms present in the cycle, and each heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R6is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R18; R7is independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17; R15is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, -S-, -O-, -NR6-, -S-alkyl-, -O-alkyl-, -NR6-alkyl-, -alkyl-C(O)-, -alkyl-C(O)-alkyl-, -alkyl-C(O)-NR6-alkyl-, -C(O)-NR6-alkyl-, -alkyl-C(O)-NR6-, -alkyl-C(O)-O-alkyl-, -C(O)-O-alkyl-, -alkyl-C(O)-O-, -C(O)-, -NR6C(O)NR6-, -C(O)NR6-, -OC(O)NR6-, -NR6S(O)2NR6-, -S(O)2NR6-, bicycle, tricycle, and heteroaryl, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R7; R17is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6; R18is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R19, -OC(O)R19, -NR19C(O)R19, -C(O)OR19, -OC(O)OR19, -NR19C(O)OR19, -C(O)N(R19)2, -OC(O)N(R19)2, -NR19C(O)N(R19)2, -OR19, -N(R19)2, -S(O)R19, -S(O)2R19, -S(O)OR19, -S(O)2OR19, -S(O)N(R19)2, S(O)2N(R19)2, and -SR19; R19is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; and KRAS Recognition Moiety is a molecule which can bind to or otherwise anchors too KRAS. 56. The compound of embodiment 1, wherein the compound is Formula: ; or a pharmaceutically acceptable salt thereof. 57. The compound of any one of embodiments 53-56, wherein R3is bond. 58. The compound of any one of embodiments 53-56, wherein R3is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 59. The compound of any one of embodiments 53-56, wherein R3is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 60. The compound of any one of embodiments 53-56, wherein R3is alkenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 61. The compound of any one of embodiments 53-56, wherein R3is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 62. The compound of any one of embodiments 53-56, wherein R3is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 63. The compound of any one of embodiments 53-56, wherein R3is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 64. The compound of any one of embodiments 53-56, wherein R3is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 65. The compound of any one of embodiments 53-56, wherein R3is bicycle optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 66. The compound of any one of embodiments 1-4 or 22-65, wherein R1and R4are . 67. The compound of any one of embodiments 1-4 or 22-65, wherein R1and R4are . 68. The compound of any one of embodiments 1-4 or 22-65, wherein R1and R4are 69. The compound of any one of embodiments 1-4 or 22-65, wherein R1and R4are . 70. The compound of any one of embodiments 1-4 or 22-65, wherein R1and R4are . 71. The compound of any one of embodiments 1-4 or 22-65, wherein R1and R4are . 72. The compound of any one of embodiments 1-4 or 22-65, wherein R1and R4are . 73. The compound of any one of embodiments 1-4 or 22-65, wherein R1and R4are . 74. The compound of any one of embodiments 1-4 or 22-65, wherein R1and R4are a bicyclic heteroaryl which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 75. The compound of any one of embodiments 1-4 or 22-65, wherein R4is a heteroaryl group, where the bond to the sulfur atom is through the nitrogen present in the cycle, and each heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R7. 76. The compound of any one of embodiments 1-75, wherein R6is independently selected at each instance from alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 77. The compound of any one of embodiments 1-75, wherein R6is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 78. The compound of any one of embodiments 1-75, wherein R6is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 79. The compound of any one of embodiments 1-75, wherein R6is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 80. The compound of any one of embodiments 1-75, wherein R6is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 81. The compound of any one of embodiments 1-75, wherein R6is heterocycle optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 82. The compound of any one of embodiments 1-75, wherein R6is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R18. 83. The compound of any one of embodiments 76-82, wherein R6is not substituted with R18. 84. The compound of any one of embodiments 76-82, wherein R6is substituted with 1 substituent selected from R18. 85. The compound of any one of embodiments 76-82, wherein R6is substituted with 2 substituents independently selected from R18. 86. The compound of any one of embodiments 76-82, wherein R6is substituted with 3 substituents independently selected from R18. 87. The compound of any one of embodiments 1-86, wherein R7, R7a, R7b, R7c, and R7dare independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, and nitro, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 88. The compound of any one of embodiments 1-87, wherein one of R7, R7a, R7b, R7c, and R7dis alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 89. The compound of any one of embodiments 1-87, wherein one of R7, R7a, R7b, R7c, and R7dis haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 90. The compound of any one of embodiments 1-87, wherein one of R7, R7a, R7b, R7c, and R7dis phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 91. The compound of any one of embodiments 1-87, wherein one of R7, R7a, R7b, R7c, and R7dis heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 92. The compound of any one of embodiments 1-87, wherein one of R7, R7a, R7b, R7c, and R7dis haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 93. The compound of any one of embodiments 1-87, wherein one of R7, R7a, R7b, R7c, and R7dis heterocycle optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 94. The compound of any one of embodiments 1-87, wherein one of R7, R7a, R7b, R7c, and R7dis cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17. 95. The compound of any one of embodiments 87-94, wherein R7, R7a, R7b, R7c, and R7dare not substituted. 96. The compound of any one of embodiments 87-94, wherein R7, R7a, R7b, R7c, and R7dare optionally substituted with 1 or 2 substituents selected from R17. 97. The compound of any one of embodiments 1-87, wherein one of R7, R7a, R7b, R7c, and R7dis halogen. 98. The compound of any one of embodiments 1-87, wherein one of R7, R7a, R7b, R7c, and R7dis -OR6. 99. The compound of any one of embodiments 1-87, wherein one of R7, R7a, R7b, R7c, and R7dis H. 100. The compound of any one of embodiments 1-87, wherein one of R7, R7a, R7b, R7c, and R7dis cyano. 101. The compound of any one of embodiments 1-87, wherein one of R7, R7a, R7b, R7c, and R7dis nitro. 102. The compound of any one of embodiments 1-101, wherein R17is selected in each instance from halogen, alkyl, haloalkyl, alkenyl, and cyano. 103. A compound selected from Table 1. 104. A compound selected from Table 2. 105. A pharmaceutical composition comprising a compound of any one of embodiments 1-104 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 106. The pharmaceutical composition of embodiment 105, wherein the composition is suitable for oral delivery. 107. The pharmaceutical composition of embodiment 105, wherein the composition is suitable for intravenous delivery. 108. The pharmaceutical composition of embodiment 105, wherein the composition is suitable for parental delivery. 109. A method of treating a disorder mediated by KRAS comprising administering an effective amount of a compound of any one of embodiments 1-104 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of embodiments 105-108 to a patient in need thereof. 110. The method of embodiment 109, wherein the patient is a human. 111. The method of embodiment 109 or 110, wherein the disorder is a cancer. 112. The method of embodiment 111, wherein the cancer is a solid cancer. 113. The method of embodiment 111, wherein the cancer is a hematological cancer. 114. The method of embodiment 111, wherein the disorder is lung cancer. 115. The method of embodiment 111, wherein the disorder is pancreatic cancer. 116. The method of embodiment 111, wherein the disorder is colorectal cancer. 117. The method of embodiment 111, wherein the disorder is ovarian or endometrial cancer. 118. The method of embodiment 111, wherein the disorder is breast cancer. 119. The method of any one of embodiments 111-119, wherein the cancer is metastatic. 120. The method of any one of embodiments 111-120, wherein the cancer is relapsed. 121. The method of any one of embodiments 111-121, wherein the cancer is refractory. 122. The method of embodiment 109 or 110, wherein the disorder is a tumor. 123. The method any one of embodiments 109-122, wherein the disorder is mediated by mutant KRAS. 124. Use of a compound of any one of embodiments 1-104 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of embodiments 105-108 to treat a KRAS mediated disorder in a patient in need thereof. 125. Use of a compound of any one of embodiments 1-104 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of embodiments 105-108 in the manufacture of a medicament to treat a KRAS mediated disorder in a patient in need thereof. 126. The use of embodiment 124 or 125, wherein the patient is a human. 127. The use of any one of embodiments 124-126, wherein the disorder is a cancer. 128. The use of embodiment 127, wherein the cancer is a solid cancer. 129. The use of embodiment 127, wherein the cancer is a hematological cancer. 130. The use of embodiment 127, wherein the disorder is lung cancer. 131. The use of embodiment 127, wherein the disorder is pancreatic cancer. 132. The use of embodiment 127, wherein the disorder is colorectal cancer. 133. The use of embodiment 127, wherein the disorder is breast cancer. 134. The use of embodiment 127, wherein the disorder is ovarian or endometrial cancer. 135. The use of any one of embodiments 127-134, wherein the cancer is metastatic. 136. The use of any one of embodiments 127-135, wherein the cancer is relapsed. 137. The use of any one of embodiments 127-136, wherein the cancer is refractory. 138. The use of any one of embodiments 124-126, wherein the disorder is a tumor. 139. The use of any one of embodiments 125-138, wherein the disorder is mediated by mutant KRAS. 140. A compound of any one of embodiments 1-104 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of embodiments 105-108 for use in the treatment of a KRAS mediated disorder in a patient in need thereof. 141. The compound or pharmaceutical composition of embodiment 140, wherein the patient is a human. 142. The compound or pharmaceutical composition of embodiment 140 or 141, wherein the disorder is a cancer. 143. The compound or pharmaceutical composition of embodiment 142, wherein the cancer is a solid cancer. 144. The compound or pharmaceutical composition of embodiment 142, wherein the cancer is a hematological cancer. 145. The compound or pharmaceutical composition of embodiment 142, wherein the disorder is lung cancer. 146. The compound or pharmaceutical composition of embodiment 142, wherein the disorder is pancreatic cancer. 147. The compound or pharmaceutical composition of embodiment 142, wherein the disorder is breast cancer. 148. The compound or pharmaceutical composition of embodiment 142, wherein the disorder is ovarian or endometrial cancer. 149. The compound or pharmaceutical composition of embodiment 142, wherein the disorder is fallopian tube cancer. 150. The compound or pharmaceutical composition of any one of embodiments 142- 149, wherein the cancer is metastatic. 151. The compound or pharmaceutical composition of any one of embodiments 142- 150, wherein the cancer is relapsed. 152. The compound or pharmaceutical composition of any one of embodiments 142- 151, wherein the cancer is refractory. 153. The compound or pharmaceutical composition of embodiment 140 or 141, wherein the disorder is a tumor. 154. The compound or pharmaceutical composition of any one of embodiments 140- 153, wherein the disorder is mediated by mutant KRAS. Additional Heteroaryl Sulfonyl Compounds of the Present Invention In certain embodiments the heteroaryl sulfonyl compound of the present invention is selected from: Į In certain embodiments the heteroaryl sulfonyl compound of the present invention is selected from: Linker In certain embodiments Linker is selected from:

[0037] 1. In certain embodiments X1is alkyl; 2. In certain embodiments X1is cycloalkyl; 3. In certain embodiments X1is heterocycle; 4. In certain embodiments X1is heterocycle; 5. In certain embodiments X1is aryl; 6. In certain embodiments X1is bicycle; 7. In certain embodiments X1is tricycle; 8. In certain embodiments X1is -C(O)-; 9. In certain embodiments X1is -C(O)-NR6-; 10. In certain embodiments X1is -(CH2CH2O)P-; 11. In certain embodiments X1is -S(O)2NR6-; 12. In certain embodiments X1is -S(O)2O-; 13. In certain embodiments X1is –CH2-; 14. In certain embodiments X1is -CH2CH2-; 15. Any one of embodiments 1-14, wherein X2is -O-; 16. Any one of embodiments 1-14, wherein X2is -NR6-; 17. Any one of embodiments 1-14, wherein X2is -S-; 18. Any one of embodiments 1-14, wherein X2is alkyl; 19. Any one of embodiments 1-14, wherein X2is cycloalkyl; 20. Any one of embodiments 1-14, wherein X2is heterocycle; 21. Any one of embodiments 1-14, wherein X2is aryl; 22. Any one of embodiments 1-14, wherein X2is bicycle; 23. Any one of embodiments 1-14, wherein X2is -C(O)-; 24. Any one of embodiments 1-14, wherein X2is -C(O)-NR6-; 25. Any one of embodiments 1-14, wherein X2is -(CH2CH2O)P-; 26. Any one of embodiments 1-14, wherein X2is -S(O)2NR6-; 27. Any one of embodiments 1-14, wherein X2is -S(O)2O-; 28. Any one of embodiments 1-14, wherein X2is –CH2-; 29. Any one of embodiments 1-14, wherein X2is -CH2CH2-; 30. Any one of embodiments 1-14, wherein X2is bond; 31. Any one of embodiments 1-14, wherein X2is ; 32. Any one of embodiments 1-14, wherein X2is ; 33. Any one of embodiments 1-14, wherein X2is ; 34. Any one of embodiments 1-14, wherein X2is ; 35. Any one of embodiments 1-14, wherein X2is ; 36. Any one of embodiments 1-14, wherein X2is 37. Any one of embodiments 1-14, wherein X2is 38. Any one of embodiments 1-14, wherein X2is 39. Any one of embodiments 1-14, wherein X2is 40. Any one of embodiments 1-14, wherein X2is ; 41. Any one of embodiments 1-14, wherein X2is ; 42. Any one of embodiments 1-14, wherein X2is ; 43. Any one of embodiments 1-14, wherein X2is ; 44. Any one of embodiments 1-14, wherein X2is ; 45. Any one of embodiments 1-14, wherein X2is ; 2 46. Any one of embodiments 1-14, wherein X is ; 47. Any one of embodiments 1-14, wherein X2is ; 48. Any one of embodiments 1-14, wherein X2is ; 49. Any one of embodiments 1-14, wherein X2is ; 50. Any one of embodiments 1-14, wherein 51. Any one of embodiments 1-14, wherein 52. Any one of embodiments 1-14, wherein X2is 53. Any one of embodiments 1-14, wherein X2is ; 54. Any one of embodiments 1-14, wherein X2is 55. Any one of embodiments 1-14, wherein X2is 56. Any one of embodiments 1-14, wherein X2is 57. Any one of embodiments 1-14, wherein X2is 58. Any one of embodiments 1-14, wherein X2is 59. Any one of embodiments 1-14, wherein X2is 60. Any one of embodiments 1-14, wherein X2is 61. Any one of embodiments 1-14, wherein X2is 62. Any one of embodiments 1-14, wherein X2is 63. Any one of embodiments 1-14, wherein X2is 64. Any one of embodiments 1-14, wherein X2is 65. Any one of embodiments 1-14, wherein X2is 66. Any one of embodiments 1-65, wherein X3is alkyl; 67. Any one of embodiments 1-65, wherein X3is cycloalkyl; 68. Any one of embodiments 1-65, wherein X3is heterocycle; 69. Any one of embodiments 1-65, wherein X3is heterocycle; 70. Any one of embodiments 1-65, wherein X3is aryl; 71. Any one of embodiments 1-65, wherein X3is bicycle; 72. Any one of embodiments 1-65, wherein X3is tricycle; 73. Any one of embodiments 1-65, wherein X3is -C(O)-; 74. Any one of embodiments 1-65, wherein X3is -C(O)-NR6-; 75. Any one of embodiments 1-65, wherein X3is -(CH2CH2O)P-; 76. Any one of embodiments 1-65, wherein X3is -S(O)2NR6-; 77. Any one of embodiments 1-65, wherein X3is -S(O)2O-; 78. Any one of embodiments 1-65, wherein X3is –CH2-; 79. Any one of embodiments 1-65, wherein X3is -CH2CH2-; 80. Any one of embodiments 1-65, wherein X3is -NR6-; 81. Any one of embodiments 1-65, wherein X3is bond 82. Any one of embodiments 1-65, wherein X3is 83. Any one of embodiments 1-65, wherein X3is 84. Any one of embodiments 1-65, wherein X3is 85. Any one of embodiments 1-65, wherein X3is 86. Any one of embodiments 1-65, wherein X3is 87. Any one of embodiments 1-65, wherein X3is 88. Any one of embodiments 1-65, wherein X3is 89. Any one of embodiments 1-65, wherein X3is 90. Any one of embodiments 1-65, wherein X3is 91. Any one of embodiments 1-65, wherein X3is 92. Any one of embodiments 1-65, wherein X3is 93. Any one of embodiments 1-65, wherein X3is 94. Any one of embodiments 1-65, wherein X3is 95. Any one of embodiments 1-65, wherein X3is ; 96. Any one of embodiments 1-65, wherein X3is ; 3 97. Any one of embodiments 1-65, wherein X is ; 98. Any one of embodiments 1-65, wherein X3is ; 99. Any one of embodiments 1-65, wherein X3is ; 100. Any one of embodiments 1-65, wherein X3is ; 101. Any one of embodiments 1-65, wherein 102. Any one of embodiments 1-65, wherein 103. Any one of embodiments 1-65, wherein 104. Any one of embodiments 1-65, wherein 105. Any one of embodiments 1-65, wherein X3is 106. Any one of embodiments 1-65, wherein X3is 107. Any one of embodiments 1-65, wherein X3is 108. Any one of embodiments 1-65, wherein X3is 109. Any one of embodiments 1-65, wherein X3is 110. Any one of embodiments 1-65, wherein X3is 111. Any one of embodiments 1-65, wherein X3is 112. Any one of embodiments 1-65, wherein X3is 113. Any one of embodiments 1-65, wherein X3is 114. Any one of embodiments 1-65, wherein X3is 115. Any one of embodiments 1-65, wherein X3is 116. Any one of embodiments 1-65, wherein X3is 117. Any one of embodiments 1-116, wherein X4is -O-; 118. Any one of embodiments 1-116, wherein X4is -NR6-; 119. Any one of embodiments 1-116, wherein X4is -S-; 120. Any one of embodiments 1-116, wherein X4is alkyl; 121. Any one of embodiments 1-116, wherein X4is cycloalkyl; 122. Any one of embodiments 1-116, wherein X4is heterocycle; 123. Any one of embodiments 1-116, wherein X4is aryl; 124. Any one of embodiments 1-116, wherein X4is bicycle; 125. Any one of embodiments 1-116, wherein X4is -C(O)-; 126. Any one of embodiments 1-116, wherein X4is -C(O)-NR6-; 127. Any one of embodiments 1-116, wherein X4is -(CH2CH2O)P-; 128. Any one of embodiments 1-116, wherein X4is -S(O)2NR6-; 129. Any one of embodiments 1-116, wherein X4is -S(O)2O-; 130. Any one of embodiments 1-116, wherein X4is –CH2-; 131. Any one of embodiments 1-116, wherein X4is -CH2CH2-; 132. Any one of embodiments 1-116, wherein X4is bond; 133. Any one of embodiments 1-116, wherein X4is 134. Any one of embodiments 1-116, wherein X4is ; 135. Any one of embodiments 1-116, wherein X4is ; 136. Any one of embodiments 1-116, wherein X4is ; 137. Any one of embodiments 1-116, wherein X4is ; 138. Any one of embodiments 1-116, wherein X4is ; 139. Any one of embodiments 1-116, wherein X4is ; 140. Any one of embodiments 1-116, wherein X4is ; 141. Any one of embodiments 1-116, wherein X4is 142. Any one of embodiments 1-116, wherein X4is ; 143. Any one of embodiments 1-116, wherein X4is ; 144. Any one of embodiments 1-116, wherein X4is ; 145. Any one of embodiments 1-116, wherein X4is ; 146. Any one of embodiments 1-116, wherein X4is ; 147. Any one of embodiments 1-116, wherein X4is ; 148. Any one of embodiments 1-116, wherein X4is ; 149. Any one of embodiments 1-116, wherein X4is ; 150. Any one of embodiments 1-116, wherein X4is 151. Any one of embodiments 1-116, wherein X4is 152. Any one of embodiments 1-116, wherein . Any one of embodiments 1-116, wherein 154. Any one of embodiments 1-116, wherein 155. Any one of embodiments 1-116, wherein 156. Any one of embodiments 1-116, wherein X4is 157. Any one of embodiments 1-116, wherein 158. Any one of embodiments 1-116, wherein 159. Any one of embodiments 1-116, wherein 160. Any one of embodiments 1-116, wherein 161. Any one of embodiments 1-116, wherein 162. Any one of embodiments 1-116, wherein 163. Any one of embodiments 1-116, wherein 164. Any one of embodiments 1-116, wherein X4is ; 165. Any one of embodiments 1-116, wherein X4is ; 166. Any one of embodiments 1-116, wherein X4is 167. Any one of embodiments 1-116, wherein X4is ; 168. Any one of embodiments 1-116, wherein 169. Any one of embodiments 1-116, wherein X4is 170. Any one of embodiments 1-116, wherein X4is ; 171. Any one of embodiments 1-116, wherein X4is ; 172. Any one of embodiments 1-116, wherein X4is ; 173. Any one of embodiments 1-116, wherein X4is ; 174. Any one of embodiments 1-116, wherein X4is ; 175. Any one of embodiments 1-116, wherein X4is ; 176. Any one of embodiments 1-116, wherein X4is ; 177. Any one of embodiments 1-116, wherein 178. Any one of embodiments 1-116, wherein 179. Any one of embodiments 1-116, wherein X4is 180. Any one of embodiments 1-116, wherein X4is ; 181. Any one of embodiments 1-116, wherein X4is 182. Any one of embodiments 1-116, wherein X4is ; 183. Any one of embodiments 1-116, wherein 184. Any one of embodiments 1-116, wherein 185. Any one of embodiments 1-116, wherein 186. Any one of embodiments 1-185, wherein X5is alkyl; 187. Any one of embodiments 1-185, wherein X5is cycloalkyl; 188. Any one of embodiments 1-185, wherein X5is heterocycle; 189. Any one of embodiments 1-185, wherein X5is aryl; 190. Any one of embodiments 1-185, wherein X5is bicycle; 191. Any one of embodiments 1-185, wherein X5is -C(O)-; 192. Any one of embodiments 1-185, wherein X5is -C(O)-NR6-; 193. Any one of embodiments 1-185, wherein X5is -(CH2CH2O)P-; 194. Any one of embodiments 1-185, wherein X5is -S(O)2NR6-; 195. Any one of embodiments 1-185, wherein X5is -S(O)2O-; 196. Any one of embodiments 1-185, wherein X5is –CH2-; 197. Any one of embodiments 1-185, wherein X5is -CH2CH2-; 198. Any one of embodiments 1-185, wherein X5is bond; 199. Any one of embodiments 1-185, wherein X5is ; 200. Any one of embodiments 1-185, wherein X5is ; 201. Any one of embodiments 1-185, wherein X5is ; 202. Any one of embodiments 1-185, wherein X5is ; 203. Any one of embodiments 1-185, wherein X5is ; 204. Any one of embodiments 1-185, wherein X5is ; 205. Any one of embodiments 1-185, wherein X5is 206. Any one of embodiments 1-185, wherein X5is ; 207. Any one of embodiments 1-185, wherein X5is ; 208. Any one of embodiments 1-185, wherein X5is 209. Any one of embodiments 1-185, wherein X5is ; 210. Any one of embodiments 1-185, wherein X5is ; 211. Any one of embodiments 1-185, wherein X5is ; 212. Any one of embodiments 1-185, wherein X5is ; 213. Any one of embodiments 1-185, wherein X5is ; 214. Any one of embodiments 1-185, wherein X5is ; 215. Any one of embodiments 1-185, wherein X5is ; 216. Any one of embodiments 1-185, wherein X5is 217. Any one of embodiments 1-185, wherein X5is 218. Any one of embodiments 1-185, wherein 219. Any one of embodiments 1-185, wherein 220. Any one of embodiments 1-185, wherein 221. Any one of embodiments 1-185, wherein 222. Any one of embodiments 1-185, wherein X5is 223. Any one of embodiments 1-185, wherein 224. Any one of embodiments 1-185, wherein 225. Any one of embodiments 1-185, wherein 226. Any one of embodiments 1-185, wherein 227. Any one of embodiments 1-185, wherein 228. Any one of embodiments 1-185, wherein 229. Any one of embodiments 1-185, wherein 230. Any one of embodiments 1-185, wherein X5is ; 231. Any one of embodiments 1-185, wherein X5is 232. Any one of embodiments 1-185, wherein X5is ; 233. Any one of embodiments 1-185, wherein X5is ; 234. Any one of embodiments 1-185, wherein 235. Any one of embodiments 1-185, wherein X5 ; 236. Any one of embodiments 1-185, wherein X5 ; 237. Any one of embodiments 1-185, wherein X5is ; 238. Any one of embodiments 1-185, wherein X5is ; 239. Any one of embodiments 1-185, wherein X5is ; 240. Any one of embodiments 1-185, wherein X5is ; 241. Any one of embodiments 1-185, wherein X5is ; 242. Any one of embodiments 1-185, wherein X5is ; 243. Any one of embodiments 1-185, wherein 244. Any one of embodiments 1-185, wherein 245. Any one of embodiments 1-185, wherein X5is 5 246. Any one of embodiments 1-185, wherein X is ; 247. Any one of embodiments 1-185, wherein X5is 248. Any one of embodiments 1-185, wherein X5is ; 249. Any one of embodiments 1-185, wherein 250. Any one of embodiments 1-185, wherein 251. Any one of embodiments 1-185, wherein 252. Any one of embodiments 1-251, wherein X6is -O-; 253. Any one of embodiments 1-251, wherein X6is -NR6-; 254. Any one of embodiments 1-251, wherein X6is -S-; 255. Any one of embodiments 1-251, wherein X6is alkyl; 256. Any one of embodiments 1-251, wherein X6is cycloalkyl; 257. Any one of embodiments 1-251, wherein X6is heterocycle; 258. Any one of embodiments 1-251, wherein X6is aryl; 259. Any one of embodiments 1-251, wherein X6is bicycle; 260. Any one of embodiments 1-251, wherein X6is -C(O)-; 261. Any one of embodiments 1-251, wherein X6is -C(O)-NR6-; 262. Any one of embodiments 1-251, wherein X6is -(CH2CH2O)P-; 263. Any one of embodiments 1-251, wherein X6is –CH2-; 264. Any one of embodiments 1-251, wherein X6is -CH2CH2-; 265. Any one of embodiments 1-251, wherein X6is bond; 266. Any one of embodiments 1-251, wherein X6is ; 267. Any one of embodiments 1-251, wherein X6is ; 268. Any one of embodiments 1-251, wherein X6is ; 269. Any one of embodiments 1-251, wherein X6is ; 270. Any one of embodiments 1-251, wherein X6is ; 271. Any one of embodiments 1-251, wherein X6is ; 272. Any one of embodiments 1-251, wherein X6is ; 6 273. Any one of embodiments 1-251, wherein X is ; 274. Any one of embodiments 1-251, wherein X6is ; 275. Any one of embodiments 1-251, wherein X6is 276. Any one of embodiments 1-251, wherein X6is . In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from . In certain embodiments, Linker is selected from

