COVALENT KRAS-BINDING COMPOUNDS FOR THERAPEUTIC 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, typically through tyrosine or lysine.

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, 50006-3495 (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 the allosteric binding pocket. (Goebel et al. RSC Medicinal Chemistry 11, 260 (2020)). 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)). Despite the extensive effort to develop a KRAS inhibitor, there are currently no specific FDA approved drugs that act on KRAS.

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).

It is an object of the present invention to provide new compositions of matter 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 residue on KRAS attacks the heteroaryl sulfonyl compound of the present invention to form a covalent bond between the lysine and the compound and force 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.

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 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.

KRAS Recognition Moiety is a molecule that has a functional group linking it to the heteroaryl sulfonyl compound of the present invention, and is, for example a synthetic or naturally occurring small molecule that binds to KRAS, for example mutant KRAS, as an inhibitor or alternatively has no apparent biological effect on KRAS. In non-limiting embodiments, the KRAS Recognition Moiety is a protein binding domain of a drug or pharmaceutically active compound which modulates KRAS (or the full drug or pharmaceutically active compound). In alternative embodiments, the KRAS Recognition Moiety may be a peptide, RNA, DNA, oligonucleotide, or another biologic compound or fragment thereof which can be suitably stabilized, as necessary.

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.

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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 R⁴are 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, R², R⁵, and R¹³are Attaching Groups.

A non-limiting example of the covalent modification of KRAS via a tyrosine that reacts with the heteroaryl sulfonyl compound of the present invention is provided below:

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The KRAS Recognition Moiety brings the activated heteroaryl sulfonyl compound of the present invention 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, or alternatively, a lysine moiety in or near an allosteric binding pocket, for example the Switch-II Pocket (Ostrem et al. Nature, 503(7477), 548-551, (2013)).

In certain aspects, a heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or Formula VII, is provided:

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

R¹is selected from:

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- b) a bicyclic heteroaryl or tricyclic heteroaryl, each of which is optionally substituted as allowed by valence 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 as allowed by valence 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 as allowed by valence 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 as allowed by valence 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 as allowed by valence 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 as allowed by valence 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 as allowed by valence 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 as allowed by valence 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 as allowed by valence with 1, 2, 3, or 4 substituents selected from R¹⁸;
  - R⁷, R^7a, R^7b, R^7c, and R^7dare 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 as allowed by valence 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;
  - R^8a, R^8b, R^8c, and R^8dare independently selected at each instance from R⁷and R¹²wherein at least one of R^8a, R^8b, R^8c, and R^8dis 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 as allowed by valence with 1, 2, 3, or 4 substituents selected from R⁷;
  - or 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 as allowed by valence 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 as allowed by valence 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 as allowed by valence with 1, 2, 3, or 4 substituents selected from R¹⁷; and
  - KRAS Recognition Moiety is a molecule which can bind to or otherwise anchors too KRAS.

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 (Ostrem et al. Nature, 503(7477), 548-551, (2013)).

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 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.

In one aspect a heteroaryl sulfonyl compound of Formula VIII is provided:

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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 as allowed by valence 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 as allowed by valence with 1, 2, 3, or 4 substituents selected from R⁷;
  
  and all other variables are as defined herein.

In a typical embodiment, R²is selected in each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, —(CH₂)_p—C(O)—, —(OCH₂CH₂)_p—, —C(O)—, —NR⁶C(O)—, and heteroaryl, each of which except bond is optionally substituted as allowed by valence with 1, 2, 3, or 4 substituents selected from R⁷, wherein if R²is bond, R³is R³*; wherein

- R³* is selected in each instance from bond, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocycle, —(CH₂)_p—C(O)—, —(OCH₂CH₂)_p—, —C(O)—, —NR⁶C(O)—, bicycle, and heteroaryl, each of which except bond is optionally substituted as allowed by valence with 1, 2, 3, or 4 substituents selected from R⁷.

In a typical embodiment R⁵is selected from alkyl, alkenyl, haloalkyl, cycloalkyl, naphthyl, heterocycle, —(OCH₂CH₂)_p—, —C(O)—, —NR⁶C(O)—, bicycle, and heteroaryl, each of which is optionally substituted as allowed by valence with 1, 2, 3, or 4 substituents selected from R⁷.

In certain embodiments of the invention, the KRAS Recognition Moiety is a small organic molecule (i.e., a non-biologic) that adequately binds to KRAS in a manner that it is covalently modified. In other embodiments of the invention, the KRAS Recognition Moiety is a peptide or oligonucleotide that adequately binds to the protein in such a manner that it is covalently modified. In certain embodiments the KRAS Recognition Moiety is a residue of a pharmaceutically active compound that binds to KRAS (for example but not limited to a compound of the sort that would be reviewed as a drug by CDER of the FDA, or an approved or clinical stage drug) or a peptide, protein or biologic or a binding fragment thereof that adequately binds to the protein in such a manner that it is covalently modified. A plethora of illustrative nonlimiting examples of KRAS Recognition Moieties for use in the heteroaryl sulfonyl compound of the present invention are provided in the detailed description and additional KRAS Recognition Moieties are readily apparent.

In principle embodiments, the KRAS Recognition Moiety is not a fluorophore, is not a detectable labeling group, and is not a moiety comprising an alkyne. In certain embodiments the KRAS Recognition Moiety is selective for KRAS and is not a non-selective protein binder, for example a promiscuous binder of a range of enzymes or of kinases.

In principle embodiments, the heteroaryl sulfonyl compound of the present invention is also not a chemical probe used to perturb the function of a variety of proteins in a biological sample, but instead a focused KRAS binder.

In certain embodiments the KRAS Recognition Moiety is

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wherein

- R^27aand R^27bare independently selected at each instance from the group consisting of 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 optionally substituted as allowed by valence 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;
- q is 0, 1, 2, 3, 4, or 5;
- and wherein all other variables are as defined herein.

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 the KRAS Recognition Moiety is

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In certain embodiments the KRAS Recognition Moiety is

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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 Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, 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 one embodiment, a heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, 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 one embodiment, the heteroaryl sulfonyl compound of the present invention is not fluorescent, including but not limited to not a fluorophore.

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:

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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 as allowed by valence with 1, 2, 3, or 4 substituents independently selected from R⁷; and wherein all other variables are as defined herein.

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 Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, as described herein, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof;
- (b) A method for treating a disorder mediated by KRAS, for example mutant KRAS, comprising administering an effective amount of a heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof;
- (c) A heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder that is mediated by KRAS, for example mutant KRAS;
- (d) Use of a heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, 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;
- (e) Use of a heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, 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;
- (f) A pharmaceutical composition comprising an effective patient-treating amount of a heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent;
- (g) A heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, as described herein as a mixture of enantiomers or diastereomers (as relevant), including as a racemate;
- (h) A heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, 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
- (i) A process for the preparation of therapeutic products that contain an effective amount of a heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, or a pharmaceutically acceptable salt thereof, as described herein.
- (j) A heteroaryl sulfonyl compound of Formula I′, Formula II′, Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII′, or Formula VIII′, as described herein, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof;
- (k) A method for treating a disorder mediated by KRAS, for example mutant KRAS, comprising administering an effective amount of a heteroaryl sulfonyl compound of Formula I′, Formula II′, Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII′, or Formula VIII′, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof,
- (l) A heteroaryl sulfonyl compound of Formula I′, Formula II′, Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII′, or Formula VIII′, or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder that is mediated by KRAS, for example mutant KRAS;
- (m) Use of a heteroaryl sulfonyl compound of Formula I′, Formula II′, Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII′, or Formula VIII′, 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;
- (n) Use of a heteroaryl sulfonyl compound of Formula I′, Formula II′, Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII′, or Formula VIII′, 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;
- (o) A pharmaceutical composition comprising an effective patient-treating amount of a heteroaryl sulfonyl compound of Formula I′, Formula II′, Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII′, or Formula VIII′, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent;
- (p) A heteroaryl sulfonyl compound of Formula I′, Formula II′, Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII′, or Formula VIII′, as described herein as a mixture of enantiomers or diastereomers (as relevant), including as a racemate;
- (q) A heteroaryl sulfonyl compound of Formula I′, Formula II′, Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII′, or Formula VIII′, 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
- (r) A process for the preparation of therapeutic products that contain an effective amount of a heteroaryl sulfonyl compound of Formula I′, Formula II′, Formula III′, Formula IV′, Formula V′, Formula VI′, Formula VII′, or Formula VIII′, or a pharmaceutically acceptable salt thereof, as described herein.

BRIEF DESCRIPTION OF THE FIGURES

As used in the figures R¹⁷is independently selected at each instance from the group consisting of 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 optionally substituted as allowed by valence with 1, 2, 3, or 4 substituents selected from R¹⁸;

As used in the figures n is 0, 1, 2, 3, or 4.

As used in the figures

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is an Anchor Bond. Anchor Bond is 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.

In the context of crystal structures three letter codes used below refer to specific ligands in the RCSB PDB database which is accessible on https://www.rcsb.org/.