[0038] In certain embodiments, Linker is selected from . In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from . In certain embodiments, Linker is selected from

[0039] In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from

[0040] In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from . In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from . In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from

[0041] In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from

[0042] In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from

[0043] In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from In certain embodiments, Linker is selected from Exemplary Methods of Treatment of Diseases Mediated by KRAS The present invention can be used to treat any disorder that is mediated by KRAS, for example mutant KRAS. Typically, the KRAS Recognition Moiety is a targeting ligand or portion of a targeting ligand that binds or is bound by KRAS, for example mutant KRAS. Nonlimiting examples of disorders that can be treated with a heteroaryl sulfonyl compound of the present invention include abnormal cellular proliferation disorders such as a cancer or a tumor. In certain embodiments a heteroaryl sulfonyl compound of the present invention is used to treat a pancreatic cancer. In certain embodiments a heteroaryl sulfonyl compound of the present invention is used to treat a colon cancer. In certain embodiments a heteroaryl sulfonyl compound of the present invention is used to treat a lung cancer for example small cell lung cancer. In certain embodiments, diseases associated with KRAS include, but are not limited to, cancer (for example, non-small cell lung cancer (NSCLC), pancreatic cancer, Adenocarcinoma, lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, colorectal carcinoma, breast cancer, Bile Duct Cancer, colon cancer, ovarian cancer, solid tumor, urothelial carcinoma, rectal cancer, gastrointestinal cancer, lymphoma, hematopoietic and lymphoid cell neoplasm, peritoneal carcinomatosis, head and neck squamous cell carcinoma, bone metastases, advanced malignant neoplasm, melanoma, braf mutated melanoma, liver metastases, NUT midline carcinoma, stomach cancer, oral cancer, endometrial cancer, leukemia, cholangiocarcinoma, acute myeloid leukemia, thyroid cancer, juvenile myelomonocytic leukemia (JMML), myelodysplastic syndromes (MDS), human hepatic vascular cavernomas), Oculoectodermal Syndrome, ocular disease (for example, Noonan Syndrome 3, Noonan-like CBL syndrome), Adnexal Diseases, Steatohepatitis, KRAS Gene Mutation (for example, Cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type I, and Legius syndrome), sporadic arteriovenous malformations, cardio- skeletal muscle disease associated with syndromes, autoimmune lymphoproliferative syndrome, epidermal nevus, costello syndrome (CS), inflammatory disease (for example, inflammatory and immune modulation specifically in KRAS-mutant cancers, Acute graft-versus-host disease), and autoimmune disease (for example, immune thrombocytopenia, recurrent HenochSchönlein purpura and intestinal Behçet disease). (Nikolaev et al., “Somatic activating KRAS mutations in arteriovenous malformations of the brain”, New England Journal of Medicine (2018), 378(3), 250- 261; Bollag et al., “Biochemical characterization of a novel KRAS insertion mutation from a human leukemia”, Journal of Biological Chemistry, 1996, 271(51), 32491-32494; Kim et al., “MicroRNA-mediated regulation of KRAS in cancer”, Journal of Hematology & Oncology (2014), 7, 84 / 1-84 / 8; Jancik et al., “Clinical relevance of KRAS in human cancers”, Journal of Biomedicine and Biotechnology (2010); McCormick, Frank, “KRAS as a Therapeutic Target”, Clinical Cancer Research, 2015, 21(8), 1797-1801; Gremer et al., “Germline KRAS Mutations Cause Aberrant Biochemical and Physical Properties Leading to Developmental Disorders”, Hum Mutat., 2011, Jan; 32(1): 33–43; Moritake et al., “Autoimmunity Including Intestinal Behçet Disease Bearing the KRAS Mutation in Lymphocytes: A Case Report”, Pediatrics, 2016, 137(3), :e 20152891; Niemeyer, Charlotte, “RAS diseases in children”, Hematologica, 2014, 99(11);) Non-limiting examples of cancers that can be treated according to the present invention include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarinoma), Ewing’s sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) – also known as acute lymphoblastic leukemia or acute lymphoid leukemia (e.g., B–cell ALL, T–cell ALL), acute myelocytic leukemia (AML) (e.g., B–cell AML, T–cell AML), chronic myelocytic leukemia (CML) (e.g., B–cell CML, T–cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B–cell CLL, T–cell CLL); lymphoma such as Hodgkin lymphoma (HL) (e.g., B–cell HL, T–cell HL) and non–Hodgkin lymphoma (NHL) (e.g., B–cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B–cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B–cell lymphomas (e.g., mucosa–associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B–cell lymphoma, splenic marginal zone B–cell lymphoma), primary mediastinal B–cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., “Waldenström's macroglobulinemia”), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B–lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T–cell NHL such as precursor T–lymphoblastic lymphoma / leukemia, peripheral T–cell lymphoma (PTCL) (e.g., cutaneous T–cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T–cell lymphoma, extranodal natural killer T–cell lymphoma, enteropathy type T–cell lymphoma, subcutaneous panniculitis–like T–cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non–small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP–NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer (e.g., Paget’s disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget’s disease of the vulva). In certain embodiments, the cancer is a hematopoietic cancer. In certain embodiments, the hematopoietic cancer is a lymphoma. In certain embodiments, the hematopoietic cancer is a leukemia. In certain embodiments, the leukemia is acute myelocytic leukemia (AML). In certain embodiments, the proliferative disorder is a myeloproliferative neoplasm. In certain embodiments, the myeloproliferative neoplasm (MPN) is primary myelofibrosis (PMF). In certain embodiments, the cancer is a solid tumor. A solid tumor, as used herein, refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of classes of solid tumors include, but are not limited to, sarcomas, carcinomas, and lymphomas, as described above herein. Additional examples of solid tumors include, but are not limited to, squamous cell carcinoma, colon cancer, breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, and melanoma. Abnormal cellular proliferation, notably hyperproliferation, can occur as a result of a wide variety of factors, including genetic mutation, infection, exposure to toxins, autoimmune disorders, and benign or malignant tumor induction. There are a number of skin disorders associated with cellular hyperproliferation. Psoriasis, for example, is a benign disease of human skin generally characterized by plaques covered by thickened scales. The disease is caused by increased proliferation of epidermal cells of unknown cause. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma. Other hyperproliferative cell disorders include blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancers. Blood vessel proliferative disorders include angiogenic and vasculogenic disorders. Proliferation of smooth muscle cells in the course of development of plaques in vascular tissue cause, for example, restenosis, retinopathies and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions. Fibrotic disorders are often due to the abnormal formation of an extracellular matrix. Examples of fibrotic disorders include hepatic cirrhosis and mesangial proliferative cell disorders. Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar. Hepatic cirrhosis can cause diseases such as cirrhosis of the liver. An increased extracellular matrix resulting in a hepatic scar can also be caused by viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis. Mesangial disorders are brought about by abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell disorders include various human renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic micro- angiopathy syndromes, transplant rejection, and glomerulopathies. Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease that is thought to be associated with activity of autoreactive T cells, and to be caused by autoantibodies produced against collagen and IgE. Other disorders that can include an abnormal cellular proliferative component include Bechet’s syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post- dialysis syndrome, leukemia, acquired immune deficiency syndrome, vasculitis, lipid histiocytosis, septic shock and inflammation in general. Exemplary cancers which may be treated by the disclosed heteroaryl sulfonyl compounds either alone or in combination with at least one additional anti-cancer agent include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using the disclosed heteroaryl sulfonyl compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive / infiltrating breast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma metastatic breast cancer, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis;; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma, T cell / histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric, Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. Pharmaceutical Compositions A heteroaryl sulfonyl compound of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof as disclosed herein can be administered as a neat chemical, but is more typically administered as a pharmaceutical composition that includes an effective amount for a host, typically a human, in need of such treatment to treat a disorder mediated by the target extracellular protein, as described herein or otherwise well-known for that extracellular protein. The heteroaryl sulfonyl compounds of the present invention can be administered in any manner that allows the heteroaryl sulfonyl compound to covalently modify KRAS, for example mutant KRAS. As such, examples of methods to deliver a heteroaryl sulfonyl compound of the present invention include, but are not limited to, oral, intravenous, sublingual, subcutaneous, parenteral, buccal, rectal, intra-aortal, intracranial, subdermal, transdermal, controlled drug delivery, intramuscular, or transnasal, or by other means, in dosage unit formulations containing one or more conventional pharmaceutically acceptable carriers, as appropriate. In certain embodiments, a heteroaryl sulfonyl compound of the present invention is provided in a liquid dosage form, a solid dosage form, a gel, particle, etc. In certain embodiments the heteroaryl sulfonyl compound of the present invention is administered subcutaneously. Typically, the heteroaryl sulfonyl compound will be formulated in a liquid dosage form for subcutaneous injection, such as a buffered solution. Non-limiting examples of solutions for subcutaneous injection include phosphate buffered solution and saline buffered solution. In certain embodiments the solution is buffered with multiple salts. In certain embodiments the heteroaryl sulfonyl compound of the present invention is administered intravenously. Typically, if administered intravenously, the heteroaryl sulfonyl compound will be formulated in a liquid dosage form for intravenous injection, such as a buffered solution. Non-limiting examples of solutions for intravenous injection include phosphate buffered solution and saline buffered solution. In certain embodiments the solution is buffered with multiple salts. Therefore, the disclosure provides pharmaceutical compositions comprising an effective amount of heteroaryl sulfonyl compound or its pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier for any appropriate use thereof. The pharmaceutical composition may contain a heteroaryl sulfonyl compound or salt as the only active agent, or, in an alternative embodiment, the heteroaryl sulfonyl compound and at least one additional active agent. The term "pharmaceutically acceptable salt" as used herein refers to a salt of the described heteroaryl sulfonyl compound which is, within the scope of sound medical judgment, suitable for administration to a host such as a human without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for its intended use. Thus, the term "pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic and organic acid addition salts of the presently disclosed heteroaryl sulfonyl compounds. These salts can be prepared during the final isolation and purification of the heteroaryl sulfonyl compounds or by separately reacting the purified heteroaryl sulfonyl compound in its free form with a suitable organic or inorganic acid and then isolating the salt thus formed. Basic heteroaryl sulfonyl compounds are capable of forming a wide variety of different salts with various inorganic and organic acids. Acid addition salts of the basic heteroaryl sulfonyl compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms may differ from their respective salt forms in certain physical properties such as solubility in polar solvents. Pharmaceutically acceptable base addition salts may be formed with a metal or amine, such as alkali and alkaline earth metal hydroxide, or an organic amine. Examples of metals used as cations, include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. The base addition salts of acidic heteroaryl sulfonyl compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents. Salts can be prepared from inorganic acids sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like. Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference. Any dosage form can be used that achieves the desired results. In certain embodiments the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 1500 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 heteroaryl sulfonyl compound and optionally from about 0.1 mg to about 1500 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms with at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active heteroaryl sulfonyl compound, or its salt. In certain embodiments the dose ranges from about 0.01-100 mg / kg of patient bodyweight, for example about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg. In some embodiments, heteroaryl sulfonyl compounds disclosed herein or used as described are administered once a day (QD), twice a day (BID), or three times a day (TID). In some embodiments, heteroaryl sulfonyl compounds disclosed herein or used as described are administered at least once a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or longer. In certain embodiments the heteroaryl sulfonyl compound of the present invention is administered once a day, twice a day, three times a day, or four times a day. The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., a pill, capsule, tablet, an injection or infusion solution, a syrup, an inhalation formulation, a suppository, a buccal or sublingual formulation, a parenteral formulation, or in a medical device. Some dosage forms, such as tablets and capsules, can be subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. Carriers include excipients and diluents and 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 heteroaryl sulfonyl compound is sufficient to provide a practical quantity of material for administration per unit dose of the heteroaryl sulfonyl compound. If provided as in a liquid, it can be a solution or a suspension. Representative carriers include phosphate buffered saline, water, solvent(s), diluents, pH modifying agents, preservatives, antioxidants, suspending agents, wetting agent, viscosity agents, tonicity agents, stabilizing agents, and combinations thereof. In some embodiments, the carrier is an aqueous carrier. Examples of aqueous carries include, but are not limited to, an aqueous solution or suspension, such as saline, plasma, bone marrow aspirate, buffers, such as Hank’s Buffered Salt Solution (HBSS), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), Ringers buffer, ProVisc®, diluted ProVisc®, Provisc® diluted with PBS, Krebs buffer, Dulbecco’s PBS, normal PBS, sodium hyaluronate solution (HA, 5 mg / mL in PBS), citrate buffer, simulated body fluids, plasma platelet concentrate and tissue culture medium or an aqueous solution or suspension comprising an organic solvent. Acceptable solutions include, for example, water, Ringer’s solution and isotonic sodium chloride solutions. The formulation may also be a sterile solution, suspension, or emulsion in a non-toxic diluent or solvent such as 1,3-butanediol. Viscosity agents may be added to the pharmaceutical composition to increase the viscosity of the composition as desired. Examples of useful viscosity agents include, but are not limited to, hyaluronic acid, sodium hyaluronate, carbomers, polyacrylic acid, cellulosic derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextin, polysaccharides, polyacrylamide, polyvinyl alcohol (including partially hydrolyzed polyvinyl acetate), polyvinyl acetate, derivatives thereof and mixtures thereof. Solutions, suspensions, or emulsions for administration may be buffered with an effective amount necessary to maintain a pH suitable for the selected administration. Suitable buffers are well known by those skilled in the art. Some examples of useful buffers are acetate, borate, carbonate, citrate, and phosphate buffers. Solutions, suspensions, or emulsions for topical, for example, ocular administration may also contain one or more tonicity agents to adjust the isotonic range of the formulation. Suitable tonicity agents are well known in the art. Some examples include glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes. Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the heteroaryl sulfonyl compound of the present invention. The pharmaceutical compositions / combinations can be formulated for oral administration. These compositions can contain any amount of active heteroaryl sulfonyl compound that achieves the desired result, for example between 0.1 and 99 weight % (wt.%) of the heteroaryl sulfonyl compound and usually at least about 1 wt.% of the heteroaryl sulfonyl compound. Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the heteroaryl sulfonyl compound. Enteric coated oral tablets may also be used to enhance bioavailability of the heteroaryl sulfonyl compounds for an oral route of administration. Formulations suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the active heteroaryl sulfonyl compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. Processes of Manufacture: The heteroaryl sulfonyl compounds of the present invention can be manufactured according to routes described in the Working Examples below or as otherwise known in the patent or scientific literature and if appropriate supported by the knowledge of the ordinary worker or common general knowledge. Some of the carbons in the heteroaryl sulfonyl compounds described herein are drawn with designated stereochemistry. Other carbons are drawn without stereochemical designation. When drawn without designated stereochemistry, that carbon can be in any desired stereochemical configuration that achieves the desired purpose. One skilled in the art will recognize that pure enantiomers, enantiomerically enriched heteroaryl sulfonyl compounds, racemates and diastereomers can be prepared by methods known in the art as guided by the information provided herein. Examples of methods to obtain optically active materials include at least the following: i) chiral liquid chromatography – a technique whereby diastereomers are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including vial chiral HPLC). The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; ii) non-chiral chromatography of diastereomers-Often diastereomers can be separated using normal non-chiral column conditions; iii) chiral gas chromatography – a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; iv) simultaneous crystallization – a technique whereby the individual diastereomers are separately crystallized from a solution; v) enzymatic resolutions – a technique whereby partial or complete separation of diastereomers are separated by virtue of differing rates of reaction with an enzyme; vi) chemical asymmetric synthesis – a synthetic technique whereby the desired diastereomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e. chirality) in the product, which may be achieved by chiral catalysts or chiral auxiliaries; vii) diastereomer separations – a technique whereby a racemic heteroaryl sulfonyl compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences the chiral auxiliary later removed to obtain the desired enantiomer; and viii) extraction with chiral solvents – a technique whereby diastereomers are separated by virtue of preferential dissolution of one over the others in a particular chiral solvent. Fluorescence Polarization Assay The ability of a compound to inhibit the SOS1-catalyzed nucleotide exchange reaction of wild type KRAS was measured using a fluorescence polarization assay. BODIPY-GDP-loaded N- terminal His-tagged recombinant human wild type KRAS (40 nM final, corresponding to amino acids 1 to 169, produced at Viva Biotech, Shanghai, China) was incubated with compound (2% DMSO final) in buffer (25 mM HEPES (pH 7.5), 1 mM MgCl2, 100 mM NaCl, 0.5 mM TCEP, 0.003% fatty acid free BSA, and 0.003% Triton X-100). After a 60-minute incubation at 22 ^C, the nucleotide exchange reaction was initiated by addition of recombinant human SOS1 (50 nM final, corresponding to amino acids 564 to 1049) and GTP (1 uM final). The reaction was measured using a PHERAstar-FSX multimode plate reader in fluorescence polarization mode by subtracting the polarization (mP) at t = 0 from that at t = 120 min to obtain the delta mP value. Percent inhibition was calculated by comparison to the maximum delta mP calculated as the difference between the delta mP observed for a zero percent inhibition control (no added compound) and the delta mP observed for the one hundred percent inhibition control containing a saturating concentration of the control inhibitor BAY-293. The percent inhibition values were fit to a 4- parameter logistic curve and the IC50value was determined as the concentration where the curve crosses 50 percent inhibition. Data from this assay is shown in Table 1. For the data in pIC50 = - Log(IC50 in Molar units), wherein pIC50 < 3 is *; 3-5 = **; and >5=***. Table 1. KRAS activity data

[0044]

[0045] Nucleotide exchange assay TR-FRET 2 nM of human GDP-bound mutant KRAS 4B (G12D) protein (corresponding to amino acids 1-169, expressed in E. Coli with a GST tag) and 1nM anti-GST-Tb antibody was incubated at room temperature with serial dilutions of tested compounds for 10-60 minutes in assay buffer (10 mM Hepes, pH 7.4, 150 mM NaCl, 0.05% BSA, 0.0025% Igepal, 5mM, MgCl2). 20 nM SOS- 1 and 10 nM EDA-GTP-Dy-647P1 in assay buffer was added and incubated for 60-120 minutes at room temperature after which time the plate was read on a Synergy Neo2 (BioTek) at 665nm and 620 nm. The HTRF ratio was calculated using the formula [emission 665 / emission 620]. Percent inhibition was calculated using the formula [100-100*(SAMPLE SINGLE- AVG(LOW)) / (AVG(HIGH)-AVG(LOW))] where high control is KRAS (G12D)+Tb+SOS1+DY+1% DMSO and low control is KRAS (G12D)+Tb+SOS1+DY+ 10uM KRpep-2d (1% DMSO). Dose response curves were fitted using XLfit 4 parameter curve fitting model 205. The results of the assay are shown in Table 2, Table 3, Table 4, Table 5, and Table 6, wherein >100 µM is *; 10 µM – 100 µM is **; < 10 µM is *** Table 2 KRAS NEA Activity IC50: [KRAS Form: KRAS-G12D, Enzyme Conc (nM): 2, Preincubation Time (minutes): 60, Readout time (minutes): 120, Readout: TR-FRET] Table 3 KRAS NEA Activity IC50: [KRAS Form: KRAS-G12D, Enzyme Conc (nM): 2, Preincubation Time (minutes): 60, Readout time (minutes): 60, Readout: TR-FRET] Table 4 KRAS NEA Activity IC50: [KRAS Form: KRAS-G12D, Enzyme Conc (nM): 2, Preincubation Time (minutes): 10, Readout time (minute): 60, Readout: TR-FRET] Table 5 KRAS NEA Activity IC50: [KRAS Form: KRAS-G12D, Enzyme Conc (nM): 2, Preincubation Time (minutes): 60, Readout time (minute): 120, Readout: TR-FRET] Table 6 KRAS NEA Activity IC50: [KRAS Form: KRAS-G12D, Enzyme Conc (nM): 2, Preincubation Time (minutes): 60, Readout time (minute): 120, Readout: TR-FRET] Scheme 1 Preparation of 4-(3-phenyl-1,2,4-triazol-1-ylsulfonyl)-aniline (1-2) A solution of 4-nitrobenzenesulfonyl chloride (150 mg, 0.67 mmol, 1 equiv) and 3-phenyl-1H- 1,2,4-triazole (118 mg, 0.81 mmol, 1.2 equiv) DIEA (263 mg, 2.03 mmol, 3 equiv) in THF (2 mL) was stirred for 1 h at 25 °C under N2 atmosphere. The resulting solution containing 1-1 was used in the next step directly without further purification. No mass signal in LCMS. To the above reaction solution of 1-(4-nitrobenzenesulfonyl)-3-phenyl-1,2,4-triazole in THF was added Pd / C (65 mg, 0.606 mmol, 2 equiv), and diluted with THF (2 mL). The resulting mixture was stirred for 1 h at 25 °C under H2 atmosphere. The resulting mixture was filtered; the filter cake was washed with THF (2 mL X 2). The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Xtimate C18100*30mm*3um, condition: 22-53% B (A = water (0.05% ammonia hydroxide v / v)), B = acetonitrile), flow rate: 40 mL / min, UV Detector 220nm) to afford 4-(3-phenyl-1,2,4-triazol-1-ylsulfonyl)-aniline (1-2) (57 mg, 62.69%) as a white solid. m / z: [M+H]+Calcd for C14H13N4O2S 301.1; Found 301.1. (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.05 – 7.93 (m, 2H), 7.78 – 7.67 (m, 2H), 7.52 – 7.47(m, 3H), 6.74 – 6.63 (m, 4H). Scheme 2 Preparation of 4-((3-cyclopropyl-1H-1,2,4-triazol-1-yl)sulfonyl)aniline (2-2) To a solution of 3-cyclopropyl-1H-1,2,4-triazole (164 mg, 1.51 mmol, 1.0 eq.), DIEA (700.5 mg, 5.43 mmol, 3.5 eq.) in THF (3 mL) 4-nitrobenzenesulfonyl chloride (400 mg, 1.81 mmol, 1.2 eq.) in THF (2 mL) was added dropwise at 0 ℃. The residue was stirred at room temperature for 2 h. To the mixture was added Pd / C (200 mg, 10%) and stirred at room temperature for 2 h under H2. The mixture was filtered, the filtrate was purified by Prep-HPLC (column: Xtimate C18 100*30mm*3um, condition: 32-72% B (A = water (0.05% ammonia hydroxide v / v)), B = acetonitrile), flow rate: 25 mL / min, UV Detector 220nm), and then froze it to give 2-1 (60 mg, two isomer). The isomers were separated by chiral SFC (Column: CHIRALPAK IF, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: isocratic 50% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT2(min): 5.2; Sample Solvent: ACN; Injection Volume: 9 mL; Number Of Runs: 3) to give 2-2 (23 mg, 20.8%) as a white solid. m / z: [M+H]+Calcd for C11H13N4O2S 265.1; Found 295.1.1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.68 – 7.60 (m, 2H), 6.71 – 6.62 (m, 4H), 1.99 (tt, J = 8.4, 4.8 Hz, 1H), 0.99 – 0.88 (m, 2H), 0.88 – 0.76 (m, 2H). Scheme 3 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(3-((3-cyclopropyl- 1H-1,2,4-triazol-1-yl)sulfonyl)propyl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-2-carboxamide (Compound 2) Preparation of 3-1 1-a (50 g, 361.98 mmol, 1 equiv) and ethyl pyruvate (210.16 g, 1809.94 mmol, 5 equiv) were combined neat and stirred for 15 min at room temperature. POCl3(500 mL) was added and the resulting mixture was stirred for 1 h at 100 °C. The mixture was allowed to cool down to room temperature and concentrated under vacuum. The resulting dark oil was taken up in ice cold water (500 mL). The mixture basified to pH 8 with saturated aqueous NaHCO3. The resulting mixture was extracted with ethyl acetate (3 x 1 L). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether: ethyl acetate (3:1) to afford 3-1 (23 g, 26.85%) as a brown solid. m / z: [M+H]+Calcd for C11H10ClN2O2237.0; Found 237.0. Preparation of 3-2 To a stirred solution of 3-1 (5 g, 21.12 mmol, 1 equiv) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (6.73 g, 31.69 mmol, 1.5 equiv) in NMP (100 mL) was added DIEA (8.19 g, 63.38 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 16 h at 110 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether in ethyl acetate (20% to 50%, 10 min) to afford 3-2 (7 g, 80.32%) as a brown solid. m / z: [M+H]+Calcd for C22H29N4O4413.2; Found 413.2. Preparation of 3-3 To a stirred solution of 3-2 (7 g, 16.97 mmol, 1 equiv) in acetic acid (150 mL) was added NaBH3CN (3.20 g, 50.91 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The mixture was adjusted to pH 8 with saturated aqueous NaHCO3. The resulting mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM in methanol (10%) to afford 3-3 (5 g, 70.74%) as a yellow oil. m / z: [M+H]+Calcd for C22H33N4O4417.3; Found 417.3. Preparation of 3-4 To a solution of 1,8-dibromonaphthalene (25 g, 88.03 mmol, 1 equiv) in THF (250 mL) was added dropwise CH3Li (105.6 mL, 105.6 mmol, 1.2 equiv, 1 mol / L in THF) at 25 °C under N2atmosphere. The mixture was stirred for 1 h at 0 °C, and MeI (18.8 g, 132.05 mmol, 1.5 equiv) was added at 0 °C. The mixture was stirred for 16 h at room temperature. The resulting mixture was quenched by saturated aqueous NH4Cl solution (200 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, H2O in acetonitrile, 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 1-bromo-8-methylnaphthalene (3-4)(8.0 g, 41.32%) as a yellow solid. [M] Calcd for C11H9Br 220.0; GCMS, Found 220.1. Preparation of 3-5 To a solution of ethyl 3-3 (1 g, 2.40 mmol, 1 equiv) and 3-4 (1.06 g, 4.80 mmol, 2 equiv) in dioxane (20 mL) were added Cs2CO3 (2.35 g, 7.20 mmol, 3 equiv) and RuPhos Palladacycle Gen.3 (200 mg, 0.24 mmol, 0.1 equiv). After stirring for 16 h at 100 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether in ethyl acetate (30% to 50%, 10 min) to afford 3-5 (500 mg, 37.41%) as a yellow oil. m / z: [M+H]+Calcd for C33H41N4O4557.3; Found 557.3. Preparation of 3-6 To a stirred solution of 3-5 (100 mg, 0.18 mmol, 1 equiv) and DIEA (69 mg, 0.54 mmol, 3 equiv) in DCM (5 mL) was added TMSOTf (119 mg, 0.54 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-6 (90 mg, crude) as a yellow oil, which was used directly in the next step without purification. m / z: [M+H]+Calcd for C28H33N4O2457.3; Found 457.3. Preparation of 3-7 To a stirred solution of 3-6 (560 mg, 1.22 mmol, 1 equiv) and DIEA (475 mg, 3.67 mmol, 3 equiv) in DCM (10 mL) was added chloro(prop-2-en-1-yloxy)methanone (221 mg, 1.84 mmol, 1.5 equiv) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-7 (640 mg, 96.51%) as a yellow solid, which was used in the next step without purification. m / z: [M+H]+ Calcd for C32H37N4O4541.3; Found 541.3. Preparation of 3-8 To a stirred solution of 3-7 (640 mg, 1.18 mmol, 1 equiv) in THF (10 mL) and H2O (2 mL) was added LiOH.H2O (100 mg, 2.36 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 5 h at room temperature. The mixture was acidified to pH 3 with 2 M aqueous HCl. The precipitated solids were collected by filtration to afford 3-8 (500 mg, 82.40%) as a yellow solid. m / z: [M+H]+Calcd for C30H33N4O4513.3; Found 513.3. Preparation of 3-9 To a stirred solution of 3-8 (400 mg, 0.78 mmol, 1 equiv) and homotaurine (162 mg, 1.17 mmol, 1.5 equiv) in DMF (10 mL) were added DIEA (302 mg, 2.34 mmol, 3 equiv), EDCI (224 mg, 1.17 mmol, 1.5 equiv), HOBT (158 mg, 1.17 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature. The mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.5% formic acid in water, acetonitrile 40% to 60% gradient in 10 min; detector, UV 254 nm to afford 3-9 (260 mg, 52.6%) as a yellow solid. m / z: [M+H]+Calcd for C33H40N5O6S 634.3; Found 634.3. Preparation of 3-10 To a stirred solution of 3-9 (100 mg, 0.161 mmol, 1 equiv) and 1 drop DMF in DCM (5 mL) was added oxalyl chloride (61 mg, 0.48 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-10 (80 mg, 76.26%) as a yellow oil. The crude product was used in the next step directly without further purification. m / z: [M+H]+Calcd for C33H38ClN5O5S 651.2; Found 651.2. Preparation of Compound 1 To a stirred solution of 3-cyclopropyl-1H-1,2,4-triazole (20 mg, 0.18 mmol, 1.5 equiv) and triethylamine (37 mg, 0.37 mmol, 3 equiv) in DCM (4 mL) was added 3-10 (80 mg, 0.123 mmol, 1 equiv) in DCM (1 mL) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.5% NH3.H2O in water, acetonitrile 65% to 95% gradient in 15 min; detector, UV 254 nm to afford 3-11 (40 mg, 44.99%) as a white solid. m / z: [M+H]+Calcd for C38H45N8O5S 725.3; Found 725.3. Preparation of Compound 2 To a stirred solution of Compound 1 (30 mg, 0.04 mmol, 1 equiv) and morpholine (7 mg, 0.08 mmol, 2 equiv) in THF (1 mL) was added Pd(PPh3)4 (10 mg, 0.008 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.5% NH3.H2O in water, acetonitrile 65% to 85% gradient in 15 min; detector, UV 254 nm to afford Compound 2 (5 mg, 18.85%) as a white solid. m / z: [M+H]+ Calcd for C34H41N8O3S 641.3; Found 641.4.1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.68-8.65 (t, J = 6.3 Hz, 1H), 7.78 – 7.76 (d, J = 8.1 Hz, 1H), 7.71 – 7.69 (d, J = 8.0 Hz, 1H), 7.49 – 7.45 (t, J = 7.7 Hz, 1H), 7.39 – 7.36 (m, 1H), 7.40 – 7.35 (m, 1H), 7.34 – 7.32 (d, J = 7.4 Hz, 1H), 7.26 (d, J = 7.1 Hz, 1H), 4.25 – 4.23 (d, J = 16.6 Hz, 1H), 3.88 – 3.76 (m, 3H), 3.55 – 3.51 (m, 1H), 3.50 – 3.47 (m, 1H), 3.45 – 3.42 (m, 1H), 3.19 – 3.11 (m, 3H), 3.36 – 3.33 (m, 1 H), 2.88 – 2.85 (m, 6H), 2.69 – 2.64 (m, 1H), 2.56 – 2.53 (m, 1H), 2.07 – 1.95 (m, 2H), 1.85 – 1.77 (m, 3H), 1.72 – 1.67 (m, 2H), 0.97 – 0.92 (m, 2H), 0.88 – 0.79 (m, 2H).