FIG. 1A, 1B, 1C, 1D, 1E, IF, and 1G present non-limiting examples of ligands that bind to Kirsten Rat Sarcoma (KRAS), including the compounds EZZ, F0N, F0K, F0B, GNP, 1M1, 18F, 1M0, 17X, 91D, 91G, K9J, K9M, MZQ, MZN, JJN, MOV, 6ZD, O67, O5Y, O5V, O5S, C8G, 8ZG, D2W, D2Z, R6W, 5UT, 91S, M1X, M1R, QH4, OHY, D1W, and D1Z. For additional non-limiting examples and related ligands, see ligands identified by Zhou et al., “KRASQ61HPreferentially Signals through MAPK in a RAF Dimer-Dependent Manner in Non-Small Cell Lung Cancer”, Cancer Res., 2020, 80: 3719-3731; Poulin et al., “Tissue-Specific Oncogenic Activity of KRASA146T”, Cancer Discov., 2019, 9: 738-755; Kessler et al., “Drugging an undruggable pocket on KRAS”, Proc Natl Acad Sci USA., 2019, 116: 15823-15829; Hobbs et al., “Atypical KRASG12RMutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer”, Cancer Discov., 2020, 10: 104-123; Zimmermann et al., “Small molecule inhibition of the KRAS PDEd interaction impairs oncogenic KRAS signalling”, Nature, 2013, 497: 638-642; Zeng et al., “Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C”, Cell Chem Biol., 2017, 24: 1005-1016.e3; Fell et al., “Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity”, ACS Med Chem Lett., 2018, 9: 1230-1234; Fell et al., “Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity”, ACS Med Chem Lett., 2018, 9: 1230-1234; Mortier et al., “Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRASG12C”, ChemMedChem., 2020, 15: 827-832; Bergner et al., “KRAS Binders Hidden in Nature”, Chemistry, 2019, 25: 12037-12041; Canon et al., “The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity”, Nature, 2019, 575: 217-223; Xoing et al., “Covalent Guanosine Mimetic Inhibitors of G12C KRAS”, ACS Med Chem Lett., 2017 8: 61-66; Shin et al., “Discovery of N-(1-Acryloylazetidin-3-yl)-2-(1H-indol-1-yl)acetamides as Covalent Inhibitors of KRASG12C”, ACS Med Chem Lett., 2019, 10: 1302-1308; Hansen et al., “The reactivity-driven biochemical mechanism of covalent KRASG12Cinhibitors”, Nat Struct Mol Biol., 2018, 25: 454-462; Quevedo et al., “Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment”, Nat Commun., 2018, 9: 3169-3169; Kessler et al., “crystal structure of an active KRAS G12D (GPPCP) dimer in complex with BI-5747”, to be published; Patricelli et al., “Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State”, Cancer Discov., 2016, 6: 316-329; Janes et al., “Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor”, Cell, 2018, 172: 578-589.e17; Fell et al., “Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer”, J Med Chem., 2020, 63: 6679-6693; Lanman et al., “Discovery of a Covalent Inhibitor of KRASG12C(AMG 510) for the Treatment of Solid Tumors”, J Med Chem., 2020, 63: 52-65.

FIG. 2 is a non-limiting example of a Formula 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 residue on KRAS, for example mutant KRAS, to form a covalent bond. The invention provides a heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, 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.

In one aspect a heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, or a pharmaceutically acceptable salt thereof, is provided:

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wherein the variables are as defined herein.

Embodiments of Formula I

In certain embodiments the heteroaryl sulfonyl compound of Formula I is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula II

In certain embodiments the heteroaryl sulfonyl compound of Formula II is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula III

In certain embodiments the heteroaryl sulfonyl compound of Formula III is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula IV

In certain embodiments the heteroaryl sulfonyl compound of Formula IV is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula V

In certain embodiments the heteroaryl sulfonyl compound of Formula V is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula VI

In certain embodiments the heteroaryl sulfonyl compound of Formula VI is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula VII

In certain embodiments the heteroaryl sulfonyl compound of Formula VII is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula VIII

In certain embodiments the heteroaryl sulfonyl compound of Formula VIII is selected from:

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or a pharmaceutically acceptable salt thereof.

In certain embodiments the heteroaryl sulfonyl compound of Formula VIII is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula I′

In certain embodiments the heteroaryl sulfonyl compound of Formula I′ is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula II′

In certain embodiments the heteroaryl sulfonyl compound of Formula II′ is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula III′

In certain embodiments the heteroaryl sulfonyl compound of Formula III′ is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula IV′

In certain embodiments the heteroaryl sulfonyl compound of Formula IV′ is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula V′

In certain embodiments the heteroaryl sulfonyl compound of Formula V′ is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula VI′

In certain embodiments the heteroaryl sulfonyl compound of Formula VI′ is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula VII′

In certain embodiments the heteroaryl sulfonyl compound of Formula VII′ is selected from:

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or a pharmaceutically acceptable salt thereof.

Embodiments of Formula VIII′

In certain embodiments the heteroaryl sulfonyl compound of Formula VIII′ is selected from:

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or a pharmaceutically acceptable salt thereof.

In certain embodiments the heteroaryl sulfonyl compound of Formula VIII′ is selected from:

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or a pharmaceutically acceptable salt thereof.

ADDITIONAL EMBODIMENTS

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

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

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

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

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

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In certain embodiments the heteroaryl sulfonyl compound of the present invention is

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

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

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

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

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

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

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

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

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

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

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

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wherein m is independently selected from 1, 2, 3, and 4; and a floating bond on one ring of a bicyclic system means the substituent or substituents are optionally placed on any ring of the system.

For example,

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represents, but is not limited to:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Embodiments of R¹

In certain embodiments R¹is

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In certain embodiments R¹is

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In certain embodiments R¹is

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In certain embodiments R¹is

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In certain embodiments R¹is

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In certain embodiments R¹is

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In certain embodiments R¹is

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In certain embodiments R¹is

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In certain embodiments R¹is a fused bicyclic heteroaryl.