[0046] Scheme 4 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(4-((3-cyclopropyl- 1H-1,2,4-triazol-1-yl)sulfonyl)phenyl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-2-carboxamide (Compound 4) Preparation of Compound 3 To a stirred solution of 3-8 (60 mg, 0.11 mmol, 1 equiv) and 2-2 (46 mg, 0.17 mmol, 1.5 equiv) in ethyl acetate (1 mL) was added DIEA (45 mg, 0.35 mmol, 3 equiv) and T3P (1 mL, 50% in ethyl acetate) at room temperature. The resulting mixture was stirred for 2 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.5% NH3H2O in water acetonitrile, 60% to 95% gradient in 15 min; detector, UV 254 nm to afford Compound 3 (30 mg, 33.77%) as a yellow solid. m / z: [M+H]+Calcd for C41H43N8O5S 759.3; Found 759.3. Preparation of Compound 4 To a stirred solution of Compound 3 (30 mg, 0.04 mmol, 1 equiv) and morpholine (7 mg, 0.08 mmol, 2 equiv) in THF (2 mL) was added Pd(PPh3)4 (10 mg, 0.008 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.5% NH3H2O in water, acetonitrile 60% to 85% gradient in 15 min; detector, UV 254 nm to afford Compound 4 (2 mg, 7.50%) as a white solid. m / z: [M+H]+Calcd for C37H39N8O3S 675.3; Found 675.4.1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.20 – 8.16 (dd, J = 8.9, 4.2 Hz, 2H), 8.09 – 8.01 (m, 2H), 7.79 – 7.77 (d, J = 8.0 Hz, 1H), 7.72 – 7.70 (d, J = 8.2 Hz, 1H), 7.54 (s, 1 H), 7.49 (t, J = 7.7 Hz, 1H), 7.42 – 7.33 (m, 2H), 7.78 – 7.26 (d, J = 7.1 Hz, 1H), 4.37 – 4.35 (d, J = 16.8 Hz, 1H), 3.89 – 7.87 (d, J = 16.7 Hz, 1H), 3.59 – 3.53 (m, 3H), 3.5 – 3.46 (m, 2H), 3.23 – 3.18 (m, 2H), 2.96 – 2.88 (m, 5H), 2.75 – 2.71 (m, 2H), 2.04 – 1.97 (m, 2H), 1.86 – 1.70 (m, 3H), 1.02 – 0.91 (m, 2H), 0.88 – 0.75 (m, 2H). Scheme 5 Preparation of 2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-N-(4-((3-cyclopropyl-1H- 1,2,4-triazol-1-yl)sulfonyl)phenyl)acetamide (Compound 6)

[0047] Preparation of 5-1 A solution of 2-chloro-3-fluoropyridin-4-amine (42 g, 286.59 mmol, 1 equiv) and NIS (77.37 g, 343.91 mmol, 1.2 equiv) in ACN (220 mL) was added TsOH (2.47 g, 14.33 mmol, 0.05 equiv) at room temperature and was stirred for 16 h at 70oC. After that, the resulting mixture was diluted with water and EA, the organic layer was washed with saturated NaHCO3 solution, saturated Na2SO3 solution and brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the 5-1 (90 g, crude) as a yellow solid m / z: [M+H]+Calcd for C5H4ClFIN2272.9;Found 272.9. Preparation of 5-2 To a solution of 2-chloro-3-fluoro-5-iodopyridin-4-amine (90 g, 330.33 mmol, 1 equiv) in EtOH (1.7L) was added Pd(PPh3)2Cl2(23 g, 33.03 mmol, 0.1 equiv) and TEA (120 g, 1189.21 mmol, 3.6 equiv) and was stirred for 15 h at 80oC under CO (15 Psi) atmosphere. The resulting mixture was filtered, the filtrate was concentrated under reduced pressure to remove 70% of MeOH and the residue was filtered. The filter cakes was concentrated under reduced pressure to afford the 5- 2 (68 g, 94.16%) as a yellow solid m / z: [M+H]+Calcd for C8H9ClFN2O2219.0;Found 219.0. Preparation of 5-3 A mixture of 1-bromo-8-chloronaphthalene (40 g, 165 mmol,), AcOK (48.76 g, 496 mmol) bis(pinacolato)diboron (84.12 g, 331 mmol), Pd(dppf)Cl2(12.12 g, 16 mmol) in dioxane (1 L) was stirred at 100 °C for 8 h under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (3 x 300 mL) and concentrated under reduced pressure to afford the crude product, which was purified by flash chromatography on silica gel (EtOAc / petroleum ether = 0 / 1 to 1 / 1) to give 5-3 (40 g, 83% yield) as a white solid. Preparation of 5-4 A mixture of ethyl 4-amino-6-chloro-5-fluoronicotinate (15 g, 68 mmol), 2-(8-chloronaphthalen- 1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30 g, 103 mmol), Pd(dppf)Cl2(5 g, 6.8 mmol), CuI (2.61 g, 13.7 mmol), BINAP (8.55 g, 13.7 mmol) and K3PO4.3H2O (54 g, 204 mmol) in toluene (300 mL) was stirred at 100 °C for 8 h under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 100 ml) and concentrated under reduced pressure to afford the crude product, which was purified by flash chromatography on silica gel (EtOAc / petroleum ether = 0 / 1 to 1 / 1) to give 5-4 (16 g, 67% yield) as a white solid. m / z: [M+H]+Calcd for C18H15ClFN2O2345.1; Found 345.1. Preparation of 5-5 A mixture of 4-amino-6-(8-chloronaphthalen-1-yl)-5-fluoronicotinate (2.5 g, 7.25 mmol, 1 equiv) and trichloroethanecarbonyl isocyanate (1.50 g, 7.976 mmol, 1.1 equiv) in THF (25 mL) was stirred for 2 h at 25 °C under N2 atmosphere. The residue was purified by trituration with MTBE (30 mL) to afford 5-5 (3 g, 79.70%) as a white solid m / z: [M+H]+Calcd for C20H13Cl4FN3O4518.0; Found 518.0. Preparation of 5-6 A mixture of methyl 6-(8-chloronaphthalen-1-yl)-5-fluoro-4-(3-(2,2,2- trichloroacetyl)ureido)nicotinate (3 g, 5.77 mmol, 1 equiv) in amino in methanol (30 mL, 7 M) was stirred for 1 h at 25oC under N2atmosphere. The residue was purified by slurrying with MTBE (30 mL) to afford 5-6 (1.8 g, 91.15%) as a white solid m / z: [M+H]+Calcd for C17H10ClFN3O2 342.0; Found 342.0. Preparation of 5-7 A solution of 7-(8-chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (2 g, 5.85 mmol, 1 equiv) and DIEA (3.78 g, 29.26 mmol, 5 equiv) in POCl3 (20 mL) was stirred for 16 h at 110 °C under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (5-7) was used in the next step directly without further purification. m / z: [M+H]+Calcd for C17H8Cl3FN3378.0;Found 378.0. Preparation of 5-8 To A mixture of 2,4-dichloro-7-(8-chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (2 g, 5.28 mmol, 1 equiv) in DCM (20 mL) was added DIEA (2.05 g, 15.84 mmol, 3 equiv) at -40oC under N2 atmosphere, and then tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.68 g, 7.92 mmol, 1.5 equiv) was added into the above solution at the same temperature, the mixture solution was stirred for 1 h at -40 °C under N2atmosphere. The resulting mixture was extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by silica gel column chromatography, eluted with PE : EA (0%~50%) to afford 5-8 (1.4 g, 47.80%) as a white solid m / z: [M+H]+Calcd for C28H27Cl2FN5O2554.1;Found 554.1. Preparation of 5-9 A mixture of tert-butyl (1R,5S)-3-(2-chloro-7-(8-chloronaphthalen-1-yl)-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.90 mmol, 1 equiv) and ethyl 2-hydroxyacetate (140.82 mg, 1.353 mmol, 1.5 equiv) in THF (5 mL) was cooled to 0oC, and then NaH (35 mg, 1.353 mmol, 1.5 equiv, ~60% in oi) in portions, the mixture was stirred for 1 h at 0 °C under N2 atmosphere. The reaction was quenched with NH4Cl at 0°C. The aqueous layer was extracted with EA (2 x 10 mL). After concentration, the residue was purified by silica gel column chromatography, eluted with PE:EA (0%~60%) to afford 5-9 (460 mg, 82.0%) as a yellow solid m / z: [M+H]+Calcd for C32H34ClFN5O5621.1;Found 622.1. Preparation of 5-10 To the solution of tert-butyl (1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-2-(2-ethoxy-2-oxoethoxy)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 0.96 mmol, 1 equiv) in DCM (6 mL) were added DIEA (373.97 mg, 2.89 mmol, 3 equiv), TMSOTf (643.07 mg, 2.89 mmol, 3 equiv) respectively, the mixture solution was stirred for 1 h at 25°C under N2 atmosphere. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-10 (800 mg, crude) as a yellow solid. It can be used in next step without any purification. m / z: [M+H]+Calcd for C27H26ClFN5O3 522.2; Found 522.2. Preparation of 5-11 To the solution of ethyl ethyl 2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)acetate (400 mg, 0.76 mmol, 1 equiv) in DCM (4 mL) was added DIEA (300 mg, 2.29 mmol, 3 equiv) at room temperature, and the mixture was cooled down to 0°C under N2atmosphere, and then allyl chlorocarbonate (140 mg, 1.14 mmol, 1.5 equiv) was added dropwise at this temperature. The resulting mixture was stirred for 0.5 h at 0°C under N2 atmosphere. The resulting mixture was extracted with DCM (2 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography, eluted with PE / EA (0%~80%) to afford 5-11 (300 mg, 64.60%) as a white solid, m / z: [M+H]+Calcd for C31H30ClFN5O5606.2; Found 606.2. Preparation of 5-12 To the solution of allyl (1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-2-(2-ethoxy-2-oxoethoxy)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.15 mmol, 1 equiv) in H2O (4 mL) THF (4 mL) was added LiOH.H2O (243 mg, 5.77 mmol, 5 equiv) at room temperature. The resulting mixture was stirred for 3 h at 25 °C under N2atmosphere. The mixture was basified to pH 6 with aqueous HCl (1 M). The resulting mixture was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-12 (600 mg, 89.87%) as a yellow solid, it can be used in the next step without any purification. m / z: [M+H]+Calcd for C29H26ClFN5O5578.2;Found 578.2 Preparation of Compound 5 A mixture of 2-((4-((1R,5S)-8-((allyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)acetic acid (100 mg, 0.173 mmol, 1 equiv) and 2-2 (68.59 mg, 0.259 mmol, 1.5 equiv), DIEA (67.08 mg, 0.519 mmol, 3 equiv) in T3P (2 mL) and EA (2 mL) was stirred for 2 h at 50 °C under N2 atmosphere. The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with DCM (2 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / DCM (0%~20%) to afford Compound 5 (80 mg, 56.10%) as a white solid m / z: [M+H]+ Calcd for C40H35ClFN9O6S 823.2;Found 824.2 Preparation of Compound 6 To the solution of allyl (1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-2-(2-((4-((3-cyclopropyl-1H- 1,2,4-triazol-1-yl)sulfonyl)phenyl)amino)-2-oxoethoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.09 mmol, 1 equiv) and morpholine (23 mg, 0.29 mmol, 3 equiv) in THF (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol, 0.1 equiv) under N2atmosphere. The mixture was stirred for 1 h at 25°C under N2atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product which was purified by prep-HPLC (column: Xtimate C18 100*30mm*3um, condition: 32-72% B (A = water (0.05% ammonia hydroxide v / v)), B = acetonitrile), flow rate: 25 mL / min, UV Detector 220nm) to afford Compound 6 (24 mg, 33.41%) m / z: [M+H]+Calcd for C36H32ClFN9O4S 740.2;Found 740.31H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.11 (d, J = 17.2 Hz, 2H), 8.20 (dd, J = 8.3, 1.4 Hz, 1H), 8.10 (dd, J = 8.3, 1.4 Hz, 1H), 8.07 – 7.98 (m, 2H), 7.96 – 7.87 (m, 2H), 7.76 – 7.68 (m, 1H), 7.68 – 7.51 (m, 3H), 4.98 (s, 2H), 4.45 – 4.37 (m, 2H), 3.58 (d, J = 12.3 Hz, 2H), 3.43 (s, 2H), 2.00 (tt, J = 8.6, 4.9 Hz, 1H), 1.46-1.40 (m, 4H), 0.96 (ddt, J = 11.9, 8.3, 3.2 Hz, 2H), 0.88 – 0.76 (m, 2H).

[0048] Scheme 6 Preparation of 2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-N-(4-((3-phenyl-1H-1,2,4- triazol-1-yl)sulfonyl)phenyl)acetamide (Compound 8) Preparation of Compound 7 To the solution of 2-((4-((1R,5S)-8-((allyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)acetic acid (100 mg, 0.17 mmol, 1 equiv) and 1-2 (78 mg, 0.25 mmol, 1.5 equiv) in in T3P (2 mL, 50% EA) and EA (2 mL) was added DIEA (67 mg, 0.51 mmol, 3 equiv) under N2atmosphere, the mixture was stirred for 1 h at 50 °C under N2 atmosphere. The resulting mixture was extracted with EA (2 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / DCM: (0%~20%) to afford Compound 7 (80 mg, 53.75%) as a white solid m / z: [M+H]+Calcd for C43H36ClFN9O6S 860.2;Found 860.2. Preparation of Compound 8 To the mixture of allyl (1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(2-oxo-2-((4-((3- phenyl-1H-1,2,4-triazol-1-yl)sulfonyl)phenyl)amino)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.093 mmol, 1 equiv) and morpholine (16 mg, 0.18 mmol, 2 equiv) in THF (3 mL) was added Pd(PPh3)4 (4 mg, 0.009 mmol, 0.2 equiv) under N2 atmosphere, the mixture was stirred for 1 h at 25°C under N2atmosphere. The resulting mixture was filtered, the filtrate was concentrated under reduced pressure to give the crude product which was purified by prep-HPLC (column: Xtimate C18100*30mm*3um, condition: 32-72% B (A = water (0.05% ammonia hydroxide v / v)), B = acetonitrile), flow rate: 25 mL / min, UV Detector 220nm) to Compound 8 (10.5 mg, 14.55%). m / z: [M+H]+Calcd for C39H32ClFN9O4S 776.2; Found 776.31H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.42 (s, 1H), 9.06 (s, 1H), 8.18 (dd, J = 8.3, 1.4 Hz, 1H), 8.10 (dd, J = 10.9, 8.3 Hz, 3H), 7.99 (dd, J = 6.6, 2.9 Hz, 2H), 7.96 – 7.90 (m, 2H), 7.70 (t, J = 7.7 Hz, 1H), 7.63 (dd, J = 7.5, 1.4 Hz, 1H), 7.62 – 7.49 (m, 3H), 7.53 – 7.45 (m, 2H), 4.96 (s, 2H), 4.37 (d, J = 11.9 Hz, 2H), 3.54 (d, J = 12.2 Hz, 2H), 3.33 – 3.35 (m, 2 H), 1.38 – 1.33 (m, 4 H). Scheme 7 Preparation of 4-(2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)acetamido)benzenesulfonyl fluoride (Compound 10)

[0049] Preparation of 7-1 A solution of 4-nitrobenzenesulfonyl fluoride (2 g, 9.76 mmol, 1 equiv), Fe (2.73 g, 48.8 mmol, 5 equiv), NH4Cl (5.27 g, 97.6 mmol, 10 equiv) in EtOH (40 mL) and H2O (4 mL) was stirred at 60 °C for 1 h. The mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether: ethyl acetate (3:1) to afford 7-1 (1.1 g, 64.7%) as a yellow solid. m / z: [M+H]+Calcd for C6H7FNO2S 176.0; Found 176.0 Preparation of Compound 9 To a stirred solution of 5-12 (150 mg, 0.260 mmol, 1 equiv) and 7-1 (70 mg, 0.39 mmol, 1.5 equiv) in ethyl acetate (2 mL) was added DIEA (100 mg, 0.780 mmol, 3 equiv) and T3P (2 mL, 50% in ethyl acetate) at room temperature. The resulting mixture was stirred for 2 h at 50 °C. The resulting mixture was used in the next step directly without further purification. m / z: [M+H]+Calcd for C35H30ClF2N6O6S 735; Found 735. Preparation of Compound 10 To a stirred solution of Compound 9 and morpholine (23 mg, 0.272 mmol, 2 equiv) in ethyl acetate (4 mL) was added Pd(PPh3)4(31 mg, 0.027 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.5% NH3H2O in water, acetonitrile 60% to 85% gradient in 15 min; detector, UV 254 nm to afford Compound 10 (13 mg, 14.68%) as a white solid. m / z: [M+H]+Calcd for C31H26ClF2N6O4S 651; Found 651.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.09 (s, 1H), 8.21-8.19 (d, J = 8.2 Hz, 1H), 8.11-8.09 (d, J = 8.5 Hz, 3H), 8.00- 7.98 (d, J = 8.7 Hz, 2H), 7.74 – 7.70 (m, 1H), 7.66-7.55 (m, 3H), 5.01 (s, 2H), 4.42-4.40 (d, J = 12.1 Hz, 2H), 3.59-3.56 (d, J = 12.1 Hz, 2H), 3.42-3.39 (m, 2 H), 1.46 (s, 4H). Scheme 8 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-(4-((3-cyclopropyl- 1H-1,2,4-triazol-1-yl)sulfonyl)phenoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (Compound 12)

[0050] To a stirred solution of 4-bromonaphthalen-2-ol (5 g, 22.41 mmol, 1 equiv) and bis(pinacolato)diboron (6.83 g, 26.89 mmol, 1.2 equiv) in dioxane (75 mL) were added AcOK (6.60 g, 67.24 mmol, 3 equiv) and Pd(dppf)Cl2 (1.64 g, 2.24 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. Concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 8- 1 (5.1 g, 84%) as a white solid. m / z: [M+H]+Calcd for C16H20BO3271.1; Found 271.2. Preparation of 8-3 To a stirred solution of 8-2 (3.0 g, 5.62 mmol, 1 equiv) and 8-1 (1.98 g, 7.31 mmol, 1.3 equiv) in dioxane (32 mL) and H2O (4 mL) were added K2CO3(1.56 g, 11.25 mmol, 2 equiv) and Pd(dppf)Cl2 (0.41 g, 0.56 mmol, 0.1 equiv). The resulting mixture was stirred for 4 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (40 mL), extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (1 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5:1 to 2:3) to afford 8-3 (2.0 g, 55%) as a colorless oil. m / z: [M+H]+Calcd for C36H42FN6O4641.3; Found 641.3 Preparation of 8-5 To a stirred solution of 4-aminobenzenethiol (20 g, 159.75 mmol, 1 equiv) and K2CO3 (44 g, 319.51 mmol, 2 equiv) in DMF (200 mL) was added benzyl bromide (28.7 g, 167.74 mmol, 1.05 equiv) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with ice-water (200 mL), extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (2 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (10:0 to 10:1) to afford 8-4 (23 g, 67%) as a light yellow oil. m / z: [M+H]+Calcd for C13H14NS 216.1; Found 216.1. To a stirred solution of 8- 4 (10 g, 46.44 mmol, 1 equiv) in CH3CN (120 mL) was added TsOH (24 g, 139.33 mmol, 3 equiv). The resulting mixture was cooled down to 0 °C. A solution of NaNO2 (6.4 g, 92.89 mmol, 2 equiv) in H2O (40 mL) was added dropwise into the above solution at 0 °C. The resulting mixture was stirred for 5 min at 0 °C. A solution of KI (19.3 g, 116.11 mmol, 2.5 equiv) in H2O (40 mL) was added dropwise at 0 °C. The resulting mixture was stirred for 2 h at 0 °C. The reaction was diluted with H2O (200 mL), extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (1 x 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0 to 20:1) to 8-5 (11 g, 72%) as a light yellow solid. m / z: [GCMS] Calcd for C13H11IS 326.0; Found 326.0 Preparation of 8-5 To a stirred solution of 8-3 (2.0 g, 3.12 mmol, 1 equiv) and 8-5 (1.53 g, 4.68 mmol, 1.5 equiv) in DMSO (30 mL) were added K2CO3(0.86 g, 6.24 mmol, 2 equiv) and CuI (0.30 g, 1.56 mmol, 0.5 equiv) and Fe(acac)3 (0.33 g, 0.93 mmol, 0.3 equiv). The resulting mixture was stirred for 16 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (1 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5:1 to 1:1) to afford 8-6 (800 mg, 30%) as an off-white solid. m / z: [M+H]+Calcd for C49H52FN6O4S 839.4; Found 839.4 To a stirred solution of 8-6 (600 mg, 0.71 mmol, 1 equiv) in CH3CN (6 mL) were added AcOH (257 mg, 4.29 mmol, 6 equiv) and H2O (77 mg, 4.29 mmol, 6 equiv). To the above mixture was added NCS (286 mg, 2.14 mmol, 3 equiv) in portions at 0 °C. The reaction mixture was stirred for additional 20 h at room temperature. The resulting mixture was added dropwise to a solution of 3- cyclopropyl-1H-1,2,4-triazole (312 mg, 2.86 mmol, 4 equiv) and DIEA (924 mg, 7.15 mmol, 10 equiv) in DCM (6 mL). The mixture was stirred for 3 h at room temperature. Concentrated under reduced pressure to remove the solvent. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18-120 g, mobile phase, MeCN in water (0.1% FA), 10% to 70% gradient in 15 min, detector, UV 254 nm. This resulted in 8-7 (260 mg, 45%) as an off-white solid. m / z: [M+H]+Calcd for C42H46FN6O7S 797.3; Found 797.3 Preparation of Compound 11 To a stirred solution of 8-7 (120 mg, 0.15 mmol, 1 equiv) and pyridine (59 mg, 0.75 mmol, 5 equiv) in DCM (3 mL) was added POCl3(69 mg, 0.45 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was dropwise to a solution of 3-cyclopropyl-1H-1,2,4-triazole (65 mg, 0.60 mmol, 4 equiv) and pyridine (59 mg, 0.75 mmol, 5 equiv) in DCM (3 mL) at room temperature. The resulting mixture was stirred for 3 h at room temperature. Concentrated under reduced pressure to remove the solvent. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18- 120 g, mobile phase, MeCN in water (10 mmol / L NH4HCO3), 50% to 90% gradient in 15 min, detector, UV 254 nm. This resulted in Compound 11 (45 mg, 33%) as a white solid. m / z: [M+H]+Calcd for C47H51FN9O6S 888.4; Found 888.4 Preparation of Compound 12 To a stirred solution of Compound 11 (45 mg, 0.05 mmol, 1 equiv) in DCM (1 mL) was added DIEA (26 mg, 0.20 mmol, 4 equiv). TMSOTf (56 mg, 0.26 mmol, 5 equiv) was added at 0 °C. The mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in CH3CN (5 mL) and purified by reversed-phase flash chromatography with the following conditions: column, C18-120 g, mobile phase, MeCN in water (10 mmol / L NH4HCO3), 50% to 90% gradient in 15 min, detector, UV 254 nm. The fraction of the target was freezing dried, this resulted in Compound 12 (16.2 mg, 41%) as a white solid. m / z: [M+H]+Calcd for C42H43FN9O4S 788.3; Found 788.5.1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 9.16 (s, 1H), 8.16 – 8.01 (m, 3H), 7.94 (d, J = 2.5 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.67 – 7.59 (m, 1H), 7.57 – 7.49 (m, 2H), 7.40 – 7.29 (m, 2H), 4.45 (d, J = 12.0 Hz, 2H), 4.06 (s, 2H), 3.69 – 3.45 (m, 4H), 2.97 – 2.90 (m, 2H), 2.60 – 2.56 (m, 2H), 2.07 – 1.98 (m, 1H), 1.93 – 1.72 (m, 6H), 1.64 – 1.53 (m, 6H), 1.00 – 0.96 (m, 2H), 0.88 – 0.80 (m, 2H). Scheme 9 Preparation of 2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-N-(3-((3-cyclopropyl-1H- 1,2,4-triazol-1-yl)sulfonyl)phenyl)acetamide (Compound 14) Preparation of 9-1 To a stirred solution of 3-cyclopropyl-1H-1,2,4-triazole (270 mg, 2.48 mmol, 1.1 equiv.) and TEA (685 mg, 6.77 mmol, 3 equiv.) in THF (20 mL) was added 3-nitrobenzenesulfonyl chloride (500 mg, 2.25 mmol, 1 equiv) at 0°C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EA (2 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-cyclopropyl-1-(3-nitrobenzenesulfonyl)-1,2,4-triazole (400 mg, 60.24%) as a white solid. It was used into the next step without any purification. m / z: [M+H]+Calcd for C11H11N4O4S 295.1; Found 295.1. Preparation of 9-2 To a stirred solution of 3-cyclopropyl-1-(3-nitrobenzenesulfonyl)-1,2,4-triazole (400 mg, 1.36 mmol, 1 equiv) in THF (10 mL) was added Fe (380 mg, 6.80 mmol, 5 equiv) and NH4Cl (365 mg, 6.80 mmol, 5 equiv) at room temperature. The resulting mixture was stirred for 16 h at room temperature, filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 5% NH3H2O in water, MeCN 40% to 75% gradient in 12 min; detector, UV 254 nm and then separated the regeisomer by Chiral-SFC: Column: CHIRALPAK IF, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: isocratic 50% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 2.5; RT2(min): 6; Sample Solvent: ACN(0.2% DEA); Injection Volume: 9 mL; Number Of Runs: 4 to afford 3-(3-cyclopropyl-1,2,4-triazol-1-ylsulfonyl) aniline (300 mg, 83.51%) as a yellow solid. m / z: [M+H]+Calcd for C11H13N4O2S 265.1; Found 265.1. Preparation of Compound 13 To a stirred mixture of {[7-(8-chloronaphthalen-1-yl)-8-fluoro-4-[(1R,5S)-8-[(prop-2-en-1-yloxy) carbonyl]-3,8-diazabicyclo [3.2.1] octan-3-yl] pyrido[4,3-d]pyrimidin-2-yl]oxy}acetic acid (200 mg, 0.35 mmol, 1 equiv) and 3-(3-cyclopropyl-1,2,4-triazol-1-ylsulfonyl)aniline (110 mg, 0.42mmol, 1.2 equiv) in EA (2.40 mL) was added DIEA (134 mg, 1.04 mmol, 3.0 equiv) and T3P (3 mL, 50% in EA) at room temperature. The resulting mixture was stirred for additional 1 h at 50°C. The mixture was basified to pH=8 with DIEA. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / THF (9:1) to afford prop-2-en-1-yl (1R,5S)-3-[7-(8-chloronaphthalen-1-yl)-2-({[3-(3- cyclopropyl-1,2,4-triazol-1-ylsulfonyl) phenyl] carbamoyl}methoxy)-8-fluoropyrido[4,3-d] pyrimidin-4-yl]-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg, 70.12%) as off-white solid. m / z: [M+H]+Calcd for C40H36ClFN9O6S 824.2; Found 824.2. Preparation of Compound 14 To a stirred solution of prop-2-en-1-yl (1R,5S)-3-[7-(8-chloronaphthalen-1-yl)-2-({[3-(3- cyclopropyl-1,2,4-triazol-1-ylsulfonyl) phenyl] carbamoyl} methoxy)-8-fluoropyrido[4,3-d] pyrimidin-4-yl]-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg, 0.24 mmol, 1 equiv) in THF (7 mL) were added morpholine (63 mg, 0.73 mmol, 3.0 equiv) and Pd(PPh3)4 (84 mg, 0.07 mmol, 0.3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 1 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions: column, C18 silica gel; mobile phase, 5% NH3H2O in water, MeCN 31% to 65% gradient in 7 min; detector, UV 254 nm to afford 2-{[7-(8-chloronaphthalen-1-yl)-4- [(1R,5S)-3,8-diazabicyclo [3.2.1] octan-3-yl]-8-fluoropyrido[4,3-d] pyrimidin-2-yl] oxy}-N-[3- (3-cyclopropyl-1,2,4-triazol-1-ylsulfonyl) phenyl]acetamide (17 mg, 9.47%) as off-white solid. m / z: [M+H]+Calcd for C36H32ClFN9O4S 740.2; Found 740.2.1H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.21 (s, 1H), 9.09 (s, 1H), 8.47 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.79 – 7.51 (m, 6H), 4.96 (s, 2H), 4.44 – 4.36 (m, 2H), 3.57 (d, J = 12.1 Hz, 2H), 3.37 – 3.35 (m, 2H), 2.03 – 1.96 (m, 1H), 1.39 (brs, 4H), 0.94 (dd, J = 8.1, 3.1 Hz, 2H), 0.81 (q, J = 3.2, 2.7 Hz, 2H). Scheme 10 Preparation of 2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-N-(4-(N,N- dimethylsulfamoyl)phenyl)acetamide (Compound 16)

[0051] Preparation of Compound 15 A mixture of 5-12 (100 mg, 0.173 mmol), 4-amino-N,N-dimethylbenzenesulfonamide (52 mg, 0.26 mmol) and DIEA (70 mg, 0.519 mmol) in T3P (1 mL, 50% in ethyl acetate) and ethyl acetate (1 mL) was stirred at 50 °C for 1 h under a N2atmosphere. The mixture was concentrated under reduced pressure to afford the crude product, which was purified by flash chromatography on silica gel (ethyl acetate / petroleum ether = 0 / 1 to 1 / 1) to give Compound 15 (80 mg, 60% yield) as a white solid. m / z: [M-H]- Calcd for C37H34ClFN7O6S 758.2; Found 758.2. Preparation of Compound 15 To a mixture of Compound 15 (70 mg, 0.092 mmol) in THF (1 mL) and morpholine (40 mg, 0.46 mmol) was added Pd(PPh3)4(21 mg, 0.018 mmol), and then the mixture was stirred at 20 °C for 1 h. The resulting mixture was filtered. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by prep-HPLC (column: Xtimate C18100*30mm*3um, condition: 32-72% B (A = water (0.05% ammonia hydroxide v / v)), B = acetonitrile), flow rate: 25 mL / min, UV Detector 220nm) to afford Compound 16 (23 mg, 37% yield) as a white solid. m / z: [M+H]+Calcd for C33H32ClFN7O4S 676.2; Found 676.3.1H NMR (300 MHz, DMSO-d6) δ 10.73 (s, 1H), 9.09 (s, 1H), 8.21-2.18 (d, J = 8.2 Hz, 1H), 8.11-8.09 (d, J = 8.1 Hz, 1H), 7.89-7.86 (d, J = 8.6 Hz, 2H), 7.76 – 7.69 (m, 3H), 7.66-7.54 (m, 3H), 4.98 (s, 2H), 4.44-4.40 (m, 2H), 3.60-3.56 (m, 2H), 3.44-3.36 (m, 2H), 2.57 (s, 6H), 1.46 (s, 4H). Scheme 11 Preparation of 2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-N-(4-((3-cyclopropyl-1H- 1,2,4-triazol-1-yl)sulfonyl)-3-methylphenyl)acetamide (Compound 18) Preparation of 11-1 A solution of 3-cyclopropyl-1H-1,2,4-triazole (0.93 g, 8.49 mmol, 1 equiv) in CH2Cl2 (15 mL) was treated with DIEA (1.65 g, 12.73 mmol, 1.5 equiv) at 0°C followed by the addition of 2- methyl-4-nitrobenzenesulfonyl chloride (2 g, 8.49 mmol, 1 equiv) in CH2Cl2(15 mL) dropwise at 0°C. The resulting mixture was stirred for 2h at room temperature. The resulting mixture was washed with water (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-cyclopropyl-1-(2-methyl-4- nitrobenzenesulfonyl)-1,2,4-triazole (2.2 g, 84.07%) as a yellow solid. It was used into the next step without any purification. m / z: [M+H]+Calcd for C12H12N4O4S 309.0; Found 309.0. Preparation of 11-2 To a solution of 3-cyclopropyl-1-(2-methyl-4-nitrobenzenesulfonyl)-1,2,4-triazole (2.2 g, 7.14 mmol, 1 equiv) in EtOAc (30 mL), was added Pd / C (0.22 g). The mixture was hydrogenated at room temperature under about 3-4 atm of hydrogen pressure for 2 h, filtered through a Celite pad and concentrated under reduced pressure. The crude product which was purified by prep-HPLC with the following conditions (column: Xtimate C18100*30mm*3um, condition: 32-72% B (A = water (0.05% ammonia hydroxide v / v)), B = acetonitrile), flow rate: 25 mL / min, UV Detector 220nm) and then SFC used as Column: CHIRALPAK IF, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: isocratic 50% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 2.6; RT2(min): 7.5; Sample Solvent: ACN; Injection Volume: 7 mL; Number of Runs: 4, to afford 4-(3- cyclopropyl-1,2,4-triazol-1-ylsulfonyl)-3-methylaniline (1.19 g, 60.57%) as a yellow solid. m / z: [M+H]+Calcd for C12H14N4O2S 279.1; Found 279.1. Preparation of Compound 17 To a stirred mixture of {[7-(8-chloronaphthalen-1-yl)-8-fluoro-4-[(1R,5S)-8-[(prop-2-en-1-yloxy) carbonyl]-3,8-diazabicyclo [3.2.1] octan-3-yl] pyrido[4,3-d] pyrimidin-2-yl] oxy}acetic acid (130 mg, 0.23 mmol, 1 equiv) and 4-(3-cyclopropyl-1,2,4-triazol-1-ylsulfonyl)-3-methylaniline (75 mg, 0.27 mmol, 1.2 equiv) in EA (2.5 mL) were added DIEA (87 mg, 0.66 mmol, 3.0 equiv) and T3P (2.5 mL, 50% in EA) at room temperature. The resulting mixture was stirred for additional 1 h at 50 °C. The mixture was basified to pH= 8 with DIEA. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / THF (10:1) to afford prop-2-en-1-yl (1R,5S)-3-[7-(8-chloronaphthalen-1-yl)-2-({[4- (3-cyclopropyl-1,2,4-triazol-1-ylsulfonyl)-3-methylphenyl] carbamoyl} methoxy)-8- fluoropyrido[4,3-d] pyrimidin-4-yl]-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (130 mg, 68.95%) as off-white solid.m / z: [M+H]+Calcd for C41H38ClFN9O6S 838.2; Found 838.2. Preparation of Compound 18 To a stirred solution of bis(prop-2-en-1-yl (1R,5S)-3-[7-(8-chloronaphthalen-1-yl)-2-({[4-(3- cyclopropyl-1,2,4-triazol-1-ylsulfonyl)-3-methylphenyl]carbamoyl}methoxy)-8- fluoropyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) (120 mg, 0.14 mmol, 1 equiv) in THF (2.5 mL) were added morpholine (37 mg, 0.43 mmol, 3.0 equiv) and Pd(PPh3)4 (50 mg, 0.04 mmol, 0.3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 1 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions: column, C18 silica gel; mobile phase, 5% NH3H2O in water, MeCN 31% to 65% gradient in 7 min; detector, UV 254 nm to afford 2-{[7-(8- chloronaphthalen-1-yl)-4-[(1R,5S)-3,8-diazabicyclo [3.2.1] octan-3-yl]-8-fluoropyrido[4,3-d] pyrimidin-2-yl]oxy}-N-[4-(3-cyclopropyl-1,2,4-triazol-1-ylsulfonyl)-3-methylphenyl]acetamide (Compound 18) (25 mg, 23.16%) as off-white solid. m / z: [M+H]+Calcd for C37H34ClFN9O4S 754.2; Found 754.2.1H NMR (300 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.24 (s, 1H), 9.09 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.09 (dd, J = 8.3, 2.6 Hz, 2H), 7.81 – 7.66 (m, 3H), 7.66 – 7.51 (m, 3H), 4.98 (s, 2H), 4.40 (d, J = 12.5 Hz, 2H), 3.57 (d, J = 12.1 Hz, 2H), 3.41 (brs, 2H), 2.46 (s, 3H), 1.99 (dt, J = 8.1, 3.9 Hz, 1H), 1.45 (brs, 4H), 1.01 – 0.89 (m, 2H), 0.86 – 0.77 (m, 2H). Scheme 12 Preparation of 2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-N-(4-((3-cyclopropyl-1H- 1,2,4-triazol-1-yl)sulfonyl)-3-(trifluoromethyl)phenyl)acetamide (Compound 20)

[0052] Preparation of 12-1 A solution of 4-nitro-2-(trifluoromethyl)aniline (5 g, 24.26 mmol, 1 equiv) in AcOH (30 mL), HCl (10 mL) was treated with NaNO2(1.67 g, 24.26 mmol, 1 equiv) for 1 hour at 0 °C under nitrogen atmosphere. And then the saturated solution of SO2, CuCl (2.40 g, 24.26 mmol, 1 equiv) in AcOH (30 mL) was added into the above mixture dropwise at 0 °C and stirred for 1 hour. The mixture was neutralized to pH 7 with NaHCO3solid. The resulting mixture was extracted with EA (3 x 300 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 12-1 (4 g, 57%) as a yellow solid, it was used in the next step without any purification. m / z: [M+H]+Calcd for C7H4ClF3NO4S 289.9; Found 289.9. Preparation of 12-2 A solution of 3-cyclopropyl-1H-1,2,4-triazole (1.13 g, 10.36 mmol, 1.5 equiv) in DCM (20 mL) was treated with DIEA (2.68 g, 20.72 mmol, 3 equiv) at 0 °C, followed by the addition of 12-1 (2 g, 6.91 mmol, 1 equiv) dropwise at 0°C and stirred for 1 hour. The residue was purified by silica gel column chromatography, eluted with EA:PE (10%-40%) to afford 12-2 (2 g, 80%) as a yellow solid. m / z: [M+H]+Calcd for C12H10F3N4O4S 363.0; Found 363.0. Preparation of 12-3 A solution of 12-2 (1.8 g, 4.97 mmol, 1 equiv) in EA (40 mL) was treated with Pd / C (0.53 g) under H2atmosphere (3-4 atm) at 20 °C and stirred for 8 hours. The resulting mixture was filtered; the filter cake was washed with EA (3 x 100 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with conditions: C18-120 g, CH3CN / H2O (1% NH4OH), from 10% to 80% within 12 min, Flow rate: 70 mL / min, Detector, 254 nm. The fraction of the target was freezing dried to afford 12-3 (1 g, 60%) as a yellow solid. m / z: [M+H]+Calcd for C12H12F3N4O2S 333.1; Found 333.1. Preparation of Compound 19 To a solution of 5-12 (240 mg, 0.42 mmol, 1 equiv), DIEA (161 mg, 1.24 mmol, 3 equiv) and 12- 3 (152 mg, 0.46 mmol, 1.1 equiv) in EA (2 mL) was added T3P (1 mL, 50% in EA) at room temperature. The reaction mixture was stirred for 2 h at 50oC. Removed the solvent under reduce pressure, the residue was purified by Prep-HPLC with conditions: C18-120 g, Flow rate, 70 mL / min, CH3CN / H2O (0.05% NH4OH), from 20% to 90% within 12 min, Detector, 254 nm. Compound 19 (170 mg, 46%) was obtained as off-white solid. m / z: [M+H]+Calcd for C38H33ClFN9O6S 892.2; Found 892.2. Preparation of Compound 20 To the solution of Compound 19 (130 mg, 0.15 mmol, 1 equiv) in THF (4 mL), were added morpholine (38 mg, 0.44 mmol, 3 equiv) and Pd(PPh3)4(17 mg, 0.01 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction solution was purified by Prep-HPLC with the following conditions: Column, YMC-Actus Triart C18 Column, 30*150 mm, 5 um, mobile phase, H2O (0.5% NH4HCO3) / MeCN, 40% to 86% gradient in 7 min, detector, UV 254 nm. The fraction of the target was freezing dried, this resulted in Compound 20 (35 mg, 32%) as a white solid. m / z: [M+H]+Calcd for C38H33ClFN9O6S 808.2; Found 808.3.1H NMR (400 MHz, DMSO-d6) δ = 11.23 (s, 1H), 9.18 (s, 1H), 9.10 (s, 1H), 8.43 (d, J = 8.9 Hz, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.21 (ddd, J = 8.3, 7.3, 1.8 Hz, 2H), 8.10 (dd, J = 8.2, 1.4 Hz, 1H), 7.71 (dd, J = 8.2, 7.1 Hz, 1H), 7.66 – 7.51 (m, 3H), 5.01 (s, 2H), 4.41 (d, J = 12.3 Hz, 2H), 3.60 (d, J = 12.4 Hz, 2H), 3.45 (s, 2H), 1.98 (tt, J = 8.6, 4.8 Hz, 1H), 1.46 (s, 4H), 1.00 – 0.89 (m, 2H), 0.81 (dt, J = 4.8, 3.1 Hz, 2H). Scheme 13 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen- 1-yl)-2-(2-(4-((3-cyclopropyl-1H-1,2,4-triazol-1-yl)sulfonyl)-1H-pyrazol-1-yl)ethoxy)-8- fluoropyrido[4,3-d]pyrimidine (Compound 22)

[0053] Preparation of 13-1 Into a 50 mL round-bottom flask were added 3-cyclopropyl-1H-1,2,4-triazole (983 mg, 9.01 mmol, 3 eq.), DIEA (776 mg, 6.01 mmol, 2 eq) and DCM (15 mL) at room temperature. To the above mixture was added 1H-pyrazole-4-sulfonyl chloride (500 mg, 3 mmol, 1 eq.) in portions at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. After the reaction was over, the mixture was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 13-1. m / z: [M+H]+ Calcd for C8H10N5O2S 240.0; Found 240.1. Preparation of 13-2 Into the solution of 4 (500 mg, 0.90 mmol, 1 eq.) in DCM (20 mL) was added DIEA (350 mg, 2.71 mmol, 3 eq.) at room temperature. The mixture was cooled to 0oC, and then added TMSOTf (602 mg, 2.71 mmol, 3 eq.) dropwise into the above solution at 0oC. The resulting mixture was allowed to warm into the room temperature for 1 h. After the reaction was over, the reaction mixture was quenched by water and extracted with DCM (3 x 25 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 13-2 (390 mg, 95.19%) as a yellow solid., it was used into the next step directly without any purification. m / z: [M+H]+ Calcd for C23H19Cl2FN5454.1; Found 454.1. Preparation of 13-3 Into a 40 mL vial were added 13-2 (390 mg, 0.86 mmol, 1 eq.), DIEA (333 mg, 2.57 mmol, 3 eq.) and DCM (15 mL) at room temperature. To the above mixture was added chloro(prop-2-en-1- yloxy)methanone (104 mg, 0.86 mmol, 1 eq.) dropwise at 0 °C. The mixture was allowed to warm to RT and stirred for 30 min. The reaction mixture was quenched by water and extracted with DCM (3 x 25 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by EA / PE (50% to 80%, 6 min), this resulted in 13-3 (360 mg, 77.89%) as a yellow solid. m / z: [M+H]+ Calcd for C27H23Cl2FN5O2538.1; Found 538.2. Preparation of 13-4 To the solution of 13-3 (200 mg, 0.37 mmol, 1 eq.) in CH3CN (10 mL), were added K2CO3(154 mg, 1.11 mmol, 3 eq.) and ethylene glycol (231 mg, 3.71 mmol, 10 eq.) at room temperature. The resulting mixture was stirred for additional 2 h at 60°C. After the reaction was over, the resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL). The solid was filtered; the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. This resulted in 13-4 (200 mg, 95.46%) as a light yellow solid, it was used into the next step directly without any purification. m / z: [M+H]+ Calcd for C29H28ClFN5O4564.2; Found 564.1. Preparation of 13-5 To the solution of 13-4 (170 mg, 0.30 mmol, 1 eq.) in DCM (10 mL), was added TEA (61 mg, 0.60 mmol, 2eq.) at room temperature. To the above mixture was added MsCl (345 mg, 3.01 mmol, 10 eq.) dropwise at 0 °C. The mixture was allowed to warm to RT and stirred for overnight. The reaction mixture was quenched by water and extracted with DCM (3 x 25 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 13-5 (130 mg, 74.05%) as a yellow crude oil, it was used into the next step directly without any purification. m / z: [M+H]+ Calcd for C29H27Cl2FN5O3582.1; Found 582.1. Preparation of Compound 21 To the mixture of 13-5 (100 mg, 0.17 mmol, 1 eq.) and 3-cyclopropyl-1-(1H-pyrazole-4-sulfonyl)- 1,2,4-triazole (41 mg, 0.17 mmol, 1 eq.) in CH3CN (6 mL), were added K2CO3 (72 mg, 0.52 mmol, 3 eq.) and KI (14 mg, 0.07 mmol, 0.4 eq.) at room temperature. The resulting mixture was stirred for additional 12 h at 60 °C. After the reaction was over, the resulting mixture was filtered, the filter cake was washed with MeCN (20 mL). The filtrate was concentrated under reduced pressure. This resulted in Compound 21(100 mg, 74.18%) as a yellow crude oil, it was used into the next step directly without any purification. m / z: [M+H]+ Calcd for C37H35ClFN10O5S 785.2; Found 785.2. Preparation of Compound 22 To the solution of Compound 21(90 mg, 0.12 mmol, 1 eq.) in THF (5 mL), were added morpholine (100 mg, 1.15 mmol, 10 eq.) and Pd(PPh3)4 (53 mg, 0.05 mmol, 0.4 eq.) at room temperature. The resulting mixture was stirred for additional 1h at room temperature. After the reaction was over, the resulting mixture was filtered, the filter cake was washed with THF (5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: Column: Fluoro-Phenyl, 19x150 mm, 5μm; Mobile Phase A: Water(0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B to 36% B in 8min; Wave Length: 254 / 220 nm. This resulted in Compound 22 (16 mg, 19.31%) as a white solid. m / z: [M+H]+ Calcd for C33H31ClFN10O3S 701.2; Found 701.2.1H NMR (300 MHz, DMSO- d6) δ 9.22 (s, 1H), 9.02 (brs, 2H), 8.83 (d, J = 11.8 Hz, 2H), 8.23 (d, J = 8.1 Hz, 1H), 8.16 – 8.07 (m, 1H), 8.00 (s, 1H), 7.81 – 7.64 (m, 2H), 7.64 – 7.53 (m, 2H), 4.51 (dd, J = 36.9, 18.4 Hz, 6H), 4.18 (s, 2H), 3.77 (d, J = 13.8 Hz, 2H), 2.06 – 1.87 (m, 5H), 1.02 – 0.90 (m, 2H), 0.82 (dt, J = 5.0, 3.0 Hz, 2H). Scheme 14 Preparation of 2-((7-(2-(1-chlorovinyl)phenyl)-8-fluoro-4-(piperazin-1-yl)pyrido[4,3- d]pyrimidin-2-yl)oxy)-N-(4-((3-cyclopropyl-1H-1,2,4-triazol-1-yl)sulfonyl)phenyl)acetamide (Compound 24)

[0054] Preparation of 14-1 To a solution of 5-7 (500 mg, 1.37 mmol, 1 equiv, crude) and ethyl pyruvate (493 mg, 2.65 mmol, 2 equiv) in DCM (10 mL) was added DIEA ( 1767 mg, 13.7 mmol, 10 equiv) to confirm the pH = 9 at -20oC. The mixture was stirred at -20oC for 1 h. The mixture was quenched by H2O (10 mL), extracted by DCM (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA (3:1) to afford 14-1 (280 mg, 40.1%) as a yellow solid. m / z: [M+H]+Calcd for C26H24Cl2FN5O2528; Found 528. Preparation of 14-2 To a solution of ethyl 2-hydroxyacetate (110.5 mg, 1.06 mmol, 2 equiv) in THF (5 mL) was added NaH (53 mg, 1.32 mmol, 2.5 equiv) at 0oC. The resulting mixture was stirred for 10 min, and then was added to the solution of 14-1 (280 mg, 0.53 mmol, 1 equiv) in THF (1 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with sat. NH4Cl (10 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA (5:1-1:1) to afford 14-2 (220 mg, 69.62%) as a light yellow solid. m / z: [M+H]+Calcd for C30H32ClFN5O5596; Found 596. Preparation of 14-3 A stirred solution of 14-2 (220 mg, 0.37 mmol, 1 equiv) and DIEA (143 mg, 1.11 mmol, 3 equiv) in DCM (5 mL) was added TMSOTf (246 mg, 1.11 mmol, 3 equiv) at 0oC. The resulting mixture was stirred for 2 h at room temperature. The mixture was quenched by H2O (5 mL). The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure afford 14-3 (300 mg, crude) as a brown oil, it was used in the next step without any purification. m / z: [M+H]+Calcd for C25H24ClFN5O3496; Found 496. Preparation of 14-4 To a solution of l 14-3 (300 mg, 0.61 mmol, 1 equiv) and DIEA (234.5 mg, 1.82 mmol, 3.00 equiv) in DCM (5 mL), was added Alloc-Cl (65.9 mg, 0.55 mmol, 0.9 equiv) at 0oC. The mixture was stirred at room temperature for 2 h. The resulting mixture was quenched by H2O (5 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA (5:1-1:1) to afford 14-4 (180 mg, 51.4%) as a light yellow solid. m / z: [M+H]+Calcd for C29H27ClFN5O5579; Found 579. Preparation of Compound 23 To a stirred mixture of {[7-(8-chloronaphthalen-1-yl)-8-fluoro-4-{4-[(prop-2-en-1-yloxy) carbonyl] piperazin-1-yl} pyrido[4,3-d]pyrimidin-2-yl]oxy}acetic acid (130 mg, 0.24mmol, 1 equiv) and 4-(3-cyclopropyl-1,2,4-triazol-1-ylsulfonyl)aniline (75 mg, 0.28 mmol, 1.2 equiv) in EA (3 mL) was added DIEA (91 mg, 0.71 mmol, 3.0 equiv) and T3P (3 mL, 50% in EA) at room temperature under air atmosphere. The resulting mixture was stirred for additional 1 h at 50 °C. The mixture was basified to pH=8 with DIEA. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / THF (10:1) to afford prop-2-en-1-yl 4-[7-(8-chloronaphthalen-1-yl)-2-({[4-(3- cyclopropyl-1,2,4-triazol-1-ylsulfonyl) phenyl] carbamoyl} methoxy)-8-fluoropyrido[4,3-d] pyrimidin-4-yl] piperazine-1-carboxylate (120 mg, 63.83%) as a colorless solid. m / z: [M+H]+Calcd for C38H34ClFN9O6S 798.2; Found 798.2. Preparation of Compound 24 To a stirred solution of prop-2-en-1-yl 4-[7-(8-chloronaphthalen-1-yl)-2-({[4-(3-cyclopropyl- 1,2,4-triazol-1-ylsulfonyl) phenyl] carbamoyl} methoxy)-8-fluoropyrido[4,3-d] pyrimidin-4-yl] piperazine-1-carboxylate (100 mg, 0.13 mmol, 1 equiv) and morpholine (33 mg, 0.38 mmol, 3.0 equiv) in THF (2.50 mL), was added Pd(PPh3)4 (22 mg, 0.02 mmol, 0.15 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 1h at room temperature under nitrogen atmosphere. The crude product (120 mg) was purified by Prep-HPLC with the following conditions: column, C18 silica gel; mobile phase, 10 mmol / L NH4HCO3+0.1% NH3H2O in water, MeCN 30% to 45% gradient in 7 min; detector, UV 254 nm to afford 2-{[7-(8- chloronaphthalen-1-yl)-8-fluoro-4-(piperazin-1-yl) pyrido[4,3-d] pyrimidin-2-yl] oxy}-N-[4-(3- cyclopropyl-1,2,4-triazol-1-ylsulfonyl) phenyl] acetamide (Compound 24) (18 mg, 20.12%) as a white solid. m / z: [M+H]+Calcd for C34H30ClFN9O4S 714.2; Found 714.2.1H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.12 (d, J = 10.5 Hz, 2H), 8.20 (dd, J = 8.4, 1.4 Hz, 1H), 8.10 (dd, J = 8.2, 1.5 Hz, 1H), 8.05 – 7.97 (m, 2H), 7.93 – 7.84 (m, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.69 – 7.49 (m, 3H), 5.01 (s, 2H), 3.91 (s, 4H), 2.82 (d, J = 5.6 Hz, 4H), 2.00 (tt, J = 8.7, 4.8 Hz, 1H), 0.94 (dt, J = 8.2, 3.2 Hz, 2H), 0.89 – 0.75 (m, 2H). Scheme 15 Preparation of 2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7- fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-N-(4-((3-cyclopropyl-1H- 1,2,4-triazol-1-yl)sulfonyl)phenyl)acetamide (Compound 26) Preparation of 15-1 To a stirred solution of para-toluene sulfonate (520 mg, 3.05 mmol, 0.1 eq.) and NBS (6.5 g, 36.55 mmol, 1.2 eq.) in DCM (100 mL) was added 7-fluoro-3,4-dihydro-2H-naphthalen-1-one (5 g, 30.45 mmol, 1 eq.) in portions at 0 °C, then the mixture was stirred for 2 h at 40 °C. The resulting mixture was concentrated under vacuum, purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford 15-1 (6 g, 68.89%) as a brown oil. Preparation of Compound 24 To a stirred mixture of 15-1 (6 g, 24.68 mmol, 1 eq.) in DMF (80 mL), were added lithio methaneperoxoate lithium (3.1 g, 41.96 mmol, 1.7 eq.) and lithium bromide (3.6 g, 41.96 mmol, 1.7 eq.), the mixture was stirred for 3 h at 140 °C. The resulting mixture was diluted with diethyl ether (200 mL), extracted with EA (3 x 200 mL), and combine the organic layers and washed with water (2 x 100 mL) and brine (1 x 200 mL), and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 15-2 (3 g, 63.71%) as a brown solid.1H NMR (300 MHz, Chloroform-d) δ 7.86 – 7.78 (m, 2H), 7.46 (dd, J = 8.3, 1.0 Hz, 1H), 7.35 – 7.15 (m, 2H), 6.86 (dt, J = 7.4, 1.0 Hz, 1H). Preparation of 15-3 To a stirred solution of 15-2 (3 g, 18.50 mmol, 1 eq.) and (2-bromoethynyl)triisopropylsilane (5.8 g, 22.20 mmol, 1.2 eq.) in DCE (100 mL), were added (p-Cymene) ruthenium(II) chloride dimer (1.7 g, 2.77 mmol, 0.15 eq.), potassium methaneperoxoate potassium (2.6 g, 18.50 mmol, 1 eq.) and sodium acetate (300 mg, 3.70 mmol, 0.2 eq.) under nitrogen atmosphere, the mixture was stirred at 40 °C for 12 h. The resulting mixture was concentrated under vacuum, purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford 15-3 (3 g, 42.61%) as a yellow oil.1H NMR (300 MHz, Chloroform-d) δ 9.11 (s, 1H), 7.80 (dd, J = 9.1, 5.8 Hz, 1H), 7.44 – 7.32 (m, 2H), 7.24 (t, J = 8.8 Hz, 1H), 7.09 – 7.00 (m, 1H), 1.25 – 1.19 (m, 21H). Preparation of 15-4 To a stirred solution of 15-3 (3 g, 8.76 mmol, 1 eq.) in DCM (80 mL) was added DIEA (2.3 g, 17.52 mmol, 2 eq.) and Tf2O (3.7 g, 13.14 mmol, 1.5 eq.) at -40 °C under nitrogen atmosphere, and the mixture was stirred at -40 °C for 30 min. The resulting mixture was concentrated under vacuum, purified by silica gel column chromatography, eluted with PE / EA (8:1) to afford 15-4 (3 g, 64.96%) as a yellow oil. Preparation of 15-5 To a stirred mixture of 15-4 (3 g, 6.32 mmol, 1 eq.) and bis(pinacolato)diboron (1.9 g, 7.59 mmol, 1.2 eq.) in dioxane (60 mL) were added potassium acetate (1.2 g, 12.64 mmol, 2 eq.), Pd(dppf)Cl2 (930 mg, 1.26 mmol, 0.2 eq.) under nitrogen atmosphere, the mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under vacuum, purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford 15-5 (2 g, 62.93%) as an off-white solid. Preparation of 15-6 A solution of 2-chloro-3-fluoropyridin-4-amine (42 g, 286.59 mmol, 1 equiv) and NIS (77.37 g, 343.91 mmol, 1.2 equiv) in ACN (220 mL) was added TsOH (2.47 g, 14.33 mmol, 0.05 equiv) at room temperature and was stirred for 16 h at 70oC. After that, the resulting mixture was diluted with water and EA, the organic layer was washed with saturated NaHCO3 solution, saturated Na2SO3 solution and brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the 15-6 (90 g, crude) as a yellow solid m / z: [M+H]+Calcd for C5H4ClFIN2272.9;Found 272.9. Preparation of 15-7 To a solution of 2-chloro-3-fluoro-5-iodopyridin-4-amine (90 g, 330.33 mmol, 1 equiv) in EtOH (1700 mL) was added Pd(PPh3)2Cl2(23 g, 33.03 mmol, 0.1 equiv) and TEA (120 g, 1189.21 mmol, 3.6 equiv) and was stirred for 15 h at 80oC under CO (15 Psi) atmosphere. The resulting mixture was filtered, the filtrate was concentrated under reduced pressure to remove 70% of MeOH and the residue was filtered. The filter cakes was concentrated under reduced pressure to afford the 15- 7 (68 g, 94.16%) as a yellow solid m / z: [M+H]+Calcd for C8H9ClFN2O2219.0;Found 219.0. Preparation of 15-8 To a stirred solution of ethyl 4-amino-6-chloro-5-fluoropyridine-3-carboxylate (10 g, 45.7 mmol, 1 equiv) in THF (150 mL) was added trichloroethanecarbonyl isocyanate (12.9 g, 68.6 mmol, 1.5 equiv) dropwise at 0°C under nitrogen atmosphere. Then the solution was stirred for another 1 h at room temperature. The resulting mixture was concentrated under vacuum, diluted with MTBE (150 mL), and the precipitated solids were collected by filtration and washed with MTBE (2 x 100 mL) to afford ethyl 6-chloro-5-fluoro-4-{[(2,2,2-trichloroacetyl)carbamoyl]amino}pyridine-3- carboxylate (13 g, 62.8%) as a brown solid. m / z: [M+H]+Calcd for C11H9Cl4FN3O4408.0 ;Found 408.0. Preparation of 15-9 The solution of methyl 6-chloro-5-fluoro-4-{[(2,2,2-trichloroacetyl)carbamoyl]amino}pyridine-3- carboxylate (13 g, 33 mmol, 1 equiv) in NH3(g) (150 mL, 7 M in MeOH), was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum, and the resulting mixture was diluted with MTBE (150 mL). The precipitated solids were collected by filtration and washed with MTBE (2 x 100 mL). This resulted in 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4- diol (8 g, 98.7%) as an off-white solid. m / z: [M+H]+Calcd for C7H4ClFN3O2216.0 ; Found 216.0. Preparation of 15-10 To a stirred solution of POCl3 (100 mL) was added DIEA (24 g, 0.18 mol, 5 equiv) dropwised at 5°C. To the above mixture was added 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (8 g, 37 mmol, 1 equiv) in portions at 5 °C. The resulting mixture was stirred for additional 1 h at 100 °C. The resulting mixture was concentrated under vacuum to get 15-10, it was used into the next step without any purification. m / z: [M+H]+(weak) Calcd for C7H2Cl3FN3251.9 ; Found 251.9. Preparation of 15-11 To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (6 g, 24 mmol, 1 equiv) in DCM (100 mL) was added DIEA (6.14 g, 48 mmol, 2 equiv) dropwise at -40 °C and stirred for 15 min at this temperature. To the above mixture was added tert-butyl (1R,5S)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 24 mmol, 1 equiv) in DCM (20 mL) dropwise at - 40 °C. The resulting mixture was stirred for additional 30 min at this temperature. The resulting mixture was diluted with water (100 mL) The resulting mixture was extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1 / 1) to afford 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 (6.2 g, 57.9%) as a yellow solid. m / z: [M+H]+Calcd for C18H21Cl2FN5O2, 428.1 ; Found 428.1.1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 4.48 (s, 2H), 4.30 – 4.24 (m, 2H), 3.70 (s, 2H), 1.84 – 1.77 (m, 2H), 1.62 (d, J = 7.5 Hz, 2H), 1.47 (s, 9H). Preparation of 15-12 To a solution of ethyl 2-hydroxyacetate (243 mg, 2.34 mmol, 1 eq.) in THF (30 mL) was added sodium hydride (112 mg, 2.8 mmol, 60% in oil, 1.2 eq.) in portions at 0 °C. The mixture was stirred for 15 min at this temperature. Then 15-11 (1 g, 2.34 mmol, 1 eq.) was added into the above mixture, the resulting mixture was allowed to warm to RT and stirred for 30 min. The reaction mixture was quenched by water (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 15-12 (800 mg, 69.09%) as a yellow solid. m / z: [M+H]+Calcd for C22H28ClFN5O5496.2; Found 496.2. Preparation of 15-13 To the solution of 15-12 (780 mg, 1.57 mmol, 1 eq.) and 15-5 (1.1 g, 2.60 mmol, 1.7 eq.) in DME (20 mL) at room temperature, were added K2CO3(652 mg, 4.72 mmol, 3 eq.), cataCXium A Pd G3 (115 mg, 0.16 mmol, 0.1 eq.) and H2O (2 mL) at room temperature under N2 atmosphere. The resulting mixture was stirred for additional 1 h at 80°C. After the reaction was over, the resulting mixture was diluted with CH2Cl2(100 mL). the water (50 mL) was added into the solution The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1:1) to afford 15-13(1 g, 80.89%) as a brown oil. m / z: [M+H]+Calcd for C43H54F2N5O5Si 786.4; Found 786.5. Preparation of 15-14 To the solution of 15-13 (880 mg, 1.12 mmol, 1 eq.) in DCM (20 mL), was added HCl (gas) (10 mL, 4 M in 1,4-dioxane) dropwise at 0°C. The mixture was allowed to warm to RT and stirred for 1 h. After the reaction was over, the resulting mixture was concentrated under vacuum. This resulted in 15-14 (840 mg) as a yellow solid, it was used into the next step without any purification. m / z: [M+H]+Calcd for C38H46F2N5O3Si 686.3; Found 686.4. Preparation of 15-15 To the solution of 15-14 (850 mg, 1.24 mmol, 1 eq.) in DCM (30 mL), were added DIEA (481 mg, 3.72 mmol, 3 eq.) and chloro(prop-2-en-1-yloxy) methanone (150 mg, 1.24 mmol, 1 eq.) dropwise at 0°C. The mixture was allowed to warm to RT and stirred for 30 min. The reaction mixture was quenched by water (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 15-15 (821 mg, 86.04%) as a yellow oil, it was used into the next step without any purification. m / z: [M+H]+Calcd for C42H50F2N5O5Si 770.3; Found 770.4. Preparation of 15-16 To the solution of 15-15 (400 mg, 0.52 mmol, 1 eq.) in THF (20 mL), MeOH (1 mL) and H2O (1 mL), was added LiOH.H2O (109 mg, 2.60 mmol, 5 eq.) at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. After the reaction was over, the mixture was acidified to pH 6 with 2 M HCl (aqueous). The water was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 15-16 (330 mg, 85.62%) as a yellow solid, it was used into the next step without any purification. m / z: [M+H]+Calcd for C40H46F2N5O5Si 742.3; Found 742.3. Preparation of 15-17 To the solution of 15-16 (200 mg, 0.27 mmol, 1 eq.) in DMF (10 mL), was added CsF (123 mg, 0.81 mmol, 3 eq.) at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The reaction mixture was quenched with water (50 mL). The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with water (2 x 50 mL) and brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 15-17 (140 mg, 88.69%) as a yellow crude solid, it was used into the next step without any purification. m / z: [M+H]+ Calcd for C31H26F2N5O5, 586.2; Found 586.2 Preparation of Compound 25 To the solution of 15-17 (120 mg, 0.21mmol, 1 eq.), 4-(3-cyclopropyl-1,2,4-triazol-1- ylsulfonyl)aniline (55 mg, 0.21mmol) in EA (10 mL), was added DIEA (80 mg, 0.62 mmol, 3 eq.) and T3P (652 mg, 2.05 mmol, 10 eq., 50% in ethyl acetate) at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. After the reaction was over, the resulting mixture was quenched by water (30 mL), extracted with EtOEt (3 x 50 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:9) to afford Compound 25 (110 mg, 64.53%) as a yellow solid. m / z: [M+H]+Calcd for C42H36F2N9O6S 832.2; Found 832.2

[0055] Preparation of Compound 26 To the solution of Compound 25 (100 mg, 0.12 mmol, 1 eq.) in THF (5 mL), were added morpholine (105 mg, 1.20 mmol, 10 eq.) and Pd(PPh3)4 (56 mg, 0.05 mmol, 0.4 eq.) at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. After the reaction was over, the resulting mixture was filtered, the filter cake was washed with THF (5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: Mobile Phase A: Water(10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 35 mL / min; Column: YMC- Actus Triart C18 ExRS, 30x150 mm, 5μm; Gradient: 45% B to 62% B in 7 min, 62% B; Wave Length: 220&254 nm. This resulted in Compound 26 (13 mg, 13.32%) as a white solid. m / z: [M+H]+ Calcd for C38H32F2N9O4S 748.2; Found 424.1.1H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.13 (s, 1H), 9.06 (s, 1H), 8.28 – 8.14 (m, 2H), 8.02 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H), 7.74 – 7.55 (m, 3H), 4.98 (d, J = 2.2 Hz, 2H), 4.46 (d, J = 12.4 Hz, 1H), 4.30 (d, J = 12.0 Hz, 1H), 4.00 (d, J = 1.1 Hz, 1H), 3.63 (d, J = 11.8 Hz, 1H), 3.53 (d, J = 12.0 Hz, 1H), 3.42 – 3.39 (m, 2H), 1.99 (td, J = 8.4, 4.2 Hz, 1H), 1.46 (brs, 4H), 1.01 – 0.89 (m, 2H), 0.86 – 0.74 (m, 2H). Scheme 16 Preparation of 2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-N-(4-((3-(tert-butyl)-1H-1,2,4- triazol-1-yl)sulfonyl)phenyl)acetamide (Compound 28) Preparation of 16-1 Into a 250 mL round-bottom flask were added pivalamide (5 g, 49.43 mmol, 1 eq.) and DMF- DMA (100 mL) at room temperature. The resulting mixture was stirred for additional 1 h at 90°C. After the reaction was over, the resulting mixture was concentrated under vacuum. This resulted in 16-1 (6.9 g, 89.35%) as a white solid. The crude 16-1 was used in next step directly without further purification. m / z: [M+H]+Calcd for C8H17N2O 157.1; Found 157.1. Preparation of 16-2 To the solution of 16-1 (6.9 g, 44.17 mmol, 1 eq.) in AcOH (200 mL), was added NH2NH2.H2O (4.4 g, 88.33 mmol, 2 eq.) dropwise at 10 °C. The resulting mixture was stirred for additional 3 h at room temperature. After the reaction was over, the mixture was acidified to pH 2 with 4 M HCl(gas)in 1,4-dioxane. The resulting mixture was filtered; the filter cake was washed with EtOAc (2 x 30 mL). The filtrate was concentrated under reduced pressure. This resulted in 16-2 (4.5 g, 81.40%) as a yellow crude solid. The crude 16-2 was used in next step directly without further purification. m / z: [M+H]+Calcd for C6H12N3126.1; Found 126.2 Preparation of 16-3 To the solution of 16-2 (1.7 g, 13.54 mmol, 1 eq.) in DCM (50 mL), was added DIEA (5.3 g, 40.61 mmol, 3 eq.) at room temperature. The mixture was stirred for 5 min. Then to the above mixture was added 4-nitrobenzenesulfonyl chloride (3 g, 13.54 mmol, 1 eq.) at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. After the reaction was over, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 16-3 (2.3 g, 32.85%) as a white solid. m / z: [M+H]+Calcd for C12H15N4O4S 311.1; Found 311.1. Preparation of 16-4 To a solution of 16-3 (500 mg, 1.61 mmol) in THF (50 mL), was added Pd / C (250 mg) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 1 days under hydrogen atmosphere using a hydrogen balloon. The reaction was finished, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by PE / EA (50%-70%, 5 min), this resulted 16-4 (440 mg, 48.71%) as an orange solid. m / z: [M+H]+Calcd for C12H16N4O2S 281.1; Found 281.2. Preparation of Compound 27 To the solution of 5-12 (150 mg, 0.26 mmol, 1 eq.) and 16-4 (73 mg, 0.26 mmol) in EA (25 mL), were added DIEA (101 mg, 0.78 mmol, 3 eq.) and T3P (826 mg, 2.60 mmol, 10 eq., 50% in EA) at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. After the reaction was over, the resulting mixture was diluted with EtOAc (25 mL). The resulting mixture was washed with water (50 mL). The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in Compound 27 (120 mg, 55.03%) as a yellow crude solid. It was used into the next step directly without further purification. m / z: [M+H]+Calcd for C41H40ClFN9O6S 840.2; Found 840.2. Preparation of Compound 28 To the solution of Compound 27 (110 mg, 0.13 mmol, 1 eq.) in THF (5 mL), were added morpholine (114 mg, 1.31 mmol, 10 eq.) and Pd(PPh3)4(61 g, 0.05 mmol, 0.4 eq.) at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. After the reaction was over, the resulting mixture was filtered, the filter cake was washed with THF (5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 35 mL / min; Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Gradient: 10% to 50% in 10 min; 53% B to 66% B in 7 min, 66% B; Wavelength: 220&254 nm. This resulted in Compound 28 (32 mg, 31.68%) as a white solid. m / z: [M+H]+ Calcd for C37H36ClFN9O4S 756.2; Found 756.2.1H NMR (300 MHz, DMSO- d6) δ 10.89 (s, 1H), 9.18 (s, 1H), 9.09 (s, 1H), 8.19 (dd, J = 8.2, 1.4 Hz, 1H), 8.09 (dd, J = 8.0, 1.4 Hz, 1H), 8.03 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H), 7.77 – 7.67 (m, 1H), 7.66 – 7.52 (m, 3H), 4.98 (s, 2H), 4.40 (d, J = 12.3 Hz, 2H), 3.57 (d, J = 12.2 Hz, 2H), 3.39 (brs, 2H), 1.43 (s, 4H), 1.22 (s, 9H). Scheme 17 Preparation of 2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-N-(4-((3-methyl-1H-1,2,4- triazol-1-yl)sulfonyl)phenyl)acetamide (Compound 30) Preparation of 17-1 A mixture of 3-methyl-1H-1,2,4-triazole (1.12 g, 13.54 mmol, 1.5 equiv) and DIEA (3.50 g, 27.08 mmol, 3 equiv) in THF (20 mL) was added the 4-nitrobenzenesulfonyl chloride (2 g, 9.02 mmol, 1 equiv), and stirred for 2 h at room temperature under N2 atmosphere. The resulting mixture was quenched with water (100 mL), extracted with EA (3 x 10 mL). The combined organic layer was washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 17-1 was used in the next step directly. m / z: [M+H]+Calcd for C9H8N4O4S 269.0; Found 269.0. Preparation of 17-2 A solution of 17-1 (2 g, 7.46 mmol, 1 equiv) in EA (20 mL), was added and Pd / C (2 g), and the mixture was stirred for 1 h at room temperature under H2 atmosphere (3-4 atm). The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18-120 g, mobile phase, H2O in ACN, 10% to 50% gradient in 10 min; detector, UV 254 nm. The fraction obtained was concentrate and passed through Chiral-SFC, Column: CHIRALPAK IF, 3*25 cm, 5 μm, Mobile Phase A: CO2, Mobile Phase B: ACN: DCM=2: 1, Flow rate: 80 mL / min, Gradient: isocratic 50% B, Wave Length: 220 nm to afford 17-2 (400 mg, 22%) as white solid. m / z: [M+H]+Calcd for C9H10N4O2S 239.1; Found 239.1. Preparation of Compound 29 To a mixture of 5-12 (200 mg, 0.34 mmol, 1 equiv), 17-2 (88 mg, 0.37 mmol, 1.1 equiv), DIEA (134 mg, 1.04 mmol, 3 equiv) in ethyl acetate (1 mL), T3P (1 mL, 50% in EA) was added. The mixture was stirred for 2 h at 50oC. And removed the solvent under reduce pressure, the residue was purified by Prep-HPLC with conditions: C18-120 g, CH3CN / H2O (0.05% NH4OH), from 30% to 80% within 12 min, Flow rate, 70 mL / min, Detector, 254 nm. The fraction of target was freezing fried. Compound 29 (170 mg, 61%) was obtained as white solid. m / z: [M+H]+Calcd for C38H33ClFN9O6S 798.2; Found 798.2. Preparation of Compound 30 To a solution of Compound 29 (170 mg, 0.21 mmol, 1 equiv) in THF (3 mL), Morpholine (56 mg, 0.64 mmol, 3 equiv) and Pd(PPh3)4(24 mg, 0.02 mmol, 0.1 equiv) were added at room temperature. The reaction solution was stirred for 2 h. The reaction solution was directly purified by Prep-HPLC with the following conditions: Column, Welch XB-C18, 21.2*250 mm, 5 um, mobile phase, water (0.05% NH4OH) and CH3CN (30% Phase B up to 70% in 12 min), Detector, 254 nm. The fraction of target was froze, 70 mg target was obtained with purity 83.7%. The crude was further purified by Prep-HPLC once again with the following conditions: Column, Welch XB- C18, 21.2*250 mm, 5 um, mobile phase, water (0.05% NH4OH) and CH3CN / THF (1:1) (30% Phase B up to 70% in 12 min), Detector, 254 nm. The fraction of target was freezing dried, 35 mg target was obtained with purity 82.5%. It was further purified by Prep-HPLC with the following conditions: Column, Welch XB-C18, 21.2*250 mm, 5 um, mobile phase, water (0.05% NH4OH) and CH3CN (30% Phase B up to 70% in 12 min), Detector, 254 nm. The fraction of target was freezing dried, Compound 30 (14.5 mg, 9.5%) was obtained as white solid. m / z: [M+H]+Calcd for C34H29ClFN9O4S 714.2; Found 714.2.1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.20 (s, 1H), 9.10 (s, 1H), 8.20 (dd, J = 8.2, 1.4 Hz, 1H), 8.10 (dd, J = 8.1, 1.4 Hz, 1H), 8.06 - 7.99 (m, 2H), 7.94 - 7.87 (m, 2H), 7.72 (t, J = 7.7 Hz, 1H), 7.67 - 7.51 (m, 3H), 4.99 (s, 2H), 4.42 (d, J = 12.5 Hz, 2H), 3.60 (d, J = 12.4 Hz, 2H), 3.46 (s, 2H), 2.27 (s, 3H), 1.47 (s, 4H). Scheme 18 Preparation of 2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8- chloronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)-N-(4-((3-cyclopentyl-1H- 1,2,4-triazol-1-yl)sulfonyl)phenyl)acetamide (Compound 32)

[0056] Preparation of 18-1 To the solution of cyclopentanecarbonyl chloride (9.0 g, 68 mmol, 1 equiv) in tetrahydrofuran (100 mL), was purged with NH3(gas) at 0 °C for 15 min. The resulting mixture was concentrated under vacuum to afford cyclopentanecarboxamide (14 g, crude) as a white solid. It was used in the next step without any purification. m / z: [M+H]+Calcd for C6H12NO 114; Found 114. Preparation of 18-2 The solution of cyclopentanecarboxamide (14 g, 123.7 mmol, 1 equiv) in DMF.DMA(100 mL) was stirred for 2 h at 80oC. After that, the resulting mixture was concentrated under vacuum to afford N-[(1E)-(dimethylamino)methylidene]cyclopentanecarboxamide (21 g, crude) as a brown solid. Then to a stirred mixture of N-[(1E)- (dimethylamino)methylidene]cyclopentanecarboxamide (21 g, 124.8 mmol, 1 equiv) in acetic acid (100 mL) was added hydrazine hydrate (12.5 g, 249.6 mmol, 2.0 equiv) dropwise at room temperature, and stirred for 12 h at the same temperature. The resulting mixture was concentrated under vacuum, and purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3-cyclopentyl-1H-1,2,4-triazole (6.3 g, crude) as a white solid. m / z: [M+H]+Calcd for C7H12N3138; Found 138. Preparation of 18-3 To the solution of 3-cyclopentyl-1H-1,2,4-triazole (5.8 g, 42 mmol, 1 equiv) in DCM (60 mL), was added DIEA (10.9 g, 84.5 mmol, 2 equiv). And then 4-nitrobenzenesulfonyl chloride (9.4 g, 42 mmol, 1 equiv) was added dropwise at 0 °C, it was stirred for 1 h at room temperature. The resulting mixture was diluted with CH2Cl2(100 mL), and quenched by water (100 mL). The aqueous layer was extracted with CH2Cl2(2 x 50 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 3-cyclopentyl-1-(4-nitrobenzenesulfonyl)-1,2,4-triazole (4 g, 29.3%) as a white solid. m / z: [M+H]+Calcd for C13H15N4O4S 323; Found 323. Preparation of 18-4 The solution of 3-cyclopentyl-1-(4-nitrobenzenesulfonyl)-1,2,4-triazole (400 mg, 1.2 mmol, 1 equiv) in EA (5 mL) and treated with Pd / C (400 mg) under hydrogen atmosphere at room temperature for 3 days. The resulting mixture was filtered; the filter cake was washed with EtOAc (2 x 30 mL). The filtrate was concentrated under reduced pressure to afford 310 mg 4-((3- cyclopentyl-1H-1,2,4-triazol-1-yl)sulfonyl)aniline as a white solid. The residue was purified by flash silica gel chromatography by PE / EA (50% to 80%, 6 min). m / z: [M+H]+Calcd for C13H17N4O2S 293; Found 293. Preparation of Compound 31 To the solution of {[7-(8-chloronaphthalen-1-yl)-8-fluoro-4-{8-[(prop-2-en-1-yloxy)carbonyl]- 3,8-diazabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-2-yl]oxy}acetic acid (200 mg, 0.3 mmol, 1.0 equiv) in EA (1 mL), were added 4-(3-cyclopentyl-1,2,4-triazol-1-ylsulfonyl)aniline (101 mg, 0.3 mmol, 1.0 equiv), DIEA (268 mg, 2.1 mmol, 7 equiv) and T3P (1 mL, 50% EA) at room temperature. The resulting mixture was quenched with water (20 mL). The aqueous lay was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9:1) to afford prop-2-en-1-yl 3-[7-(8-chloronaphthalen-1-yl)-2-({[4-(3-cyclopentyl-1,2,4- triazol-1-ylsulfonyl)phenyl]carbamoyl}methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 87% purity) as a yellow solid. m / z: [M+H]+ Calcd for C42H40ClFN9O6S 852; Found 852. Preparation of Compound 32 To the solution of prop-2-en-1-yl 3-[7-(8-chloronaphthalen-1-yl)-2-({[4-(3-cyclopentyl-1,2,4- triazol-1-ylsulfonyl)phenyl]carbamoyl}methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.35 mmol, 1 equiv) in THF (4 mL), were added morpholine (307 mg, 3.5 mmol, 10 equiv), tetrakis(triphenylphosphine)palladium (163 mg, 0.14 mmol, 0.4 equiv) at room temperature under N2 atmosphere, and the mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (XSelect CSH Column, 30*150mm 5um 10nm, Mobile Phase A: H2O (0.05% NH3 / H2O), Mobile Phase B: ACN (the velocity of 40ml / min,28% B to 58% B in 12min; Detector, 220 nm) to afford 2-{[7-(8- chloronaphthalen-1-yl)-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-2- yl]oxy}-N-[4-(3-cyclopentyl-1,2,4-triazol-1-ylsulfonyl)phenyl]acetamide (Compound 32) (32 mg, 11.6%) as a white solid. m / z: [M+H]+Calcd for C38H36ClFN9O4S 768.2 Found 768.2.1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.19 (s, 1H), 9.09 (s, 1H), 8.20 (dd, J = 8.3, 1.4 Hz, 1H), 8.10 (dd, J = 8.2, 1.5 Hz, 1H), 8.06 – 7.98 (m, 2H), 7.96 – 7.86 (m, 2H), 7.77 – 7.63 (m, 1H), 7.68 – 7.51 (m, 3H), 4.98 (s, 2H), 4.41 (d, J = 12.4 Hz, 2H), 3.58 (d, J = 12.2 Hz, 2H), 3.43 (s, 2H), 3.09 (d, J = 8.1 Hz, 1H), 1.94 – 1.85 (m, 2H), 1.70 – 1.55 (m, 6H), 1.45 (s, 4H). Scheme 19 Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(4-(3-((3-cyclopropyl-1H- 1,2,4-triazol-1-yl)sulfonyl)-1H-pyrazol-1-yl)butoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidine (Compound 34)

[0057] Preparation of 19-1 To a stirred solution of 3-iodo-1H-pyrazole (2 g, 10.31 mmol, 1 equiv) in ACN (40 mL) were added 4-bromobutan-1-ol (2.37 g, 15.46 mmol, 1.5 equiv) and Cs2CO3(6.72 g, 20.62 mmol, 2 equiv) in sequence. The resulting mixture was stirred for 16 h at 80 °C. The mixture was allowed to cool down to room temperature, diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford 19- 1 (0.9 g, 33%) as a colorless oil. m / z: [M+H]+Calcd for C7H12IN2O 267.0; Found 267.0.1H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 2.2 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 4.43 (t, J = 5.2 Hz, 1H), 4.11 (t, J = 7.1 Hz, 2H), 3.39 (td, J = 6.4, 5.1 Hz, 2H), 1.81 – 1.72 (m, 2H), 1.42 – 1.27 (m, 2H). Preparation of 19-3 To a stirred solution of 19-2 (2 g, 2.62 mmol, 1 equiv) and 19-1 (1.05 g, 3.93 mmol, 1.5 equiv) in toluene (30 mL) was added t-BuONa (0.50 g, 5.25 mmol, 2 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1 to 2:1) to afford 19-3 (1.7 g, 68%) as a yellow solid. m / z: [M+H]+Calcd for C46H57F2IN7O3Si 948.3; Found 948.3. Preparation of 19-4 To a stirred solution of 19-3 (1.5 g, 1.58 mmol, 1 equiv) and thiourea dioxide (0.51 g, 4.74 mmol, 3 equiv) in DMSO (30 mL) were added Cs2CO3(1.03 g, 3.16 mmol, 2 equiv) and Pd(dppf)Cl2(0.12 g, 0.15 mmol, 0.1 equiv) in sequence. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was cooled to room temperature, and stirred for 2 h at room temperature under oxygen atmosphere. The resulting mixture 19-4 was used in the next step directly without purification. m / z: [M+H]+Calcd for C46H58F2N7O6SSi 902.4; Found 902.4. Preparation of 19-5 To the reaction solution of 19-4 in DMSO (30 mL) was added CsF (1.2 g, 5 equiv). The resulting mixture was stirred for 2 h at room temperature. The PH value was adjusted to 7 with formic acid. The crude product was purified by Prep-HPLC with the following conditions: Column, Kinetex EVO C18 Column, 21.2*150 mm, 5 um; mobile phase, water (0.1% TFA) and ACN (10% Phase B up to 50% in 15 min); Detector, UV 254 nm. This resulted in 19-5 (720 mg) as a yellow solid. m / z: [M+H]+Calcd for C37H38F2N7O6S 746.2; Found 746.2 Preparation of 19-6 To a stirred solution of 19-5 (250 mg, 0.33 mmol, 1 equiv) and pyridine (132 mg, 1.67 mmol, 5 equiv) in DCM (5 mL) was added POCl3(154 mg, 1.00 mmol, 3 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 20 h at room temperature. The crude product 19-6 was used in the next step directly without purification. m / z: [M+H]+Calcd for C37H37ClF2N7O5S 764.2; Found 764.2. Preparation of Compound 33 To a stirred solution of 3-cyclopropyl-1H-1,2,4-triazole (142 mg, 1.30 mmol, 4 equiv) and pyridine (258 mg, 3.27 mmol, 10 equiv) in DCM (5 mL) were added 19-6 (reaction solution from last step) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature. Concentrated under reduced pressure to remove the solvent, the residue was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19*150 mm, 5 um; mobile phase, water (10 mmol / L NH4HCO3) and ACN (30% Phase B up to 40% in 7 min); Detector, UV 254 nm. This resulted in Compound 33 (120 mg, 44%) as a light yellow solid. m / z: [M+H]+Calcd for C42H43F2N10O5S 837.3; Found 837.3. Preparation of Compound 34 To a stirred solution of Compound 33 (110 mg, 0.13 mmol, 1 equiv) and DIEA (67 mg, 0.52 mmol, 4 equiv) in DCM (4 mL) was added TMSOTf (146 mg, 0.65 mmol, 5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep- HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19*150 mm, 5 um; mobile phase, water (10 mmol / L NH4HCO3) and ACN (30% Phase B up to 40% in 7 min); Detector, UV 254 nm. This resulted in Compound 34 (50 mg, 51%) as a white solid. m / z: [M+H]+Calcd for C37H35F2N10O3S 737.3; Found 737.3.1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.05 (s, 1H), 8.29 – 8.17 (m, 2H), 8.14 (d, J = 2.4 Hz, 1H), 7.75 – 7.55 (m, 3H), 7.05 (d, J = 2.4 Hz, 1H), 4.45 (d, J = 12.3 Hz, 1H), 4.37 – 4.26 (m, 5H), 4.00 (s, 1H), 3.67 – 3.51 (m, 4H), 2.11 – 1.88 (m, 3H), 1.69 – 1.60 (m, 6H), 1.02 – 0.89 (m, 2H), 0.86 – 0.78 (m, 2H). Scheme 20 Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7- fluoronaphthalen-1-yl)-8-fluoro-2-(4-(3-((3-methyl-1H-1,2,4-triazol-1-yl)sulfonyl)-1H-pyrazol- 1-yl)butoxy)pyrido[4,3-d]pyrimidine (Compound 36) Preparation of 20-1 To a stirred mixture of 19-5 (100 mg, 0.13 mmol, 1 equiv) and pyridine (85 mg, 1.07 mmol, 8 equiv) in DCM (20 mL) was added POCl3 (103 mg, 0.67 mmol, 5 equiv) dropwise at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture of 20-1 was used in the next step directly without purification. m / z: [M+H]+Calcd for C37H37ClF2N7O5S 764.2; Found 764.2. Preparation of Compound 35 To the reaction mixture of last step containing 20-1 was added pyridine (104 mg, 1.31 mmol, 10 equiv) and 3-methyl-1H-1,2,4-triazole (54 mg, 0.66 mmol, 5 equiv) in sequence at room temperature. The resulting mixture was stirred for additional 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18-40 g, mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 70% gradient in 15 min; detector, UV 254 nm. The fraction of the target was freezing dried, this resulted in Compound 35 (60 mg, 64%) as a light yellow solid. m / z: [M+H]+Calcd for C40H41F2N10O5S 811.3; Found 811.3 Preparation of Compound 36 To a stirred solution of Compound 35 (60 mg, 0.09 mmol, 1 equiv), DIEA (48 mg, 0.37 mmol, 4 equiv) in DCM (3 mL) was added TMSOTf (103 mg, 0.47 mmol, 5 equiv) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature. Concentrated under reduced pressure to remove the solvent at low temperature, the residue was dissolved in acetonitrile (4 mL) and purified by Prep-HPLC with the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5 um, mobile phase, water (0.05% NH4HCO3) and CH3CN (30% Phase B up to 85% in 10 min), Detector, 254 nm. The fraction of the target was freezing dried to afford Compound 36 (22.1 mg, 33%) as an off-white solid. m / z: [M+H]+Calcd for C35H32FN10O3S 711.2; Found 711.2.1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 9.06 (s, 1H), 8.27 – 8.17...

Claims

CLAIMS We claim:

1. A compound of Formulaor a pharmaceutically acceptable salt thereof; wherein: KRAS Recognition Moiety is selected from the group consisting of, , ,,R1is selected from the group consisting of:R6is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R18; R7, R7a, R7b, R7c, and R7dare independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17;R13is selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, aryl, -OR6, -N(R6)2, -C(O)R6, -NR6C(O)R6, -C(O)N(R6)2, and -NR6C(O)N(R6)2, each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R16is a heteroaryl group, where the bond to the sulfur atom is through one of the nitrogen atoms present in the cycle, and R16is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R17is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6; R18is independently selected in each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R19, -OC(O)R19, -NR19C(O)R19, -C(O)OR19, -OC(O)OR19, -NR19C(O)OR19, -C(O)N(R19)2, -OC(O)N(R19)2, -NR19C(O)N(R19)2, -OR19, -N(R19)2, -S(O)R19, -S(O)2R19, -S(O)OR19, -S(O)2OR19, -S(O)N(R19)2, S(O)2N(R19)2, and -SR19; R19is independently selected at each instance from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; R27, R27a, R27b, R27c, R27d, R27e, and R27fare independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R18; R28, R28a, R28b, and R28cis independently selected at each instance from hydrogen, F, Br, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, nitro, -C(O)R6, -OC(O)R6, -NR6C(O)R6, -C(O)OR6, -OC(O)OR6, -NR6C(O)OR6, -C(O)N(R6)2, -OC(O)N(R6)2, -NR6C(O)N(R6)2, -OR6, -N(R6)2, -S(O)R6, -S(O)2R6, -S(O)OR6, -S(O)2OR6, -S(O)N(R6)2, S(O)2N(R6)2, and -SR6, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl,heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R18; R29is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, halogen and heteroaryl each of which is optionally substituted with 1 or 2 substituents independently selected from R17; R31is selected from the group consisting of -O-, -S-, -S(O)-, -S(O)2-, -NR6-, -C(O)NR6- and -CF2- wherein one bond is to the KRAS Recognition Moiety and other bond is to Linker; R33is an aryl, heteroaryl, or bicycle optionally substituted with q substituents independently selected at each instance from R27, R27a, R27b, R27c, R27d, R27e, and R27f; R33Bis an aryl, heteroaryl, or bicycle optionally substituted with q substituents independently selected at each instance from R28, R28a, R28b, and R28c; R35is independently selected from hydrogen, alkyl, cycloalkyl, -alkyl-cycloalkyl, -alkyl- aryl, aryl, heterocycle, -alkyl-heterocycle, and heteroaryl each of which is optionally substituted with 1 or 2 substituents independently selected from R17; R43is an aryl or bicycle substituted with R41and optionally substituted with q substituents independently selected at each instance from R27; each q is independently 0, 1, 2, or 3; R29Bis cycloalkyl, heterocycle, or heteroaryl substituted with R41and is optionally substituted with 1 or 2 substituents independently selected from R17; R41is selected from the group consisting of bond, -O-, -S-, -S(O)-, -S(O)2-, -NR6-, -C(O)NR6- and -CF2- wherein one bond is to the KRAS Recognition Moiety and other bond is to Linker; R51is independently selected from the group consisting of bond, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocycle, heteroaryl, bicycle, tricycle, -S-, -O-, -NR6-, -C(O)-, - C(O)-NR6-, -C(O)-O-, –(CH2CH2O)p–, -S(O)2-, -S(O)2NR6-, and -S(O)2O-, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; R52is C0-6alkyl-N(R6)2or C0-6alkyl-heterocycle, each of which is optionally substituted with 1, 2, or 3, substituents selected from R18; Linker is:wherein: X1, X2, X3, X4, X5, and X6are bivalent moieties independently selected from the group consisting of bond, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocycle, heteroaryl, bicycle, tricycle, -S-, -O-, -NR6-, -C(O)-, -C(O)-NR6-, -C(O)-O-, –(CH2CH2O)p–, -S(O)2-, -S(O)2NR6-, and -S(O)2O-, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; and p is 1, 2, 3, 4, or 5.

2. The compound of claim 1 of Formula:or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, of Formula4. The compound of any one of claims 1-3, wherein R16is a triazole.

5. The compound of any one of claims 1-4, wherein R16is.

6. The compound of any one of claims 1-3, wherein R16is.

7. The compound of any one of claims 1-4, wherein R16is.

8. The compound of any one of claims 1-3, wherein R16is9. The compound of claim 1, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

11. The compound of claim 9 or 10, wherein R1is .

12. The compound of any one of claims 1-11, wherein R7ais hydrogen.

13. The compound of any one of claims 1-11, wherein R7cis alkyl.

14. The compound of any one of claims 1-11, wherein R7cis cyclopropyl.

15. The compound of any one of claims 1-11, wherein R7cis phenyl.

16. The compound of any one of claims 1-15, wherein R6is independently selected at each instance from alkyl, haloalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl; each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R18.

17. The compound of any one of claims 1-15, wherein R6is alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R18.

18. The compound of any one of claims 1-15, wherein R6is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R18.

19. The compound of any one of claims 1-15, wherein R6is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R18.

20. The compound of any one of claims 1-15, wherein R6is aryl optionally substituted with 1, 2, 3, or 4 substituents selected from R18.

21. The compound of any one of claims 1-15, wherein R6is heterocycle optionally substituted with 1, 2, 3, or 4 substituents selected from R18.

22. The compound of any one of claims 1-15, wherein R6is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R18.

23. The compound of any one of claims 1-22, wherein R6is not substituted with R18.

24. The compound of any one of claims 1-22, wherein R6is substituted with 1 substituent selected from R18.

25. The compound of any one of claims 1-22, wherein R6is substituted with 2 substituents independently selected from R18.

26. The compound of any one of claims 1-25, wherein R7, R7a, R7b, R7c, and R7dare independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, and nitro, wherein each alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from R17.

27. The compound of any one of claims 1-23, wherein one of R7, R7a, R7b, R7c, and R7dis alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17.

28. The compound of any one of claims 1-25, wherein one of R7, R7a, R7b, R7c, and R7dis haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17.

29. The compound of any one of claims 1-25, wherein one of R7, R7a, R7b, R7c, and R7dis phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17.

30. The compound of any one of claims 1-25, wherein one of R7, R7a, R7b, R7c, and R7dis heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from R17.

31. The compound of any one of claims 1-25, wherein one of R7, R7a, R7b, R7c, and R7dis haloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17.

32. The compound of any one of claims 1-25, wherein one of R7, R7a, R7b, R7c, and R7dis heterocycle optionally substituted with 1, 2, 3, or 4 substituents selected from R17.

33. The compound of any one of claims 1-25, wherein one of R7, R7a, R7b, R7c, and R7dis cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents selected from R17.

34. The compound of any one of claims 27-33, wherein R7, R7a, R7b, R7c, and R7dare not substituted.

35. The compound of any one of claims 27-33, wherein R7, R7a, R7b, R7c, and R7dare optionally substituted with 1 or 2 substituents selected from R17.

36. The compound of any one of claims 1-25, wherein one of R7, R7a, R7b, R7c, and R7dis halogen.

37. The compound of any one of claims 1-25, wherein one of R7, R7a, R7b, R7c, and R7dis -OR6.

38. The compound of any one of claims 1-25, wherein one of R7, R7a, R7b, R7c, and R7dis H.

39. The compound of any one of claims 1-25, wherein one of R7, R7a, R7b, R7c, and R7dis cyano.

40. The compound of any one of claims 1-23, wherein one of R7, R7a, R7b, R7c, and R7dis nitro.

41. The compound of any one of claims 1-40, wherein R17is selected in each instance from halogen, alkyl, haloalkyl, alkenyl, and cyano.

42. The compound of any one of claims 1-41, wherein the KRAS Targeting Moiety is selected from:

43. The compound of any one of claims 1-41, wherein the KRAS Targeting Moiety is selected from:

44. The compound of any one of claims 1-41, wherein the KRAS Targeting Moiety is.

45. The compound of any one of claims 1-41, wherein the KRAS Targeting Moiety is selected from:.

46. The compound of any one of claims 1-43, wherein R33is selected from the group consisting of47. The compound of claim 44, wherein R33Bis selected from the group consisting of.

48. The compound of any one of claims 1-47, wherein R33or R33Bis selected from the group consisting of49. The compound of any one of claims 1-48, wherein R29is selected from the group consisting of.

50. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is51. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is52. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is53. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is54. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is55. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is56. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is57. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is58. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is59. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is60. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is.

61. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is62. The compound of any one of claims 1-61, wherein R31is -O-.

63. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is64. The compound of claim 55, wherein the KRAS Recognition Moiety is selected from65. The compound of any one of claims 1-41, wherein the KRAS Recognition Moiety is66. The compound of claim 65, wherein R33is selected from the group consisting of67. The compound of claims 65 or 66, wherein R33is selected from the group consisting of68. The compound of any one of claims 65-67, wherein the KRAS Recognition Moiety is selected from69. The compound of any one of claims 65-68, wherein R29Bis selected from70. The compound of any one of claims 65-69, wherein R51is selected from -O-, -NR6-, and -S-.

71. The compound of any one of claims 65-70 wherein R52is selected from72. The compound of any one of claims 65-71, wherein the KRAS Recognition Moiety is selected from73. The compound of any one of claims 1-72, wherein Linker is of Formula:wherein: X1, X2, X3, X4, X5, and X6are bivalent moieties independently selected from the group consisting of bond, alkyl, cycloalkyl, aryl, heterocycle, heteroaryl, bicycle, -S-, -O-, -NR6-, -C(O)-, -C(O)-NR6-, and -C(O)-O-, each of which except bond is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R7.

74. The compound of claim 73, wherein X1is connected to the KRAS Targeting Moiety.

75. The compound of claim 73, wherein X6is connected to the KRAS Targeting Moiety.

76. The compound of any one of claims 73-75, wherein X1is alkyl.

77. The compound of any one of claims 73-75, wherein X1is bond.

78. The compound of any one of claims 73-77, wherein X2is bond.

79. The compound of any one of claims 73-77, wherein X2is bicycle.

80. The compound of any one of claims 73-79, wherein X3is alkyl.

81. The compound of any one of claims 73-79, wherein X3is bond.

82. The compound of any one of claims 73-79, wherein X3is -O-.

83. The compound of any one of claims 73-82, wherein X4is alkyl.

84. The compound of any one of claims 73-82, wherein X4is bond.

85. The compound of any one of claims 73-84, wherein X5is alkyl.

86. The compound of any one of claims 73-84, wherein X5is bond.

87. The compound of any one of claims 73-84, wherein X5is -O-.

88. The compound of any one of claims 73-87, wherein X6is alkyl.

89. The compound of any one of claims 73-87, wherein X6is bond.

90. The compound of claim 73, wherein Linker is selected from91. The compound of claim 90, wherein Linker is selected from92. The compound of claim 90, wherein Linker is selected from93. The compound of claim 90, wherein Linker is selected from94. The compound of claim 73, wherein Linker is selected from.

95. The compound of claim 73, wherein Linker is selected from96. The compound of claim 95, wherein Linker is selected from97. The compound of claim 73, wherein linker is98. The compound of claim 97, wherein linker is selected from99. The compound of claim 97, wherein linker is selected from100. The compound of claim 73, wherein linker is101. The compound of claim 100, wherein linker is selected from102. The compound of claim 100 or 101, wherein linker is selected from103. The compound of claim 73, wherein Linker is selected from104. The compound of claim 103, wherein Linker is selected from105. The compound of claim 103, wherein Linker is selected from106. The compound of claim 103, wherein Linker is selected from107. The compound of claim 106, wherein Linker is selected from108. The compound of claim 106, wherein Linker is selected from109. The compound of claim 73, wherein Linker is selected from110. The compound of claim 109, wherein Linker is selected from.

111. The compound of claim 109, wherein Linker is selected from112. A compound selected from Table 1.

113. A pharmaceutical composition comprising a compound of any one of claims 1-112 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

114. The pharmaceutical composition of claim 113, wherein the composition is a solid dosage form.

115. The pharmaceutical composition of claim 113, wherein the composition is a liquid dosage form.

116. The pharmaceutical composition of any one of claims 113-115, wherein the composition is suitable for oral delivery.

117. The pharmaceutical composition of claim 115, wherein the composition is suitable for intravenous delivery.

118. The pharmaceutical composition of claim 115, wherein the composition is suitable for parental delivery.

119. A method of treating a disorder mediated by KRAS comprising administering an effective amount of a compound of any one of claims 1-112 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 113-118 to a patient in need thereof.

120. The method of claim 119, wherein the patient is a human.

121. The method of claim 119 or 120, wherein the disorder is a cancer.

122. The method of claim 121, wherein the cancer is a solid cancer.

123. The method of claim 121, wherein the cancer is a hematological cancer.

124. The method of claim 121, wherein the disorder is lung cancer.

125. The method of claim 121, wherein the disorder is pancreatic cancer.

126. The method of claim 121, wherein the disorder is colorectal cancer.

127. The method of claim 121, wherein the disorder is ovarian or endometrial cancer.

128. The method of claim 121, wherein the disorder is breast cancer.

129. The method of any one of claims 121-128, wherein the cancer is metastatic.

130. The method of any one of claims 121-129, wherein the cancer is relapsed.

131. The method of any one of claims 121-130, wherein the cancer is refractory.

132. The method of claim 119 or 120, wherein the disorder is a tumor.

133. The method any one of claims 119-132, wherein the disorder is mediated by mutant KRAS.

134. A compound of any one of claims 1-112 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 113-118 for use to treat a disorder mediated by KRAS in a patient in need thereof.

135. The compound for use of claim 134, wherein the patient is a human.

136. The compound for use of claim 134 or 135, wherein the disorder is a cancer.

137. The compound for use of claim 136, wherein the cancer is a solid cancer.

138. The compound for use of claim 136, wherein the cancer is a hematological cancer.

139. The compound for use of claim 136, wherein the disorder is lung cancer.

140. The compound for use of claim 136, wherein the disorder is pancreatic cancer.

141. The compound for use of claim 136, wherein the disorder is colorectal cancer.

142. The compound for use of claim 136, wherein the disorder is ovarian or endometrial cancer.

143. The compound for use of claim 136, wherein the disorder is breast cancer.

144. The compound for use of any one of claims 136-143, wherein the cancer is metastatic.

145. The compound for use of any one of claims 136-144, wherein the cancer is relapsed.

146. The compound for use of any one of claims 136-145, wherein the cancer is refractory.

147. The compound for use of claim 134 or 135, wherein the disorder is a tumor.

148. The compound for use any one of claims 134-147, wherein the disorder is mediated by mutant KRAS.

149. Use of a compound of any one of claims 1-112 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 113-118 in the manufacture of a medicament to treat a disorder mediated by KRAS in a patient in need thereof.

150. The use of claim 149, wherein the patient is a human.

151. The use of claim 149 or 150, wherein the disorder is a cancer.

152. The use of claim 151, wherein the cancer is a solid cancer.

153. The use of claim 151, wherein the cancer is a hematological cancer.

154. The use of claim 151, wherein the disorder is lung cancer.

155. The use of claim 151, wherein the disorder is pancreatic cancer.

156. The use of claim 151, wherein the disorder is colorectal cancer.

157. The use of claim 151, wherein the disorder is ovarian or endometrial cancer.

158. The use of claim 151, wherein the disorder is breast cancer.

159. The use of any one of claims 151-158, wherein the cancer is metastatic.

160. The use of any one of claims 151-159, wherein the cancer is relapsed.

161. The use of any one of claims 151-160, wherein the cancer is refractory.

162. The use of claim 149 or 150, wherein the disorder is a tumor.

163. The use any one of claims 149-162, wherein the disorder is mediated by mutant KRAS.

164. A means for covalently modifying KRAS or mutant forms thereof.

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